Paraoxonase Research Articles

Assessment of the genetic contribution to brain magnetic resonance imaging lesion load and atrophy measures in multiple sclerosis patients.

Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients. Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis. Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p=0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p=0.004 and p=0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (β=-0.731, p=3.2*10-7 ) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (β=22.04, p=5.5*10-6 ) in RRMS. Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.

Increased Cholesteryl Ester Transfer Protein and Lipoprotein-Associated Phospholipase A2 Activities in Children and Adolescents Presenting High Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio.

To explore the association between Triglyceride/High-density lipoprotein cholesterol (TG/HDL-C) index and these enzymes and proteins in a pediatric population. Children and adolescents (7-14 y old) were recruited (n = 150) and anthropometric data were registered. Glucose, TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C plus cholesteryl ester transfer protein (CETP), lipoprotein-associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON1) activities were determined. Twenty-five individuals presented TG/HDL-C ratio ≥ 3.0. These individuals exhibited higher TG [164 (126-186) vs. 65 (48-72) mg/dL; p < 0.01] CETP [250 (232-263) vs. 223 (193-237)% mL/min; p < 0.01] and Lp-PLA2 (4.5 ± 1.9 vs. 3.5 ± 1.3; p < 0.05) plus lower HDL-C [41 (37-49) vs. 52 (48-62) mg/dL; p < 0.01] compared to an age-matched group with TG/HDL-C < 3.0. TG/HDL-C ratio was associated to CETP (p < 0.01) and Lp-PLA2 (p < 0.05). Multiple lineal regression analyses showed TG/HDL-C index as an independent predictor of CETP (r2 = 0.29; beta = 0.49; p < 0.01) and Lp-PLA2 (r2 = 0.21; beta = 0.32; p < 0.05) activities. Children and adolescents with TG/HDL-C ≥ 3.0 presented a more atherogenic lipid profile and higher CETP and Lp-PLA2 activities, which would indicate alterations in lipoprotein metabolism and quality.

Pesticide exposure and related health problems among farmworkers' children: a case-control study in southeast Iran.

Pesticides are potentially hazardous chemicals that can cause injury to human health and the environment. The purpose of this study was to evaluate organophosphate pesticides (OPPs) and organochlorine pesticides (OCPs) exposure in farmworkers' children aged 6 to 11years in Jiroft city in southeastern Iran. One hundred twenty farmworkers' children as case and 53 non-farmworkers' children aged 6 to 11years as control were selected and the serum levels of OCPs were measured by using gas chromatography in all participants. In addition, erythrocyte acetylcholinesterase (AChE) and arylesterase activity of paraoxonase-1 (PON-1) were measured to evaluate OPPs effects. Catalase (CAT), superoxide dismutase3 (SOD3), glutathione peroxidase (GPx3) activities, and the levels of serum malondialdehyde (MDA), total antioxidant capacity (TAC), nitric oxide (NO), and protein carbonyl (PC) were measured to investigate OCPs and OPPs effects on oxidative stress (OS). The serum levels of beta-HCH, 4,4 DDE, and 4,4 DDT in the case group were significantly higher than the control group. In addition, in the case group, AChE, PON-1, CAT, SOD3, and GPx3 activities and the levels TAC were significantly lower, while MDA, PC, and NO levels were significantly higher than the control group. OCPs as illegal pesticides are present in southeast Iran and children are exposed to OCPs and OPPs in the studied area. In addition, higher serum levels of pesticides may be a major contributor in OS development, as a cause of many diseases.

Association of SNPs in Lipid Metabolism Gene Single Nucleotide Polymorphism with the Risk of Obesity in Children.

