Organophosphates (OPs) are highly neurotoxic compounds and certain OP-compounds are also exploited as a weapon of mass destruction and chemical warfare in terrorist attacks. Available prophylactic ...and post-exposure treatments are less effective and also have serious side-effects. Thus, there is a dire need to develop effective and safe prophylactic agent(s) against OP-poisoning. Human Paraoxonase 1 (hPON1) can hydrolyze a wide range of OP molecules and can be developed as an effective and safe prophylactic agent. Thus, there is a dire need in the art to develop variant(s) of rhPON1 that not only possess ‘good’ OP-hydrolyzing activity but also have improved pharmacokinetic properties. In this report, we describe the characterization of the fused hPON1 (FHP) variant that not only exhibit enhanced in vivo pharmacokinetic properties but also delay / prevent the symptoms of OP-poisoning and prevents OP-induced mortality in rats.
•rhPON1 can be developed as prophylactic against OP poisoning.•3dHSA fused rhPON1 (FHP) is developed with improved half-life.•In vivo pharmacokinetic and prophylactic protection efficacy are determined in rat.•FHP provide prophylactic protection against paraoxon-poisoning.
Epidemiological data showing that high-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular disease have led to the idea that cholesterol contained in this lipoprotein ...may be protective. Against, recent evidence suggests that the athero-protection from HDLs may result from other functions, unrelated to the carried cholesterol. HDL accessory proteins, such as paraoxonase 1 (PON1), have been suggested to endows HDL with antioxidant and anti-inflammatory properties and to contribute to the athero-protective function of the lipoprotein. We aimed to evaluate whether extreme fluctuation in HDL-C levels correlates with PON1 activity.
Levels of PON1-related arylesterase and lactonase were assessed in subjects with primary hyperalphalipoproteinemia (HAL, HDL-C>90th percentile), hypoalphalipoproteinemia (HA, HDL-C<10th percentile) and controls. Cholesterol efflux capacity (CEC) through several pathways and other metabolic parameters and markers of vascular disease were also determined.
Despite the marked change in HDL-C and Apoliprotein A1 (APO A1) (p < 0.001 for all comparisons), arylesterase and lactonase were only slightly increased in HAL compared with HA subjects (p < 0.05), but not vs. controls. This change in PON1 activities was no longer significant after adjustment for either HDL-C or APO A1. Both enzymatic activities were positively associated only with aqueous diffusion CEC (r = 0.318, p < 0.05 and r = 0.355, p < 0.05, respectively) and negatively with the presence of plaques (p < 0.05).
We showed that extreme high/low HDL-C levels are not associated with equal increase/decrease in PON1 activities. This enzyme appears to contribute to the HDL role in reverse cholesterol transport and anti-atherosclerosis processes. Further investigation is required to corroborate our findings.
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•HDL-associated PON1 could represent one of the determinants of the biological functions of this lipoprotein.•High/low HDL-C levels are not accompanied by proportional PON1 activity changes.•PON1 specific activity is lower in hyperalphalipoproteinemia patients than in Controls.•The combination PON1/Apo A-1 is inversely related to subclinical atherosclerosis.
Background: The most prevalent form of heart disease is coronary artery disease CAD, which is currently one of the leading causes of death in the world and is predicted to remain that way for the ...next 20 years. Atherosclerosis, genetic predisposition, environment and lifestyle are the main risk factors for CAD. Paraoxonase1 PON1 is a glycoprotein enzyme associated with high-density lipoprotein HDL particles in the blood. It can prevent lipid oxidation, lowering the risk of atherogenesis, by doing so.The aim of the work: This work aims to study the frequency of association of PON1 gene polymorphism and risk of coronary artery diseases. This could help in better understanding of molecular basis and pathogenesis of coronary artery disease.Patients and Methods: The study included 80 subjects, 40 patients who admitted in Al-Azhar medical hospital in Damietta with established diagnosis of coronary artery disease by coronary angiography and 40 healthy participants. Genotyping of PON1 Q192R A/G was done.Results: A statistically significant association was observed with AG and GG genotypes of PON1 gene with CAD with P= 0.017. The G allele of PON1 was higher in CAD patients than controls suggesting that this allele may demonstrate a susceptibility effect to CAD in our cohort with P=0.025.Conclusion: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CAD among Egyptians.
•Betanin is a free radical scavenger.•Betanin enhances endogenous cellular antioxidant defense mechanism via induction of Nrf2, heme oxygenase 1, paraoxonase 1 and glutathione.•Betanin protects DNA ...against reactive oxygen species.
