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Journal of Alzheimer's Disease : JAD 2021Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease.
OBJECTIVE
We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI).
METHODS
Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates.
RESULTS
In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition.
CONCLUSION
PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.
Topics: Aryldialkylphosphatase; Brain; Cognition; Cognitive Dysfunction; Dietary Supplements; Double-Blind Method; Female; Folic Acid; Humans; Magnetic Resonance Imaging; Male; Mass Spectrometry; Neuropsychological Tests; Vitamin B 12; Vitamin B 6; Vitamin B Complex
PubMed: 33935094
DOI: 10.3233/JAD-210137 -
Epilepsy Research Sep 2012Organophosphates (OPs) inhibit the enzyme cholinesterase and cause accumulation of acetylcholine, and are known to cause seizures and status epilepticus (SE) in humans....
Organophosphates (OPs) inhibit the enzyme cholinesterase and cause accumulation of acetylcholine, and are known to cause seizures and status epilepticus (SE) in humans. The animal models of SE caused by organophosphate analogs of insecticides are not well characterized. SE caused by OPs paraoxon and diisopropyl fluorophosphate (DFP) in rats was characterized by electroencephalogram (EEG), behavioral observations and response to treatment with the benzodiazepine diazepam administered at various stages of SE. A method for SE induction using intrahippocampal infusion of paraoxon was also tested. Infusion of 200nmol paraoxon into the hippocampus caused electrographic seizures in 43/52 (82.7%) animals tested; and of these animals, 14/43 (30%) had self-sustaining seizures that lasted 4-18h after the end of paraoxon infusion. SE was also induced by peripheral subcutaneous injection of diisopropyl fluorophosphate (DFP, 1.25mg/kg) or paraoxon (1.00mg/kg) to rats pretreated with atropine (2mg/kg) and 2-pralidoxime (2-PAM, 50mg/kg) 30min prior to OP injection. SE occurred in 78% paraoxon-treated animals and in 79% of DFP-treated animals. Diazepam (10mg/kg) was administered 10min and 30min after the onset of continuous EEG seizures induced by paraoxon and it terminated SE in a majority of animals at both time points. DFP-induced SE was terminated in 60% animals when diazepam was administered 10min after the onset of continuous EEG seizure activity but diazepam did not terminate SE in any animal when it was administered 30min after the onset of continuous seizures. These studies demonstrate that both paraoxon and DFP can induce SE in rats but refractoriness to diazepam is a feature of DFP induced SE.
Topics: Animals; Anticonvulsants; Atropine; Brain; Diazepam; Electroencephalography; Isoflurophate; Male; Neurons; Paraoxon; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus
PubMed: 22578704
DOI: 10.1016/j.eplepsyres.2012.04.014 -
Toxics Sep 2023The contexts where there are mining and agriculture activities are potential sources of risk to human health due to contamination by chemical mixtures. These contexts...
The contexts where there are mining and agriculture activities are potential sources of risk to human health due to contamination by chemical mixtures. These contexts are frequent in several Colombian regions. This study explored the potential association between the frequency of micronuclei and pesticides and elements in regions with ferronickel (Montelibano, Córdoba) and gold (Nechí, Antioquia) mining, and a closed native mercury mine (Aranzazu, Caldas), with an emphasis in the potential effect of selenium as a potential chelator. A cross-sectional study was carried out with 247 individuals. Sociodemographic, occupational, and toxicological variables were ascertained. Blood and urine samples were taken for pesticide analysis (5 organophosphates, 4 organochlorines, and 3 carbamates), 68 elements were quantified in hair, and micronuclei were quantified in lymphocytes. The mixtures of elements were grouped through principal component analysis. Prevalence ratios were estimated with robust variance Poisson regressions to explore associations. Interactions of selenium with toxic elements were explored. The highest concentrations of elements were in the active mines. The potentially most toxic chemical mixture was observed in the ferronickel mine. Pesticides were detected in a low proportion of participants (<2.5%), except paraoxon-methyl in blood (27.55%) in Montelibano and paraoxon-ethyl in blood (18.81%) in Aranzazu. The frequency of micronuclei was similar in the three mining contexts, with means between 4 to 7 ( = 0.1298). There was great heterogeneity in the exposure to pesticides and elements. The "hormetic effect" of selenium was described, in which, at low doses, it acts as a chelator in Montelibano and Aranzazu, and at high doses, it can enhance the toxic effects of other elements, maybe as in Nechí. Selenium can serve as a protective agent, but it requires adaptation to the available concentrations in each region to avoid its toxic effects.