Background: Obesity is one of the most common metabolic disorders in the world, which develops due to an imbalance in energy consumption and expenditure, and both genetic and environmental factors are of great importance. We investigated the potential interactions of single nucleotide polymorphisms that might contribute to the development of polygenic obesity in children. Objective: The study involved 367 children and adolescents of both sexes aged from 4 to 18 years. The control group (normal weight) and the overweight groups included 65 and 302 children respectively. Methods: DNA for analysis was isolated from peripheral blood lymphocytes, then allelic variants rs99305069 of the FTO gene (chr16:53786615), Gln192Arg of the PON1 gene (chr7: 95308134), -250G>A of the LIPC gene (chr15: 58431740), and Ser447Ter of the LPL gene (chr8:19957678) were studied using the SNP-Express reagent kit. The results of allelic interactions were analyzed using the multifactor dimensionality reduction method. Results and Discussion: Among overweight children, the distribution of genotype and allele frequencies for the studied single nucleotide polymorphisms of the four genes corresponded to those of the control group (p > 0.05). It was found that in obese children SerSer homozygotes at the Ser447Ter polymorphism of the LPL gene, had serum triglyceride (TG) levels 2.3 times higher than in children with the same genotype from the control group. In overweight Ser447Ter heterozygotes (p < 0.0001), the TG level exceeded the control values by only 13% (p = 0.044). A two-locus genotype FTO AT/LPL SerTer, was associated with a reduced risk of childhood obesity.

Comparison of Protein Carbonyl (PCO), Paraoxonase-1 (PON1) and C-Reactive Protein (CRP) as Diagnostic and Prognostic Markers of Septic Inflammation in Dogs.

Reliable diagnostic and prognostic markers of sepsis are lacking, but essential in veterinary medicine. We aimed to assess the accuracy of C-Reactive Protein (CRP), protein carbonyls (PCO) and paraoxonase-1 (PON1) in differentiating dogs with sepsis from those with sterile inflammation and healthy ones, and predict the outcome in septic dogs. These analytes were retrospectively evaluated at admission in 92 dogs classified into healthy, septic and polytraumatized. Groups were compared using the Kruskal–Wallis test, followed by a Mann–Whitney U test to assess differences between survivors and non-survivors. Correlation between analytes was assessed using the Spearman’s test, and their discriminating power was assessed through a Receiver Operating Characteristic (ROC) curve. PON1 and CRP were, respectively, significantly lower and higher in dogs with sepsis compared with polytraumatized and clinically healthy dogs (p < 0.001 for both the analytes), and also in dogs with trauma compared with healthy dogs (p = 0.011 and p = 0.017, respectively). PCO were significantly increased in septic (p < 0.001) and polytraumatized (p < 0.005) as compared with healthy dogs. PON1 and CRP were, respectively, significantly lower and higher in dogs that died compared with survivors (p < 0.001 for both analytes). Ultimately, evaluation of CRP and PON1 at admission seems a reliable support to diagnose sepsis and predict outcomes.

Evaluation of pheniramine maleate and zofenopril in reducing renal damage induced by unilateral ureter obstruction. An experimental study.

IntroductionObstruction of the ureter may occur due to congenital, iatrogenic or other reasons. This can cause hydronephrosis in the early stage and can lead to cellular inflammation, necrosis and atrophy in the kidney tissue. The aim of this paper is to evaluate the protective effect of pheniramine maleate (PM) and zofenopril on renal damage caused by hydronephrosis due to unilateral partial ureter obstruction.Material and methodsTwenty-four female Sprague Dawley rats were divided into 4 groups. Group 1: sham group, group 2: partial unilateral ureteral obstruction (PUUO) group, group 3: PUUO + PM group, group 4: PUUO + zofenopril group. Paraoxonase (PON), total antioxidant status (TAS) and total oxidant status (TOS) of tissue and blood samples were measured and calculated. Tissue samples were evaluated histopathologically.ResultsAn increase in tissue TAS and a decrease in tissue TOS and OSI levels were detected in groups 3 and 4 compared to group 2 (both: p < 0.01). Tissue PON levels showed an increase in groups 3 and 4 compared to groups 1 and 2 (both: p < 0.01). Histopathological evaluation showed a decrease in interstitial inflammation and congestion in groups 3 and 4 compared to the control group (p < 0.001). The decrease was observed to be more significant in group 4 compared to group 3 (p < 0.01).ConclusionsIn our experimental study, we observed that PM and zofenopril reduce the oxidation and tissue damage caused by unilateral partial obstruction.

