Paraoxonase Enzyme Research Articles

Paraoxonase 1 Q192R (A/G) Gene Polymorphism as possible risk factor for coronary heart diseases among Egyptians. Case-control study

Background: Coronary heart disease (CHD) is the leading cause of morbidity and mortality worldwide. There are many risk factors for CHD but recently the role of oxidative stress in progression of atherosclerosis has been more recognized. Paraoxonase 1 (PON1) protects against oxidation of LDL and many polymorphisms in both of exons and promoter regions of (PON1) gene have been investigated for their association with CHD. The aim of the present study was to investigate the relation between CHD suceptibility and PON1 Q192R (A/G) gene polymorphism in a cohort of Egyptian individuals. Methods: The study included 100 subjects, 50 patients who admitted to cardiovascular department with established diagnosis of obstructive coronary artery disease by coronary angiography and 50 healthy participants. Genotyping of PON1 Q192R (A/G) was done, and then serum concentration of PON1 was assessed by ELISA after that by spectrophotometer. Results: Serum PON1 enzyme was lower in patients with CHD than in control group with a statistically significant difference p < 0.001. A statistically significant association was observed with AG and GG genotypes of PON1 gene with CHD with P= 0.003, OR=5.02(95% CI =1.66-15.26) and P= 0.038, OR= 9.4 (95% CI =1.07-82.5); respectively. The G allele of PON1 was higher in CHD patients than controls suggesting that this allele may demonstrate a susceptibility effect to CHD in our cohort with P<0.001, OR= 5.16 (95% CI = 2.1-12.5) Conclusion: The Q192R polymorphism in the PON1 gene may be a susceptibility gene associated with increased risk of CHD among Egyptians.

High-density lipoprotein functionality in patients with hyperbaric oxygen therapy

High-density lipoprotein (HDL) cholesterol levels are associated with decreased risk of atherosclerotic disease, but also not all HDL are functionally equivalent. The functional status of HDL is closely linked to its primary protein component, apolipoprotein A-1 (ApoA-I) levels and paraoxonase 1 (PON1) enzyme. Functional changes of HDL may arise from hyperbaric oxygen therapy (HBO) induced posttranslational modification of ApoA-1 and PON1 levels. A total of 41 patients who met the research criteria were included in the study. On average, 30 sessions of HBO therapy were performed (range: 20-39). Laboratory measurements were performed at the beginning and at the end of HBO treatment in two groups of the same patients. We measured serum levels of Apo A-1, PON1, oxidized LDL (OxLDL) and routine lipid laboratory parameters to determine possible changes in HDL function with HBO therapy. As unexpected, long term HBO treatment have no effect on OxLDL and also on PON1 enzyme. However, the mean ApoA-1 values in the second group were statistically significantly increased than their pre-treatment values (P &lt; 0.003). This preliminary study showed that HBO therapy increased the amount of serum ApoA-1. Actually, it can be assumed that the treatment of HBO does not have a negative effect on HDL functionality. The increase in ApoA-1 with HBO therapy is probably aimed at protecting against oxidative stress in patients. As a result, there is a need for larger clinical trials to determine the possible effects of HBO therapy on HDL functionality.

Complementary liver and serum protein profile in wild boars infected by the giant liver fluke Fascioloides magna using tandem mass tags quantitative approach

Liver fluke, Fascioloides magna, is an important non-native parasite introduced to Europe, posing a threat to survival of local wildlife populations. The aim of this study was to assess the serum and liver protein profile of control and F. magna infected wild boars, by means of shotgun tandem mass tag - based quantitative high resolution proteomics approach. In serum, 4 differentially abundant proteins were found out of total 1073 identified, while in liver from 3520 identified proteins, 116 were differentially abundant between healthy and F. magna infected wild boars. Pathway analysis revealed that most of the proteins differing in abundance are involved in metabolism, biological oxidations, cellular responses to stimuli, fatty acid metabolism, and others. Validation of proteomic results was performed for paraoxonase-1, ceruloplasmin, glutathione S-transferase and liver enzymes by ELISA and automated assays. Complementary analysis of liver and serum in F. magna infection enabled insight into changes of proteome profile of the host at local and sistemic level. Our findings showed that chronic infection with F. magna is associated with immune response in host, oxidative stress and metabolomic changes in liver. SignificanceLiver fluke infections are recognised as worldwide neglected diseases with considerable veterinary and public health importance. Pathological changes, clinical signs and outcome of F. magna infection are strongly related to the type of final hosts and their different tolerance to infection. In order to gain insight into host-parasite interactions in wild boars, dead-end host for F. magna, we assessed proteomics profile of serum and liver of control animals and those infected with F. magna. Proteomics analysis of serum and liver in parallel showed as advantageous and beneficial, demonstrating protein alterations mainly at local level. Bioinformatics analysis enabled elucidation of molecular pathways associated with F. magna infection. Identification and validation of proteins associated with infection may have added value to current tools for efficient liver fluke control.

