[Association of the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene with preeclampsia among Chinese women].

OBJECTIVE: To assess the association of -c.108C>T and c.192Q>R polymorphisms of paraoxonase 1 (PON1) gene with preeclampsia (PE) and the influence of genotypes on the metabolic and oxidative stress indexes among Chinese women. METHODS: This case-control study has included 334 patients with PE and 1337 healthy pregnant women. The -c.108C>T and c.192Q>R genotypes were determined by PCR and restriction fragment length polymorphism method. Metabolic and oxidative stress parameters were also analyzed. RESULTS: No statistical difference in the genotypic and allelic frequencies for the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene was found between the PE patients and the healthy controls (P > 0.05). Nevertheless, the 192Q-108T haplotype of these polymorphisms was associated with an increased risk of PE (P = 0.007). Total antioxidant capacity (TAC) and atherosderosis index were higher in patients with the -108TT genotype compared with those with a CT genotype (P < 0.05); whilst total oxidant status was lower in patients with a CT genotype compared with those with a CC genotype (P = 0.036). Malondialdehyde level was higher in patients with a 192RR genotype compared with those with a QQ genotype (P = 0.019). TAC level was higher in patients with a RR genotype compared with those with a QR genotype (P = 0.015). CONCLUSION: The 192Q-108T haplotype of the PON1 gene is associated with the risk for PE. These polymorphisms may be associated with abnormal lipid metabolism and oxidative stress among Chinese PE patients.

PON1, APOE and SDF-1 Gene Polymorphisms and Risk of Retinal Vein Occlusion: A Case-Control Study.

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3'G(801)A] for SDF-1 gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Paraoxonase 1 Activity and Phenotype Distribution in Lumbar Disc Herniation Patients.

AIM: To compare the Paraoxonase 1 (PON1) activity and phenotype distribution between lumbar disc herniation (LDH) patients and healthy individuals. MATERIAL AND METHODS: This research included 40 LDH patients and 42 healthy individuals. Spectrophotometric assays were performed to determine the serum PON1 and arylesterase activities. The PON1 ratio, which represents the salt-stimulated PON/ arylesterase level, demonstrated a trimodal distribution. This ratio was applied to identify the different phenotypes; QQ, QR, and RR of each subject. RESULTS: The LDH patients had lower PON1 activity than the healthy individuals (p < 0.05). LDH patients had a statistically significant QQ phenotype compared to the healthy subjects (p < 0.05). CONCLUSION: LDH patients had statistically lower PON1 activity, suggesting that the low PON1 activity and PON1 QQ phenotype may be a risk factor for LDH occurrence.

Paraoxonase 1: evolution of the enzyme and of its role in protecting against atherosclerosis.

PURPOSE OF REVIEW: To review the discoveries which led to the concept that serum paraoxonase 1 (PON1) is inversely related to atherosclerotic cardiovascular disease (ASCVD) incidence, how this association came to be regarded as causal and how such a role might have evolved. RECENT FINDINGS: Animal models suggest a causal link between PON1 present on HDL and atherosclerosis. Serum PON1 activity predicts ASCVD with a similar reliability to HDL cholesterol, but at the extremes of high and low HDL cholesterol, there is discordance with PON1 being potentially more accurate. The paraoxonase gene family has its origins in the earliest life forms. Its greatest hydrolytic activity is towards lactones and organophosphates, both of which can be generated in the natural environment. It is active towards a wide range of substrates and thus its conservation may have resulted from improved survival of species facing a variety of evolutionary challenges. SUMMARY: Protection against ASCVD is likely to be the consequence of some promiscuous activity of PON1, but nonetheless has the potential for exploitation to improve risk prediction and prevention of ASCVD.

FOXA1 Suppresses Endoplasmic Reticulum Stress, Oxidative Stress, and Neuronal Apoptosis in Parkinson's Disease by Activating PON2 Transcription.