Insulin Resistance Is Associated With Impaired HDL Function and Atherogenic Modification of LDL in Polycystic Ovarian Syndrome

Background and Aims: Polycystic ovarian syndrome (PCOS) is associated with increased risk of cardiovascular disease (CVD). The aim of this study was to assess the association between PCOS and markers of HDL functionality and atherogenic LDL modification. Methods: This is a cross-sectional study of 104 women with PCOS [median (IQR); age 29 (24–36) years, and BMI 32.9 (25.7–38.5) kg/m2] and 103 BMI-matched healthy participants (age 34 (27–37) years, and BMI 31.1 (27.6–35.5) kg/m2). PCOS was defined using the NIH criteria. Measurement of lipid profile and glycaemic blood parameters were undertaken. Patients with PCOS were divided into tertiles of insulin resistance assessed using the homeostatic model assessment (HOMA-IR). Cholesterol efflux capacity (CEC), and paraoxonase-1 (PON1) activity were measured as markers of HDL functionality. Oxidized LDL (OxLDL), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized phoshopholipids on apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) (OxPL-apo(a)), and glycated apoB were used as markers of atherogenic modification of LDL. Results: Patients with PCOS in the upper tertile of insulin resistance had impaired HDL functionality compared to the lower tertile and controls, with lower CEC [13.7 (12.4–14.6) vs 14.9 (13.6–17.0), P=0.003; and 14.5 (13.0–16.0) %, P=0.063 respectively] and PON1 activity [77.2 (48.2–129.2) vs 112.9 (54.0–175.4), P=0.043; and 131.6 (89.5–195.1) nmol/ml/min, P<0.001 respectively]. Markers of atherogenic modification of LDL were also increased in the upper tertile compared to the lower tertile and controls, with higher levels of OxLDL [91.6 (58.8–120.9) vs 67.2 (20.1–86.3), P=0.016; and 74.8 (47.6–89.5) ng/ml, P=0.013 respectively], LpPLA2 [1.66 (1.48–1.84) vs 1.48 (1.39–1.60), P=0.004; and 1.53 (1.37–1.70) µg/ml, P=0.015 respectively], small-dense LDL cholesterol (sdLDL) [24.8 (16.8–35.0) vs 15.3 (11.3–20.1), P<0.001; and 20.9 (14.6–29.0) mg/dl, P<0.001 respectively], and glycated apoB [4.02 (3.63–4.33) vs 3.51 (3.27–3.70), P<0.001; and 3.48 (3.20–3.96), P<0.001 respectively]. Both BMI and insulin resistance were associated with adverse lipoprotein modification, correlating positively with OxLDL, LpPLA2, sdLDL, and glycated apoB (Spearman’s ρ=0.244–0.325 and Spearman’s ρ=0.254–0.377 respectively, all P<0.050); and negatively with CEC (Spearman’s ρ=-0.244 andSpearman’s ρ=0.254 respectively, both P<0.050). OxPL-apoB, OxPL-apo(a), and lipoprotein(a) did not differ between PCOS and controls. Conclusions: Insulin resistance is a key determinant of decreased HDL functionality and increased oxidative modification and glycation of LDL in PCOS, which is likely to contribute to the increased CVD risk.

Validation of PON1 as a Biomarker of Clopidogrel Resistance in Caribbean Hispanics