PubMed: 37888671
DOI: 10.3390/toxics11100821 -
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 -
EFSA Journal. European Food Safety... May 2022The identification of pollutants is crucial to protect water resources and ensure food safety. The available analytical methodologies allow reliable detection of organic...
The identification of pollutants is crucial to protect water resources and ensure food safety. The available analytical methodologies allow reliable detection of organic pollutants such as pesticides; however, there is the need for faster, direct and continuous methodologies for real-time monitoring of pesticides. Fluorescent-based biosensors have been recently proposed as a valid alternative due to their advantage of being easy, cheap and specific. In this context, the aim of the present EU-FORA fellowship programme was to develop and apply a fluorescence-based biosensing device for the detection of organophosphate (OP) pesticides in water samples and drinkable food. The study was addressed using a mutant of the thermostable esterase-2 from (EST2-S35C) as a bioreceptor for OP pesticides. The use of EST2 involves some significant advantages including specificity and affinity towards OPs, and high stability over time in a different range of temperatures and pH. The protein was labelled to the fluorescent probe IAEDANS and fluorescence measurements of quenching in solution and in immobilised form were performed. The results showed good stability and sensitivity, reaching low limits of detection and quantification and a constant signal intensity over time. The addition of paraoxon quenched the fluorescence of the complex, reaching a plateau at 100 pmol paraoxon. The decrease of enzymatic activity of EST2-S35C-IAEDANS in the presence of paraoxon correlated the inhibition of the labelled enzyme with the decrease in fluorescence. The results from the application of the biosensor with real samples showed a decrease in fluorescence in surface water samples, contaminated by OPs. The use of the developed fluorescence-based biosensor demonstrated its applicability for real samples monitoring and could ensure the production of large amounts of data in a short period of time which can be used to address environmental and food safety risk assessment.
PubMed: 35634553
DOI: 10.2903/j.efsa.2022.e200403 -
Toxics Aug 2023Organophosphate pesticides (OPs) are toxic substances that contaminate aquatic environments, interfere with the development of the nervous system, and induce...
Organophosphate pesticides (OPs) are toxic substances that contaminate aquatic environments, interfere with the development of the nervous system, and induce Neurodevelopmental Toxicity (NDT) in animals and humans. The canonical mechanism of OP neurotoxicity involves the inhibition of acetylcholinesterase (AChE), but other mechanisms non-AChE are also involved and not fully understood. We used network toxicology and molecular docking to identify molecular targets and toxicity mechanisms common to OPs. Targets related to diazinon-oxon, chlorpyrifos oxon, and paraoxon OPs were predicted using the Swiss Target Prediction and PharmMapper databases. Targets related to NDT were compiled from GeneCards and OMIM databases. In order to construct the protein-protein interaction (PPI) network, the common targets between OPs and NDT were imported into the STRING. Network topological analyses identified EGFR, MET, HSP90AA1, and SRC as hub nodes common to the three OPs. Using the Reactome pathway and gene ontology, we found that signal transduction, axon guidance, cellular responses to stress, and glutamatergic signaling activation play key roles in OP-induced NDT.