Endoplasmic reticulum (ER) stress and oxidative stress (OS) are often related states in pathological conditions including Parkinson's disease (PD). This study investigates the role of anti-oxidant protein paraoxonase 2 (PON2) in ER stress and OS in PD, along with its regulatory molecule. PD was induced in C57BL/6 mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treatment and in SH-SY5Y cells using 1-methyl-4-phenylpyridinium. PON2 was found to be poorly expressed in the substantia nigra pars compacta (SNc) of PD mice, and its overexpression improved motor coordination of mice. Through the evaluation of tyrosine hydroxylase, dopamine transporter, reactive oxygen species (ROS), and C/EBP homologous protein (CHOP) levels and neuronal loss in mice, as well as the examination of CHOP, glucose-regulated protein 94 (GRP94), GRP78, caspase-12, sarco/endoplasmic reticulum calcium ATPase 2, malondialdehyde, and superoxide dismutase levels in SH-SY5Y cells, we observed that PON2 overexpression mitigated ER stress, OS, and neuronal apoptosis both in vivo and in vitro. Forkhead box A1 (FOXA1) was identified as a transcription factor binding to the PON2 promoter to activate its transcription. Upregulation of FOXA1 similarly protected against neuronal loss by alleviating ER stress and OS, while the protective roles were abrogated by additional PON2 silencing. In conclusion, this study demonstrates that FOXA1-mediated transcription of PON2 alleviates ER stress and OS, ultimately reducing neuronal apoptosis in PD.

Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

BACKGROUND AND OBJECTIVES: The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. MATERIALS AND METHOD: Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. RESULTS: Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. CONCLUSION: There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

Alteration of the intestinal microbiota and serum metabolites in a mouse model of Pon1 gene ablation.

Mutations in the Paraoxonase 1 (Pon1) gene underlie aging, cardiovascular disease, and impairments of the nervous and gastrointestinal systems and are linked to the intestinal microbiome. The potential role of Pon1 in modulating the intestinal microbiota and serum metabolites is poorly understood. The present study demonstrated that mice with genomic excision of Pon1 by a multiplexed guide RNA CRISPR/Cas9 approach exhibited disrupted gut microbiota, such as significantly depressed alpha-diversity and distinctly separated beta diversity, accompanied by varied profiles of circulating metabolites. Furthermore, genomic knock in of Pon1 exerted a distinct effect on the intestinal microbiome and serum metabolome, including dramatically enriched Aerococcus, linoleic acid and depleted Bacillus, indolelactic acid. Specifically, a strong correlation was established between bacterial alterations and metabolites in Pon1 knockout mice. In addition, we identified metabolites related to gut bacteria in response to Pon1 knock in. Thus, the deletion of Pon1 affects the gut microbiome and functionally modifies serum metabolism, which can lead to dysbiosis, metabolic dysfunction, and infection risk. Together, these findings put forth a role for Pon1 in microbial alterations that contribute to metabolism variations. The function of Pon1 in diseases might at least partially depend on the microbiome.

Polygenic markers of survival and longevity in the antioxidant genes PON1, PON2, MTHFR, MSRA, SOD1, NQO1, and CAT in a 20-year follow-up study in the population from the Volga-Ural region.