Background : Clopidogrel is an antiplatelet drug used to prevent heart attack and strokes in cardiovascular patients. Pharmacological studies of clopidogrel have been mainly conducted in individuals of European ancestry, therefore missing genetic diversity and enhancing disparities of care. Since admixed Caribbean Hispanics are among those often underrepresented, we want to identify predictive or risk biomarkers of the response to clopidogrel within this population. Preliminary data using Tandem Mass Tag (TMT) coupled with mass spectrometry revealed that paraoxonase-1 (PON1) is downregulated in patients treated with clopidogrel (-49.50) when compared to other cardiovascular patients. PON1 is an HDL-associated protein that protects against accumulation of oxidized lipids and prevent cardiovascular disease. Our aim is to validate the low abundance of PON1 by western blot analysis. Methods : All patients signed an informed consent approved by the Institutional Review Board (IRB-protocol number A4070417). Blood was collected and a platelet reactivity test was performed using the VerifyNow® P2Y12 assay to determine if the patient is a poor responder (PRU≥230). Plasma was separated by centrifugation and stored at -80°C. For Western Blot analysis, 25µg of plasma proteins were run on 10% sodium dodecyl sulphate-polyacrylamide gel electrophoresis for the healthy (n=6), cardiovascular (n=6), normal responders (n=14), and poor responders (n=10) groups. Proteins were electro-transferred from the gel onto polyvinylidene membrane. The membranes were incubated with PON1 (4G8D3) and goat anti-mouse IRDye 680RD antibodies, followed by an incubation with a loading control, anti-transferrin (101) rabbit monoclonal antibody and goat anti-rabbit IRDye 680RD antibody. The membranes were scanned in the Odyssey® CLx Imager in AUTO (680 nm and 800 nm channels) to reveal the immunofluorescent bands that were quantified by the Image StudioTM Software. Statistical analysis was carried out by Graphpad Prism 6.01 for Windows. After determining the normality of the data by Shapiro Wilkins Test, a one-way ANOVA was run as a variance test. Results : The total PON1 intensity signal was detected in healthy (1.11±0.34) and cardiovascular controls (1.00±0.00), normal (1.06±0.45) and poor responders (0.89±0.34), with a lower mean value in the latter but no statistical differences among the groups (p>0.05). Conclusions : PON1 could not be validated as a downregulated protein in poor responders when compared to other cardiovascular groups by western blotting.

Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment.

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.

Pregnancy exposure to organophosphate esters and the risk of attention-deficit hyperactivity disorder in the Norwegian mother, father and child cohort study

BackgroundOrganophosphate esters (OPEs) are a class of flame retardants in common use. OPEs can easily leach from materials, resulting in human exposure. Increasing concentrations have been reported in human populations over the past decade. Recent studies have linked prenatal OPE exposure to hyperactivity and attention problems in children. Such behaviors are often found among children with attention-deficit hyperactivity disorder (ADHD), however, no study has investigated OPEs in relation to clinically assessed ADHD. ObjectiveTo evaluate prenatal exposure to OPEs as risk factors for clinically assessed ADHD using a case-cohort study nested within the Norwegian Mother, Father, and Child Cohort Study (MoBa). MethodsWe included in the case group 295 ADHD cases obtained via linkage with the Norwegian Patient Registry, and the sub-cohort group 555 children sampled at baseline, irrespective of their ADHD case status. Prenatal concentrations of OPE metabolites were measured in maternal urine collected at 17 weeks of gestation, and included diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We estimated risk ratios and the corresponding 95% confidence intervals [95% CI] using logistic regression, adjusting for season of urine collection, child sex, birth year, and maternal depression, education, and sum of urinary di(2-ethylhexyl) phthalate metabolites (∑DEHP) concentration during pregnancy. To assess the overall impact of simultaneously decreasing exposure to all chemical constituents of an OPE-phthalate mixture, quantile based g-computation was implemented. The mixture constituents included OPE and phthalate metabolites commonly detected in our study. In all models, we considered effect measure modification by child sex and polymorphisms in genes encoding paraoxonase 1 (PON1) and cytochrome P450 (P450) enzymes. Mediation analysis was conducted using thyroid function biomarkers estimated from maternal blood collected at 17 weeks of gestation. ResultsDPHP was detected in nearly all samples (97.2%), with a higher geometric mean among the case group (0.70 µg/L) as compared to the sub-cohort (0.52 µg/L). DNBP was commonly detected as well (93.8%), while BBOEP (52.9%) and BDCIPP (22.9%) were detected less frequently. A higher risk of ADHD was observed in children with greater than median exposure to DPHP during pregnancy (risk ratio: 1.38 [95% CI: 0.96, 1.99]), which was slightly higher among girls (2.04 [1.03, 4.02]) and children of mothers with PON1 Q192R genotype QR (1.69 [0.89, 3.19]) or PON1 Q192R genotype RR (4.59 [1.38, 15.29]). The relationship between DPHP and ADHD (total risk ratio: 1.34 [0.90, 2.02]) was partially mediated through total triiodothyronine to total thyroxine ratio (natural direct effect: 1.29 [0.87, 1.94]; natural indirect effect: 1.04 [1.00, 1.10]; 12.48% mediated). We also observed an elevated risk of ADHD in relation to BDCIPP detection during pregnancy (1.50 [0.98, 2.28]). We did not observe notable differences in ADHD by DNBP (0.88 [0.62, 1.26]) or BBOEP (1.03 [0.73, 1.46]) during pregnancy. Simultaneously decreasing all constituents of common-detect OPE-phthalate mixture, specifically DPHP, DNBP, and 6 phthalate metabolites, by a quartile resulted in an ADHD risk ratio of 0.68 [0.64, 0.72]. ConclusionPrenatal exposure to DPHP and BDCIPP may increase the risk of ADHD. For DPHP, we observed potential modification by child sex and maternal PON1 Q192R genotype and partial mediation through maternal thyroid hormone imbalance at 17 weeks gestation.