Enzymatic synthesis of capric acid-rich structured lipids and their effects on mice with high-fat diet-induced obesity

The objective of this study was to produce structured lipids (SLs) by enzymatic acidolysis using Rhizopus oryzae lipase covalently immobilized in a low-cost material. Grape seed oil was used to synthesize SLs containing the medium-chain fatty acid (C10:0) capric acid. SL synthesis led to 38.8% medium-chain fatty acid incorporation with 5 reuses of the enzymatic derivative. The reaction conditions for the synthesis of MLM-TAGs (triacylglycerols with one long- and two medium-chain acyl residues) were at a molar ratio of fatty acid:oil of 3:1, performed at 40 °C and lipase immobilized load of 5% (w/w). The in vivo effects of SLs were studied in Swiss mice fed premade diets: control (C) diet, high-fat diet (HFD) with 100% lipid content as lard, HFD with 50% lipid content as grape seed oil (HG) or HFD with 50% lipid content as capric acid-containing SLs produced from grape seed oil (HG-MCT). Mice from HG and HG-MCT groups had decreases in body weight gain and reductions in the weights of white adipose tissues. In addition, HG and HG-MCT mice had low plasma levels of glucose and total cholesterol, and improvements in the glucose tolerance. HG and HG-MCT diets have remarkable antioxidant properties, since low plasma levels of TBARS (thiobarbituric acid reactive substances, biomarkers of lipid peroxidation) were found in mice fed these diets. Interestingly, TBARS levels in HG-MCT mice were further decreased than values of HG mice. Mice fed HG and HG-MCT diets also showed preservation in the activity of the antioxidant enzyme paraoxonase 1. Both HG and HG-MCT diets promoted reduction of IL-6 and IL-10 production by splenocytes. The capric acid-containing SLs produced from grape seed oil emerges as a functional oil capable to mitigate obesity complications resulting from oxidative stress and inflammation.

Abnormal levels of apolipoprotein A-I in chronic thromboembolic pulmonary hypertension.

Recent studies have shown low high-density lipoprotein cholesterol (HDL-C) and dysregulated lipid metabolism in chronic thromboembolic pulmonary hypertension (CTEPH). Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-C and mediates most of its functions. We hypothesize that ApoA-1 and its oxidative state might be more sensitive biomarkers in CTEPH. Plasma levels of HDL-C, ApoA-I, paraoxonase-1 enzyme activity (PON1), and the oxidized dysfunctional ApoA-I (oxTrp72-ApoA-I) were measured in patients with CTEPH and compared to those in healthy controls. Association with markers of disease severity in CTEPH was assessed. We included a total of 61 patients with CTEPH (age: 61.2 ± 15 years; male 52.5%) and 28 control subjects (age: 60.1 ± 8 years; male 59.3%). When adjusting for age, sex, body mass index, and statin use, ApoA-I was lower in CTEPH compared to controls (CTEPH:125.2 ± 27 mg/dl; control:158.3 ± 29.4 mg/dl; p < 0.001), but HDL-C levels were not statistically different. There were no significant differences in PON and oxTrp72-ApoA-I/ApoA-I ratio. In exploratory analyses, ApoA-I was associated with mean right atrial pressure (rs = −0.32, p = 0.013) and N-terminal pro B-type natriuretic peptide (rs = −0.31, p = 0.038). There were no significant associations between HDL-C, PON1, or oxTrp72-ApoA-I/ApoA-I ratio and markers of disease severity. We conclude that ApoA-I is a more sensitive biomarker than HDL-C in CTEPH, and may be associated with right heart dysfunction.

Evaluation of lipid metabolizing enzymes: Paraxonase1 (PON1) and lecithin cholesterol acyltransferase (LCAT) activities in children with nephrotic syndrome

Background: The most common glomerular disorder in children is nephrotic syndrome, associated with high morbidity despite notable advances in its treatment. Many of the nephrotic syndrome complications, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidemia. Paraoxonase enzyme is responsible for the most of the antioxidant properties of HDL, thus preventing the formation of atherogenic ox-LDL molecules, and lecithin cholesterol acyltransferase is intimately involved in HDL maturation and is a key component of the reverse cholesterol transport pathway, which removes excess cholesterol molecules from the peripheral tissues to the liver for excretion. Objectives: The present study aimed to investigate the serum activities of paraoxonase-1 (PON-1) and lecithin cholesterol acyltransferase (LCAT) in children with nephrotic syndrome in an active phase (as newly diagnosed or old cases with acute relapse). Also, to study any correlation exists between paraoxonase-1 activity and lipid profile. Methods: This study consists of group 1 with 40 cases of nephrotic syndrome in the age group of (2-14 years) and group 2 with 40 age and sex-matched healthy controls. Lipid profile and paraoxonase activity, lecithin cholesterol acyltransferase activities were measured in both groups’ serum samples. Results: Statistical analysis of student’s t-test showed that the mean levels of total cholesterol, triglycerides, LDL were significantly increased in group 1 when compared to Group 2 (p &lt;0.001). PON1 and lecithin cholesterol acyltransferase levels were significantly lower in group 1 compared to group 2, and there is no significant difference among nephrotic groups. Conclusions: Both paraoxonase-1 enzyme and lecithin cholesterol acyltransferase are considered good promising predictors for nephrotic syndrome and other parameters such as LDL, HDL, and TG. The significantly decreased paraoxonase-1 enzyme and lecithin cholesterol acyltransferase activities result in increased oxidation of LDL, thus accelerating atherosclerosis.