Betanin is a red pigment present in red beetroot. Recently, potential health benefits of betanin-rich beetroot have been suggested. However, little is known regarding the free radical scavenging and antioxidant activity of betanin. Electron spin resonance spectroscopy (ESR) and spin trapping techniques were applied to evaluate the ability of betanin to scavenge hydroxyl, superoxide, 2,2 diphenyl-1-picrylhydrazyl (DPPH), and galvinoxyl free radicals. In addition, we tested in cultured cells the ability of betanin to prevent DNA damage and to induce the transcription factor Nrf2 (nuclear factor (erythroid-derived 2)-like 2) as well as its down-stream target heme oxygenase1 (HO-1), paraoxonase1 (PON1) and glutathione (GSH). Betanin dose-dependently scavenged DPPH-, galvinoxyl-, superoxide-, and hydroxyl-radicals in the ESR and spin trapping studies and prevented hydrogen peroxide induced DNA damage as determined by the Comet assay. Furthermore, betanin treatment induced the transcription factor Nrf2 and resulted in an increase of HO-1 protein levels, PON1-transactivation and cellular GSH. Present data suggest that betanin is both a free radical scavenger and an inducer of antioxidant defense mechanism in cultured cells.
Paraoxonase 1 (PON1) is calcium-dependent aryldialkylphosphatase, thought to possess; anti-oxidant, anti-adhesion, anti-inflammatory, anti-thrombosis and anti-apoptosis effects, as well as ...lipid-modifying properties. Numerous clinical studies have shown associations between different PON1 polymorphisms and different cardiovascular pathologies. The rs622 (c.575A > G) and the rs854560 (c.163A > T) are the most studied PON1 SNPs in the coding region, with rs705381 (− 162A/G), rs854572 (− 909G/C) and rs705379 (− 108C/T) being the most studied SNPs in the regulatory PON1 gene region. The three major PON1 activities are aryldialkylphosphatase, arylesterase and lactonase activity. The different SNPs affect PON1 serum concentrations and enzyme activity, thus leading to pro-/anti-atherogenic effects. In that setting, it is very difficult to establish as to whether the genotype or phenotype of PON1 is primarily associated with cardiovascular risk. Given the current scientific evidence, PON1 genotyping might be reasonable in patients with high and very high cardiovascular risk.
Cardiovascular disease (CVD) is the leading cause of death. The mainly risks factors for CVD are diabetes, hypertension and high levels of homocysteine (Hcys), among others. Paraoxonase 1 (PON1) has ...been proposed as an antiatherogenic target for its ability to hydrolyzing oxi-Low-Density-Lipoproteins (LDL) and Hcys-thiolactone. Thus, the aim of the present study was to evaluate the association of Hcys levels, and the activities and concentration of PON1, as well as vitamin B from the diet with a risk for CVD.
A case-control study was carry out in patients with cardiovascular diseases (CVD), Arterial hypertension, but not CVD (AH), and in healthy controls (control group) from the Mexican Institute of Social Security. Lipid profile, intake of vitamin B, Hcys, serum amyloid A (SAA), PON1 concentration, and PON1 activities (Arylesterase activity (ARE), Lactonase activity (LAC), and CMPA activity (CMPA)) were evaluated.
The CVD group had the highest concentration of Hcys and SAA than in the AH and control groups (p < 0.01). ARE, LAC, and CMPA activities and PON1 concentration were lowest in the CVD group. A positive-independent association between Hcys levels and CVD was found (OR = 2.09; 95% CI: 1.69–2.56) and this increase when it was adjusted by age, BMI, ApoA1, vitamin B intake, SAA, and PON1 (OR = 14.41; 95% CI: 1.75–118.71). LAC and CMPA, as well as PON1 concentration, were inversely associated with CVD.
LAC activity, PON1 concentration, and Hcys levels might be good biomarkers for CVD and their association could be modified by the intake of vitamin B.
•Patients with cardiovascular disease (CVD) had higher Hcys and SAA levels than controls.•Activities and concentration of PON1 were low in patients with CVD.•Hcys levels were associated with an increase in the OR of belonging to the CVD group.•LAC activity, PON1 concentration, and Hcys levels might be good biomarkers for CVD.