Identification of potential metabolic biomarkers of rectal cancer and of the effect of neoadjuvant radiochemotherapy.

We report a pilot study on the feasibility of determinations of circulating levels of paraoxonase-1 (PON1) and compounds related to energy metabolism as biomarkers for the evaluation of patients with rectal cancer (RC), and the effects produced by neoadjuvant radiochemotherapy (NRCT). We studied 32 patients treated with radiotherapy plus capecitabine concomitant chemotherapy and 48 control subjects. We identified pre-NRCT PON1 and α-ketoglutarate as the parameters that best discriminated between RC patients and the control group. Receiver operating characteristics analysis of the combination of the two parameters showed an area under the curve (AUC) of 0.918. Moreover, patients who presented a pathological complete response (pCR) to treatment had lower plasma pre-NRCT valine concentrations (AUC of 0.826). Patients who had a relapse had lower concentrations of succinate (AUC of 0.833). The results of the present study illustrate the usefulness of investigating alterations in oxidative stress and metabolism in RC. Due to the small number of patients studied, our results must be considered preliminary, but they suggest that the determination of circulating levels of PON1 and α-ketoglutarate might be a valuable tool for the early diagnosis of RC, while the determination of valine and succinate might effectively predict pCR and the appearance of relapse.

Effect of prevalent polychlorinated biphenyls (PCBs) food contaminant on the MCF7, LNCap and MDA-MB-231 cell lines viability and PON1 gene expression level: proposed model of binding.

Polychlorinated biphenyls (PCBs) are a group of synthetic organic chlorine compounds known as an organic pollutant in food sources, which play important roles in malignancies. The present study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines. In the current study, MCF-7, LNCap, and MDA-MB231 cell lines were treated with serial concentrations (0.001-100μM) of PCBs for 48h and cell viability assessment was performed using MTT assay. The best concentration then applied and the expression level of PON1 was evaluated using real-time PCR. Besides, molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor. Unlike MCF-7 and LNCap cells, the viability of MDA-MB231 cells did not significantly change by different concentrations of PCBs. Meanwhile, quantitative gene expression analysis showed that the PON1 was significantly more expressed in MCF-7 and LNCap lines treated with PCB28 and PCB101. However, the expression level of this gene in other groups and also MDA-MB231cells did not demonstrate any significantly change. Also, the results of molecular docking showed that PBCs had steric interaction with AhR receptor. Current results showed that despite of hormone non-responsive cells the PCBs have a significant positive effect on hormone-responsive cell. Therefore, and regarding to the existence of PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material. This study aimed to investigate the direct effects of prevalent PCBs in food in hormone-responsive and non-responsive cell lines. Cell lines were treated with serial concentrations of PCBs and cell viability assessment was performed using MTT assay. The expression level of PON1 was evaluated using real-time PCR. Molecular docking was performed to determine the binding mechanism and predicted binding energies of PBCs compounds to the AhR receptor. PCBs contamination in food there should be serious concern about their impact on the prevalence of different malignancies which certainly should result in a standard limit for this material.