BACKGROUND: Genetic background of healthy or pathological styles of aging and human lifespan is determined by joint gene interactions. Lucky combinations of antioxidant gene polymorphisms can result in a highly adaptive phenotype, providing a successful way to interact with external triggers. Our purpose was to identify the polygenic markers of survival and longevity in the antioxidant genes among elderly people with physiological and pathological aging. METHODS: In a 20-year follow-up study of 2350 individuals aged 18-114 years residing in the Volga-Ural region of Russia, sex-adjusted association analyses of MTHFR rs1801133, MSRA rs10098474, PON1 rs662, PON2 rs7493, SOD1 rs2070424, NQO1 rs1131341 and CAT rs1001179 polymorphic loci with longevity were carried out. Survival analysis was subsequently performed using the established single genes and gene-gene combinations as cofactors. RESULTS: The PON1 rs662*G allele was defined as the main longevity marker in women (OR = 1.44, p = 3E-04 in the log-additive model; HR = 0.77, p = 1.9E-04 in the Cox-survival model). The polymorphisms in the MTHFR, MSRA, PON2, SOD1, and CAT genes had an additive effect on longevity. A strong protective effect of combined MTHFR rs1801133*C, MSRA rs10098474*T, PON1 rs662*G, and PON2 rs7493*C alleles against mortality was obtained in women (HR = 0.81, p = 5E-03). The PON1 rs662*A allele had a meaningful impact on mortality for both long-lived men with cerebrovascular accidents (HR = 1.76, p = 0.027 for the PON1 rs662*AG genotype) and women with cardiovascular diseases (HR = 1.43, p = 0.002 for PON1 rs662*AA genotype). The MTHFR rs1801133*TT (HR = 1.91, p = 0.036), CAT rs1001179*TT (HR = 2.83, p = 0.031) and SOD1 rs2070424*AG (HR = 1.58, p = 0.018) genotypes were associated with the cancer mortality. CONCLUSION: In our longitudinal 20-year study, we found the combinations of functional polymorphisms in antioxidant genes involved in longevity and survival in certain clinical phenotypes in the advanced age.

Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer's Disease.

Paraoxonase-1 (PON1), a serum antioxidant enzyme, has been implicated in Alzheimer's disease (AD) pathogenesis that involves early oxidative damage. Corinthian currants and their components have been shown to display antioxidant and other neuroprotective effects in AD. We evaluated the effect of a Corinthian currant paste-supplemented diet (CurD), provided to 1-month-old 5xFAD mice for 1, 3, and 6 months, on PON1 activity and levels of oxidation markers in serum and the brain of mice as compared to a control diet (ConD) or glucose/fructose-matched diet (GFD). Administration of CurD for 1 month increased PON1 activity and decreased oxidized lipid levels in serum compared to ConD and GFD. Longer-term administration of CurD did not, however, affect serum PON1 activity and oxidized lipid levels. Furthermore, CurD administered for 1 and 3 months, but not for 6 months, increased PON1 activity and decreased free radical levels in the cortex of mice compared to ConD and GFD. To probe the mechanism for the increased PON1 activity in mice, we studied the effect of Corinthian currant polar phenolic extract on PON1 activity secreted by Huh-7 hepatocytes or HEK293 cells transfected with a PON1-expressing plasmid. Incubation of cells with the extract led to a dose-dependent increase of secreted PON1 activity, which was attributed to increased cellular PON1 expression. Collectively, our findings suggest that phenolics in Corinthian currants can increase the hepatic expression and activity of antioxidant enzyme PON1 and that a Corinthian currant-supplemented diet during the early stages of AD in mice reduces brain oxidative stress.

Antiapoptotic PON2 expression and its clinical implications in locally advanced oral squamous cell carcinoma.

Locally advanced oral squamous cell carcinoma poses a significant challenge in oncology due to its rising incidence and mortality rates. Despite therapeutic progress, understanding molecular intricacies is essential. This study explored the role of PON2, a multifunctional enzyme implicated in antiapoptotic mechanisms. Aberrant PON2 expression in oral cancers raises questions regarding its involvement in evading programmed cell death and treatment resistance. Patients with locally advanced disease were enrolled, and molecular analyses were undertaken on the collected tumor and normal tissues. Utilizing computational datasets, this study used in silico gene expression analysis, differential gene expression analysis in our patient cohort, survival analysis, and gene set enrichment analysis to unravel role of PON2 in disease prognosis. The results showed elevated PON2 levels in advanced tumor stages, correlating with factors such as tobacco exposure, higher tumor grade, and nodal metastasis. Survival analysis revealed prognostic relevance of PON2, with lower expression linked to extended survival rates. Gene set enrichment analysis identified pathways aiding in cancer metastasis influenced by PON2. This study underscores the significance of PON2 expression as a prognostic marker for oral malignancies, with increased expression associated with advanced disease stages. Understanding the molecular profile of the PON2 gene suggests its potential as a valuable biomarker for the management of cancer.