Paraoxonase 1 (PON1) can metabolize some compounds such as aromatic carboxylic acid and unsaturated aliphatic esters, arylesters, cyclic carbonate, plucuronide drugs, some carbamate insecticide ...classes, nerve gases, and lactone compounds. Methyl benzoate has recently been shown to display potent toxicity against several insect species. In the current study, we aimed to investigate the effect of the methyl benzoate compounds (1–17) on PON1 activity. Methyl benzoate compounds inhibited PON1 with KI values ranging from 25.10 ± 4.73 to 502.10 ± 64.72 μM. Compound 10 (methyl 4‐amino‐2‐bromo benzoate) showed the best inhibition (KI = 25.10 ± 4.73 μM). Furthermore, using the ADME‐Tox, Glide XP, and MM‐GBSA tools of the Schrödinger Suite 2021‐4, a complete ligand–receptor interaction prediction was performed to characterize the methyl benzoates (1–17), probable binding modalities versus the PON1.
Antioxidant properties of HDL Soran, Handrean; Schofield, Jonathan D; Durrington, Paul N
Frontiers in pharmacology,
10/2015, Volume:
6
Journal Article
Peer reviewed
Open access
High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually ...metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL.
Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, ...particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD. To address this hypothesis, the levels of 4-hydroxynonenal (4-HNE; i.e. a marker of oxidative stress damage) along with the protein expression and enzymatic activity of PON1 and PON2 have been investigated in the brain and serum of young Postnatal day (PD)8-10, 20-25 and 60-65 asymptomatic 3xTg-AD female mice, one of the most used transgenic models of AD. At PD 8-10, there were no differences in hippocampus and prefrontal cortex (PFC) 4-HNE expression levels between 3xTg-AD mice compared to controls (Non-Tg mice). On the other hand, significant increased levels of 4-HNE were detected in PD 20-30 3xTg-AD mice hippocampus, while a significant reduction was observed in 3xTg-AD group at PD 60-65. In the PFC, 4-HNE levels were significantly reduced in 3xTg-AD mice brain at PD 20-30, while no differences in 4-HNE levels were detected at PD 60-65. No significant differences in arylesterase and lactonase activities were observed in the plasma of 3xTg-AD and Non-Tg mice at the different considered ages. Compared to Non-Tg mice, a reduction of brain arylesterase activity was found in 3xTg-AD female at PD 20-30 and PD 60-65, but it was significant only in the younger group. Finally, a similar trend was observed also for PON1 and PON2 protein levels, with both significantly, and solely, decreased in 3xTg-AD mice brain at PD 20-30. Overall, these findings suggest that the altered oxidative stress homeostasis in the 3xTg-AD female mice may be related to an early reduction in activity and expression of PONs enzymes most likely via a reduced brain arylesterases activity.
Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated lactonase that plays a significant role in the anti-atherosclerotic activity of HDL. However, several studies have shown that PON1 ...localizes in cells, where it operates independently of HDL. Previously, we showed that PON1 localizes in endothelial cells (ECs), and impairs vasodilation mediated by the endothelium-derived hyperpolarizing factor (EDHF) 5,6-δ-DHTL. However, the internalization pathway of PON1 into ECs, and the intracellular fate of PON1 are unknown. Therefore, the present study aimed to elucidate the uptake mechanism, intracellular trafficking and the function of PON1 in ECs. We conducted a series of inhibition experiments of fluorescently labeled recombinant PON1 (rePON1) in ECs, followed by FACS analyses. We found that rePON1 binds the EC membrane via specific binding sites located in lipid-rafts/caveolae microdomains that are shared with HDL, and internalized through dynamin-dependent endocytosis. Qualitative assessments of the intracellular trafficking of rePON1, using confocal z-stack images, showed colocalization of the labeled rePON1 with early and late endosome/lysosome markers. Accordingly, a “pulse-chase” incubation of rePON1, followed by lactonase activity measurement in EC lysate, revealed that rePON1 retains its lactonase activity after binding to the cells. However, this activity decreases over time. Finally, induction of endothelial dysfunction with high glucose, angiotensin II, or palmitic acid increased rePON1 uptake by ECs. In conclusion, these results indicate that free PON1 interacts with ECs via binding sites located in lipid-rafts/caveolae, where it is enzymatically active and regulates endothelial functions. However, once internalized, PON1 is degraded. Additionally, alteration in endothelial function affects PON1 uptake by ECs.
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•PON1 and HDL share binding sites on the endothelial membrane lipid-rafts/caveolae.•PON1 internalized into the EC cytoplasm in a dynamin-dependent mechanism.•PON1 is directed by endosomes toward lysosomal degradation.•Under endothelial dysfunction, the PON1 internalization into ECs is increased.
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