Cloning, sequence analysis, and tissue expression of marmoset paraoxonase 1

Paraoxonase (PON) plays roles in the metabolism of organophosphate xenobiotics and drugs. Despite the importance of marmosets for research into drug metabolism and pharmacokinetics, marmoset paraoxonase has not yet been fully characterized. Consequently, we identified the PON1 gene in the marmoset genome by sequence homology analysis. Marmoset PON1 cDNA containing an open reading frame (1065 bp) was successfully cloned from marmoset liver by reverse transcription-polymerase chain reaction. The deduced amino acid sequence (355 amino acids) has approximately 93% identity with the human ortholog and contains important amino acid residues for substrate binding and calcium ion coordination. According to a phylogenetic tree of PON1 amino acid sequences constructed using data from seven animal species, marmoset PON1 is closer to human PON1 than it is to the PON1 orthologs of experimental animals such as pigs, rabbits, rats, and mice. Marmoset PON1 mRNA was predominantly expressed in liver among the five tissues examined. Marmoset PON1 protein secreted into plasma was detected by immunoblotting. The paraoxon-hydrolyzing activity in plasma was higher in marmosets than in humans. Based on these data, we concluded that marmoset and human PON1 have similar characteristics with regard to genomic structure, amino acid sequences, and tissue distribution.

Paraoxonase 1 and Non-Alcoholic Fatty Liver Disease: A Meta-Analysis.

Oxidative stress is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, reliable biomarkers of NAFLD in relation to oxidative stress are not available. While paraoxonase 1 (PON1) is an antioxidant biomarker, there appears to be mixed data on PON-1 in patients with NAFLD. The aim of this meta-analysis was to assess the current data on PON1 activity (i.e., paraoxonase and arylesterase) in patients with NAFLD. A PubMed, CENTRAL, and Embase search identified 12 eligible articles. In the meta-analysis, the paraoxonase activity was low in patients with NAFLD (mean difference (MD) −27.17 U/L; 95% confidence interval (CI) −37.31 to −17.03). No difference was noted in the arylesterase activity (MD 2.45 U/L; 95% CI −39.83 to 44.74). In a subgroup analysis, the paraoxonase activity was low in biopsy-proven nonalcoholic steatohepatitis (MD −92.11 U/L; 95% CI −115.11 to −69.11), while the activity in NAFLD as diagnosed by ultrasonography or laboratory data was similar (MD −2.91 U/L; 95% CI −11.63 to 5.80) to that of non-NAFLD. In summary, the PON1, especially paraoxonase, activity could be a useful biomarker of NAFLD. Further studies are warranted to ascertain the relevance of PON1 measurements in patients with NAFLD.

Thiol Disulfide Balance Oxidative Stress and Paraoxonase 1 Activities in Children and Adolescents Aged 6-16 Years with Specific Learning Disorders

Introduction: Specific learning disorders (SLD) are some of the most common neurodevelopmental disorders. The aim of this study is to determine the potential relationship between children with SLD and zinc, copper, paraoxonase 1 (PON1), arylesterase (ARY), ischemia-modified albumin, thiol balance, oxidative stress index, total antioxidant status, total oxidant status, and routine biochemical parameters. Methods: All participants were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children. Total oxidant status, total antioxidant status, thiol balance, ischemia modified albumin, paraoxonase 1 activity, arylesterase activity, zinc and copper levels were measured by the spectrophotometric methods. Results: Compared to the control, the SLD group had statistically significantly lower values for PON1 antioxidant enzyme activity (p=.045), ARY antioxidant enzyme activity (p<.001), 25 OH Vitamin D (p=.005), reduced thiol ratio (p=.028), thiol oxidation reduction ratio (p=.01), native thiols (p=.024) and significantly higher values for total oxidant status (p=.017), oxidized thiol ratio (p=.028). Conclusion: The relationship between oxidative stress and SLD diagnosis in our results will be very important if it is supported by further new studies. In this case, evaluation of vitamin D, oxidative stress, antioxidant status and thiol balance may come to the agenda in the diagnosis and treatment of SLD.