Contribution of the Paraoxonase-2 Enzyme to Cancer Cell Metabolism and Phenotypes.

Paraoxonase-2 (PON2) is a ubiquitously expressed intracellular protein that is localized in the perinuclear region, the endoplasmic reticulum (ER), and mitochondria, and is also associated with the plasma membrane. PON2 functions as an antioxidant enzyme by reducing the levels of reactive oxygen species (ROS) in the mitochondria and ER through different mechanisms, thus having an anti-apoptotic effect and preventing the formation of atherosclerotic lesions. While the antiatherogenic role played by this enzyme has been extensively explored within endothelial cells in association with vascular disorders, in the last decade, great efforts have been made to clarify its potential involvement in both blood and solid tumors, where PON2 was reported to be overexpressed. This review aims to deeply and carefully examine the contribution of this enzyme to different aspects of tumor cells by promoting the initiation, progression, and spread of neoplasms.

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery-A Randomized, Controlled Clinical Trial.

OBJECTIVES: Cardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role whose activity is decreased in systemic inflammation and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by upregulating PON1 gene expression. The authors aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: The University Medical Center Ljubljana, Slovenia. PARTICIPANTS: Forty adult patients who underwent complex cardiac surgery on CPB between February 2016 and December 2017 were randomized into methylprednisolone and control groups (n = 20 each). INTERVENTIONS: Patients in the methylprednisolone group received 1 g of methylprednisolone in the CPB priming solution, whereas patients in the control group were not given methylprednisolone during CPB. MEASUREMENTS AND MAIN RESULTS: The effect of methylprednisolone from the CPB priming solution was compared with standard care during CPB on PON1 activity until postoperative day 5. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed also. No significant differences were found between study groups for PON1 activity, high-density lipoprotein, and low-density lipoprotein in any of the measurement intervals (p > 0.016). The methylprednisolone group had significantly lower tumor necrosis factor alpha (p < 0.001) and interleukin-6 (p < 0.001), as well as C-reactive protein and procalcitonin (p < 0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and tumor necrosis factor alpha, interleukin-6, and CPB duration. CONCLUSIONS: Methylprednisolone does not influence PON1 activity during cardiac surgery on CPB.

The diversity and clinical implications of genetic variants influencing clopidogrel bioactivation and response in the Emirati population.

BACKGROUND: Clopidogrel is a widely prescribed prodrug that requires activation via specific pharmacogenes to exert its anti-platelet function. Genetic variations in the genes encoding its transporter, metabolizing enzymes, and target receptor lead to variability in its activation and platelet inhibition and, consequently, its efficacy. This variability increases the risk of secondary cardiovascular events, and therefore, some variations have been utilized as genetic biomarkers when prescribing clopidogrel. METHODS: Our study examined clopidogrel-related genes (CYP2C19, ABCB1, PON1, and P2Y12R) in a cohort of 298 healthy Emiratis individuals. The study used whole exome sequencing (WES) data to comprehensively analyze pertinent variations of these genes, including their minor allele frequencies, haplotype distribution, and their resulting phenotypes. RESULTS: Our data shows that approximately 37% (n = 119) of the cohort are likely to benefit from the use of alternative anti-platelet drugs due to their classification as intermediate or poor CYP2C19 metabolizers. Additionally, more than 50% of the studied cohort exhibited variants in ABCB1, PON1, and P2YR12 genes, potentially influencing clopidogrel's transport, enzymatic clearance, and receptor performance. CONCLUSIONS: Recognizing these alleles and genotype frequencies may explain the clinical differences in medication response across different ethnicities and predict adverse events. Our findings underscore the need to consider genetic variations in prescribing clopidogrel, with potential implications for implementing personalized anti-platelet therapy among Emiratis based on their genetic profiles.