PubMed: 37624215
DOI: 10.3390/toxics11080710 -
Annals of the New York Academy of... Jun 2016In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists... (Review)
Review
In addition to the global use of organophosphate (OP) pesticides for agriculture, OP nerve agents and pesticides have been employed on battlefields and by terrorists (e.g., a recent sarin attack in Syria). These occurrences highlight the need for an effective countermeasure against OP exposure. Human butyrylcholinesterase (HuBChE) is a leading candidate, but injection of the high doses required for protection present pharmacokinetic challenges. An aerosolized recombinant form (aer-rHuBChE) that can neutralize inhaled OPs at the portal of entry has been assessed for its efficacy in protecting macaques against respiratory toxicity following inhalation exposure to the pesticide paraoxon (aer-Px). While protection in macaques has been demonstrated using the MicroSprayer® delivery device, administration to humans will likely employ a vibrating mesh nebulizer (VMN). Compared to the 50-70% lung deposition achieved in adult humans with a VMN, deposition in macaques is <5%, an initial major obstacle to demonstrating protection. Such problems have been partly overcome by using a more efficient modified VMN and proportionally higher doses, which together generate an effective rHuBChE pulmonary bioshield and protect against high levels of inhaled Px.
Topics: Aerosols; Animals; Drug Delivery Systems; Humans; Inhalation Exposure; Lung; Organophosphorus Compounds; Protective Agents
PubMed: 27371808
DOI: 10.1111/nyas.13106 -
International Journal of Molecular... Oct 2020Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be...
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
Topics: Animals; Atropine; Blood-Brain Barrier; Bridged-Ring Compounds; Cholinesterase Reactivators; Computer Simulation; Imidazoles; Mice; Molecular Docking Simulation; Oximes; Paraoxon; Pyridinium Compounds
PubMed: 33114215
DOI: 10.3390/ijms21217883 -
Proceedings of the National Academy of... Sep 2006
Topics: Acetylcholine; Acetylcholinesterase; Animals; Atropine; Benzodiazepines; Blood-Brain Barrier; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Drug Therapy, Combination; Galantamine; Guinea Pigs; Insecticides; Neurons; Neurotransmitter Agents; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Paraoxon; Pralidoxime Compounds; Pyridostigmine Bromide; Receptors, Cholinergic; Receptors, Muscarinic; Sarin; Seizures; Soman; Time Factors
PubMed: 16938861
DOI: 10.1073/pnas.0606052103 -
Applied and Environmental Microbiology Oct 2006Organophosphate compounds, which are widely used as pesticides and chemical warfare agents, are cholinesterase inhibitors. These synthetic compounds are resistant to...
Organophosphate compounds, which are widely used as pesticides and chemical warfare agents, are cholinesterase inhibitors. These synthetic compounds are resistant to natural degradation and threaten the environment. We constructed a strain of Pseudomonas putida that can efficiently degrade a model organophosphate, paraoxon, and use it as a carbon, energy, and phosphorus source. This strain was engineered with the pnp operon from Pseudomonas sp. strain ENV2030, which encodes enzymes that transform p-nitrophenol into beta-ketoadipate, and with a synthetic operon encoding an organophosphate hydrolase (encoded by opd) from Flavobacterium sp. strain ATCC 27551, a phosphodiesterase (encoded by pde) from Delftia acidovorans, and an alkaline phosphatase (encoded by phoA) from Pseudomonas aeruginosa HN854 under control of a constitutive promoter. The engineered strain can efficiently mineralize up to 1 mM (275 mg/liter) paraoxon within 48 h, using paraoxon as the sole carbon and phosphorus source and an inoculum optical density at 600 nm of 0.03. Because the organism can utilize paraoxon as a sole carbon, energy, and phosphorus source and because one of the intermediates in the pathway (p-nitrophenol) is toxic at high concentrations, there is no need for selection pressure to maintain the heterologous pathway.
Topics: Biodegradation, Environmental; Insecticides; Minerals; Paraoxon; Parathion; Pseudomonas putida
PubMed: 17021221
DOI: 10.1128/AEM.00907-06