LIPID METABOLISM AND METABOLIC DISORDERS IN THE YAKUT POPULATION: A LITERATURE REVIEW

Extreme climatic conditions of the North with low temperatures and the traditional diet are responsible for development of a specific mechanisms of lipid metabolism among the indigenous peoples of the Sakha (Yakutia) Republic. The evolutionary patterns of lipid metabolism fixed in the genome in the form of polymorphic genetic markers are important for the development of regional healthcare programs for prevention of metabolic syndrome and cardiovascular diseases. The aim of the study was to analyze the characteristic features of lipid metabolism and metabolic disorders in the Yakut population. A systematic review of the results of studies of lipid profile parameters and key candidate genes involved in lipid metabolism among the indigenous inhabitants of Yakutia over the past 10 years was performed. The available evidence suggests that in indigenous inhabitants of Yakutia, the indicators of lipid metabolism are not a matter for concern. Participants of the most studies have a high concentrations of high-density lipoprotein cholesterol, low concentrations of triglycerides and low plasma atherogenic index, which are associated with physiological adaptation to environmental conditions. However, changes in dietary patterns including increased consumption of carbohydrates and lifestyle changes including reduced physical activity and abandonment of traditional activities have led to the spread of metabolic disorders in recent decades. Prevalence estimates for the metabolic syndrome in the indigenous inhabitants of Yakutia aged 20 years or older vary from 4.9 % in men to 49.4 % in women in the Arctic regions. We also discuss the mechanisms of lipid metabolism and the role of LepR, LPL, CETP, IL6, PON1 genes in the development of metabolic disorders in the Yakut population.

Factors associated to serum paraoxonase 1 activity in patients with cardiovascular disease.

Paraoxonase 1 (PON1) is an enzyme that has antioxidant potential, which confers a protective effect against the atherosclerotic process. However, studies associating genetics, dietary patterns and PON1 activity in individuals with cardiovascular disease (CVD) are scarce. Thus, the aim of the current study was to evaluate the influence of dietary factors on serum PON1 in CVD patients. Cross-sectional, sub-study of the BALANCE Program Trial. All patients aged 45 years or older and had evidence of established atherosclerotic disease in the preceding 10 years. Body weight, height, waist circumference, blood pressure, lipid profile and fasting glucose were collected. Food intake was assessed with 24-h dietary recall. Data was analyzed using SAS University Edition and a P value ≤ 0.05 was considered statistically significant. Sample was divided into three groups, according to the PON1 T(-107)C genotype (CC, CT and TT) and serum PON1 activity (Low, Medium, High). There were no genotype differences for major factors. However, the systolic blood pressure was lower for CT individuals (p<0.05). Intake of cholesterol, saturated fatty acids (SFA) and monounsaturated fatty acids (MUFAS) was higher in patients with lower PON1 activity. Lipid ingestion tended to be higher in patients with lower PON1 activity (p=0.08). In the multivariate logistic regression model, SFA intake (P=0.03), genotype (P=0.09), gender (P=0.04), age (P=0.07) and carbohydrate intake (P=0.16) contributed the most to the serum PON1 activity. Based on these findings, nutritional guidance for these patients becomes essential, since dietary components interact with serum PON1 activity more than genotype.