Paraoxonase and arylesterase activity of paraoxonase 1 and oxidative stress parameters in cervical intraepithelial neoplasia.

Introduction: Paraoxonase 1 (PON1) is the enzyme that removes carcinogenic radicals from lipids. The aim of the study was to investigate the differences in PON1 activity and oxidation stress parameters between patients with cervical intraepithelial neoplasia (CIN) and healthy controls. Materials and methods: The study included 65 women with CIN and 109 healthy women. Lipid parameters were determined on Cobas Integra 400 plus (Roche, Mannheim, Germany). Tiols and reduced glutathione (GSH) were determined spectrophotometric using Eliman reagent. Activity of PON1 was assessed with two substrates, paraoxon and phenylacetate by spectrophotometric method. Malondialdehyde (MDA) was determined by high performance liquid chromatography (Shimadzu Corporation, Kyoto, Japan). Mann-Whitney-test, t-test, χ2-test, correlation and logistic regression was used in statistical analysis. P < 0.05 was considered statistically significant. Results: The basal (P = 0.929) and NaCl-stimulated (P = 0.985) PON1 activity and activities standardised on the concentration of high-density lipoprotein (HDL; P = 0.076; P = 0.065, respectively) and apolipoprotein AI (apo AI; P = 0.444; P = 0.499, respectively) as well as PON1 phenotypes (P = 0.842) did not differ significantly between the groups. The PON1 arylesterase activity (53±19 kU/L vs. 77±17 kU/L; P < 0.001) and HDL-standardized activity (37 (28-44) kU/mmol vs. 43 (37-50) kU/mmol; P < 0.001) and apoAI (29±11 kU/g vs. 44±11 kU/g; P < 0.001) was significantly reduced in the CIN group. The concentration of the thiol groups was similar (P = 0.519), of MDA was lower (0.39 (0.27-0.55) µmol/L vs. 0.76 (0.57-1.15) µmol/L; P < 0.001) and of GSH was higher (112.0 (66.0-129.6) µg/mL vs. 53.4 (34.8-134.4) µg/mL; P < 0.001) in the CIN group. Conclusion: Reduced PON1 arylesterase activity, lower MDA and higher GSH concentration were observed in CIN patients.

PON1 has palmitoyl-protein thioesterase (PPT) activity, and can affect the presence of SR-B1 on the endothelial cell membrane.

The high-density lipoprotein (HDL)-associated enzyme paraoxonase 1 (PON1) is expressed almost exclusively in the liver and is then transported by HDL to the peripheral tissues. The lipophilic nature of PON1 enables its easy exchange between the lipoprotein and cell membranes in a process that is dependent on the HDL receptor scavenger receptor class B, type 1 (SR-B1). In endothelial cells, PON1 binding to the cell membrane leads to its internalization by endocytosis and subsequent lysosomal degradation. PON1 is a "promiscuous" enzyme with unusually broad substrate specificity in vitro, but its actual function and substrate are still unknown. The enzyme requires a lipid environment and becomes completely inactive upon delipidation. However, when PON1 binds HDL, its active site faces the lipoprotein's core and is inaccessible to external substrates. Hence, the HDL-bound PON1 is inactive toward substrates outside the particle's lipid core and is rapidly degraded and becomes inactive upon internalization. Consequently, the enzyme is only active in the cell membrane during its transit from HDL to the cytoplasm. To assign a function to PON1, we investigated whether it is a palmitoyl-protein thioesterase (PPT) that can hydrolyze the palmitoyl moieties of membrane proteins involved in HDL and cholesterol transport, such as SR-B1, ABCA1, or their neighboring caveola proteins to facilitate the release of HDL or trigger its endocytosis. This study shows that PON1 can hydrolyze palmitoyl-cysteine thioester bonds in vitro, has direct or indirect PPT activity in vivo, and can significantly decrease the presence of SR-B1 in the endothelial membrane.