Pregabalin, a GABA Analogue Protects against Carbon Tetrachloride-Induced Oxidative Stress and Liver Injury in Rats

Pregabalin is a synthetic analogue of the neurotransmitter g-aminobutyric acid (GABA) and is used in the treatment of epilepsy and neuropathic pain. The aim of this study was to investigate the effect of pregabalin on toxic liver injury caused by the acute administration of carbon tetrachloride (CCl4). Rats were orally treated with CCl4 for two successive days either alone or along with intraperitoneal pregabalin at doses of 7 and 14 mg/kg. The control group received the vehicle (olive oil). Liver oxidative stress and damage were assessed by determining serum and/or liver tissue levels of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), DNA fragmentation, serum aminotransferases, paraoxonase-1 (PON-1), and hepatic histopathology. Results showed that CCl4 significantly (i) increased MDA and NO and decreased PON-1 in both serum and liver tissue, and (ii) decreased liver GSH content and induced marked hepatic DNA fragmentation. CCl4 treatment caused liver tissue injury as evidenced by significantly increased serum aminotransferases. In line with the above biochemical changes, the liver of CCl4-treated rats exhibited massive steatosis, vacuolar degeneration, cloudy swelling, and necrosis. In CCl4-treated rats, pregabalin given at the dose of 14 mg/kg significantly reduced the increments in MDA, NO, serum aminotransferases, and hepatic DNA fragmentation. Liver GSH was unaltered but hepatic and serum PON-1 activity increased after administering pregabalin which also improved, though not normalized, liver tissue histopathology. Collectively, these results suggest that the administration of pregabalin is associated with a reduction in experimental liver injury caused by CCl4. (First online: Apr 12, 2021)

Changes in redox plasma proteome of Pon1−/− mice are exacerbated by a hyperhomocysteinemic diet

High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-oxidative, anti-inflammatory, and antithrombotic activities, which are thought to be promoted by paraoxonase 1 (PON1), an HDL-associated enzyme. Reduced levels of PON1 are associated with increased oxidative stress and cardiovascular disease both in humans and Pon1−/− mice. However, molecular basis of these associations are not fully understood. We used label-free mass spectrometry and Ingenuity Pathway Analysis bioinformatics resources to examine plasma proteomes in four-month-old Pon1−/− mice (n = 32) and their Pon1+/+ siblings (n = 15) fed with a hyper-homocysteinemic (HHcy) diet. We found that inactivation of the Pon1 gene resulted in dysregulation of proteins involved in the maintenance of redox homeostasis in mice. Redox-responsive proteins affected by Pon1−/− genotype were more numerous in mice fed with HHcy diet (18 out of 89, 20%) than in mice fed with a control diet (4 out of 50, 8%). Most of the redox-related proteins affected by Pon1−/− genotype in mice fed with a control diet (3 out of 4, 75%) were also affected in HHcy mice, while the majority of Pon1−/− genotype-dependent redox proteins in HHcy mice (15 out of 18, 83%) were not affected by Pon1−/− genotype in control diet animals. In addition to redox-related proteins, we identified proteins involved in acute phase response, complement/blood coagulation, lipoprotein/lipid metabolism, immune response, purine metabolism, glucose metabolism, and other proteins that were dysregulated by Pon1−/− genotype in HHcy mice. Taken together, our findings suggest that Pon1 interacts with proteins involved in antioxidant defenses and other processes linked to cardiovascular disease. Dysregulation of these processes provides an explanation for the pro-oxidant and pro-atherogenic phenotypes observed in Pon1−/− mice and humans with attenuated PON1 levels.

Paraoxonase (PON)-1 activity in septic neonates: One more arrow in the quiver of biomarkers of neonatal sepsis?

Paraoxonase-1 (PON-1), a calcium ion-dependent high-density lipoprotein (HDL)-associated enzyme, has been proposed as a negative acute phase reactant biomarker in animal and human adult studies. The aim of this study was to evaluate the value of PON-1 activity in the diagnosis and monitoring of neonatal sepsis. Serum PON-1 activity, as paraoxonase and arylesterase, was prospectively studied in 48 septic neonates and matched controls. PON-1 activity was decreased at the acute phase of sepsis in comparison with values at recovery and values in controls. Paraoxonase or arylesterase at enrollment correlated significantly with serum Amyloid-A, CRP and IL-6 and could also discriminate septic than non-septic neonates. In conclusion, our results are promising regarding the role of PON-1 as a biomarker of neonatal sepsis. Larger studies are needed to validate the clinical utility of PON-1 in neonatal medicine.