Structural Characteristics of PON1 with Leu55Met and Gln192Arg Variants Influencing Oxidative-Stress-Related Diseases: An Integrated Molecular Modeling and Dynamics Study.

Background and Objectives: PON1 is a multi-functional antioxidant protein that hydrolyzes a variety of endogenous and exogenous substrates in the human system. Growing evidence suggests that the Leu55Met and Gln192Arg substitutions alter PON1 activity and are linked with a variety of oxidative-stress-related diseases. Materials and Methods: We implemented structural modeling and molecular dynamics (MD) simulation along with essential dynamics of PON1 and molecular docking with their endogenous (n = 4) and exogenous (n = 6) substrates to gain insights into conformational changes and binding affinity in order to characterize the specific functional ramifications of PON1 variants. Results: The Leu55Met variation had a higher root mean square deviation (0.249 nm) than the wild type (0.216 nm) and Gln192Arg (0.202 nm), implying increased protein flexibility. Furthermore, the essential dynamics analysis confirms the structural change in PON1 with Leu55Met vs. Gln192Arg and wild type. Additionally, PON1 with Leu55Met causes local conformational alterations at the substrate binding site, leading to changes in binding affinity with their substrates. Conclusions: Our findings highlight the structural consequences of the variants, which would increase understanding of the role of PON1 in the pathogenesis of oxidative-stress-related diseases, as well as the management of endogenous and exogenous chemicals in the treatment of diseases.

Genetic polymorphisms in the angiotensin converting enzyme, actinin 3 and paraoxonase 1 genes in women with diabetes and hypertension.

Objective: To study associations between polymorphisms in the angiotensin converting enzyme (ACE I/D), actinin 3 (ACTN3 R577X) and paraoxonase 1 (PON1 T(-107)C) genes and chronic diseases (diabetes and hypertension) in women. Materials and methods: Genomic DNA was extracted from saliva samples of 78 women between 18 and 59 years old used for genetic polymorphism screening. Biochemical data were collected from the medical records in Basic Health Units from Southern Brazil. Questionnaires about food consumption, physical activity level and socioeconomic status were applied. Results: The XX genotype of ACTN3 was associated with low HDL levels and high triglycerides, total cholesterol and glucose levels. Additionally, high triglycerides and LDL levels were observed in carriers of the TT genotype of PON1, and lower total cholesterol levels were associated to the CC genotype. As expected, women with diabetes/hypertense had increased body weight, BMI (p = 0.02), waist circumference (p = 0.01), body fat percentage, blood pressure (p = 0.02), cholesterol, triglycerides (p = 0.02), and blood glucose (p = 0.01), when compared to the control group. Conclusion: Both ACTN3 R577X and PON1 T(-107)C polymorphisms are associated with nutritional status and blood glucose and lipid levels in women with diabetes/hypertense. These results contribute to genetic knowledge about predisposition to obesity-related diseases.

High density lipoprotein heterogeneity & function among Indians with coronary artery disease.

Background & objectives: Impaired high density lipoprotein (HDL) functionality has been shown to be associated with cardiovascular disease risk. The study was aimed to identify the alterations in HDL function [antioxidative activity (AOA)] and subfraction distribution between acute coronary syndrome (ACS) and stable coronary artery disease (SCAD) individuals and analysing the accuracy of HDL parameters to discriminate between the groups. Methods: HDL subfraction distribution analysis was performed in 200 coronary artery disease patients (ACS and SCAD) and 60 control individuals using dextran sulphate, heparin and manganese chloride precipitation method. In terms of HDL function, AOA was evaluated by dihydrorhodamine-based fluorescent cell-free assay and paraoxonase (PON1) enzyme paraoxonase and arylesterase activity. Results: We found that higher AOA [odds ratio (95% confidence interval {CI})]: 0.09 (0.02-0.44), P<0.01 for SCAD; 0.008 (0.001-0.07), P<0.001 for ACS and higher PON1 activity [0.22 (0.8-0.59), P<0.01 for SCAD; 0.16 (0.06-0.4), P<0.001 for ACS] were associated with a lower odds of developing coronary artery disease (CAD). AOA of apoB-depleted serum was significantly correlated with HDL2-C/HDL3-C (HDL-cholesterol) ratio in controls (r=-0.31, P=0.01) and ACS (r=-0.18, P=0.04). It was observed that AOA and HDL subfraction distribution together could discriminate between the two groups of CAD with an accuracy of 72.8 per cent (P=0.004). Interpretation & conclusions: Impaired AOA and altered subfraction distribution of HDL may be responsible for its diminished anti-athero protective activity and can discriminate between the two groups of CAD individuals.

Longitudinal changes of oxidative stress and PON1 lactonase activity and status in older pregnant women undergoing assisted reproductive technology: a prospective nested case-control study.

BACKGROUND: Childbearing in women with advanced maternal age (AMA) has increased the need for artificial reproductive technology (ART). ART and oxidative stress are associated with many pregnancy complications. Paraoxonase (PON) 1 is one of the key components responsible for antioxidative activity in high-density lipoprotein (HDL). This study aimed to investigate the longitudinal changes of oxidative stress and PON1 lactonase activity and status in older women undergoing ART. METHODS: This prospective nested case-control study included 129 control and 64 ART women. Blood samples were obtained respectively at different stages of pregnancy. PON1 level and lactonase activity were assessed using 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) and 5-thiobutyl butyrolactone (TBBL) as a substrate, respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase to DEPCyMCase activity. Serum total oxidant status (TOS), total antioxidant capacity (TAC), malondialdehyde (MDA), homocysteine (HCY), PON1 C-108T and Q192R genetic polymorphisms, and metabolic parameters were analyzed. RESULTS: Lactonase activity and level of PON1 gradually decreased with pregnancy progression, while glycolipid metabolism parameters and TAC levels increased with pregnancy progression or significantly raised during the 2nd and 3rd trimesters, and NLA of PON1, TOS, OSI, MDA, and HCY significantly increased before delivery in the ART and control groups. Compared with the control women, the ART women had substantially higher or relatively high lactonase activity and NLA of PON1 and TAC during pregnancy; higher triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, atherogenic index, apolipoprotein (apo) B, and apoB/apoA1 ratio in the 1st trimester; and higher fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, and TG levels before delivery. No significant differences were found in the frequencies of PON1 C-108T and Q192R genotypes and alleles between the ART and control groups. CONCLUSIONS: Women with AMA undergoing ART had higher TAC, PON1 lactonase activity, and PON1 NLA than control women, suggesting increased compensatory antioxidant capacity in ART women, thus showing higher sensitivity to oxidative stress-related injury and diseases.

Genetic Susceptibility to Neurotoxicity Related to Prenatal Inorganic Arsenic Exposure in Young Spanish Children.

We explored the influence of child and maternal single nucleotide polymorphisms (SNPs) in genes related to neurological function and arsenic metabolism (i.e., ABCA1, ABCB1, PON1, CYP3A, BDNF, GSTP1, MT2A, and APOE as well as AS3MT) on the association between prenatal arsenic (As) exposure and methylation efficiency and neuropsychological development in 4-5-year-old children. Participants were 549 mother-child pairs from the INMA (Environment and Childhood) Spanish Project. We measured inorganic arsenic (iAs) and the metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in urine samples collected during pregnancy. Neuropsychological development was assessed at the age of 4-5 years using the McCarthy Scales of Children's Abilities (MSCA). Several SNPs were determined in maternal and child DNA; AS3MT and APOE haplotypes were inferred. The median ∑As (sum of iAs, DMA, and MMA) was 7.08 µg/g creatinine. Statistically significant interactions for children's APOE haplotype were observed. Specifically, ε4-carrier children had consistently lower MSCA scores in several scales with increasing ∑As and MMA concentrations. These results provide evidence regarding the neurotoxic effects of early life exposure to As, observing that the APOE ε4 allele could make children more vulnerable to this exposure.