Repeated Doses of Ketamine Affect the Infant Rat Urogenital System.

AimLong-term ketamine use is known to create an interstitial cystitis-like problem in the bladder. It is known that long-term intermittent ketamine is applied to the children receiving radiotherapy for sedation. This study was planned to investigate whether this effect seen in the bladder causes similar changes in the kidneys, testicles, epididymis and ductus deferens.Materials and MethodsA total of 12 male Wistar Albino rats for 3 weeks were used in the study. Rats were divided equally into 2 groups as, ketamine and saline. 50 mg/kg ketamine was administered intraperitoneally during 21 days to ketamine (K) groups. 1mL/kg saline was administered intraperitoneally during 21 days to saline (S) groups. At the end of 21 days kidney and testicular tissues were taken for biochemical and histopathological evaluations.ResultsHistological assessment of kidney tissue showed that tubule epithelial congestion increased significantly in the ketamine group. Epididymis congestion and distortion in the epididymal gland were found to be different in the ketamine group when testicular tissue was examined. Thiobarbituric acid reactive substances (TBARS) level in testicular and kidney tissue was found to be significantly higher in the ketamine group according to the saline group. Catalase (CAT) enzyme activity was significantly lower in the ketamine group compared to the saline group in both tissues. Paraoxonase-1 (PON-1) enzyme activity was significantly higher in the ketamine group compared to the saline group.ConclusionWe think that the results we have achieved in this study will provide guidance on ketamine, which is repeated in daily anesthesia applications, especially in radiation oncology. But these findings should be supported by clinical and experimental studies that will be conducted in a more detailed and broad series.

The Relevance of Noncoding DNA Variations of Paraoxonase Gene Cluster in Atherosclerosis-Related Diseases.

The human paraoxonase (PON) gene cluster is comprised of three contiguous genes (PON1, PON2 and PON3) of presumably common origin coding three lactonases of highly similar structure and substrate specificity. The catalytic activity of PON proteins is directed toward artificial organophosphates and in physiological conditions toward thiolactones and oxidized phospholipids. Consequently, PON enzymes are regarded as an effective defense against oxidative stress and, as a result, against atherosclerosis development. Additionally, both PON’s serum activity and its concentration are influenced by several polymorphic variations in coding and noncoding DNA regions of the PON gene cluster remaining in linkage disequilibrium. Hence, the genetic polymorphism of the PON gene cluster may contribute to atherosclerotic process progression or deceleration. In this review the authors analyzed the relevance of noncoding DNA polymorphic variations of PON genes in atherosclerosis-related diseases involving coronary and peripheral artery disease, stroke, diabetes mellitus, dementia and renal disease and concluded that the effect of PON gene cluster’ polymorphism has a considerable impact on the course and outcome in these conditions. The following PON genetic variations may serve as additional predictors of the risk of atherosclerosis in selected populations and individuals.

English

BACKGROUND Coronary artery disease is multifactorial in origin. Coronary artery disease predisposition is attributed to genetic factors also. Many gene polymorphisms are implicated out of which paraoxonase 1 (PON 1) gene is an important one. The product of paraoxonase gene is paraoxonase enzyme which is seen in serum associated with high density lipoprotein (HDL). This enzyme is mainly synthesised by the liver. The protective effect of HDL is attributed to the presence of such enzymes on it. Gln to Arg polymorphism at position 192 confers a risk of developing atherosclerosis and coronary artery disease (CAD). This study is done to assess the genotype distribution of PON 1 gene in CAD patients compared to healthy controls in a population from Kerala. METHODS The case group consists of 100 angiographically proven CAD patients with no history of hypertension, diabetes mellitus, hepatic disease or smoking. The control group had 100 healthy controls from the general population. PON 1 gene was amplified by a polymerase chain reaction (PCR) technique already reported and restriction fragment length polymorphism by the restriction enzyme Alwl was done to assess the polymorphism. to assess the polymorphism. RESULTS In this study, the frequency of heterozygous genotype QR was 86 % in control and 76 % in cases. Though there was no significant difference in allele distribution of Q or R, RR genotype was significantly higher in the case group ( 2 = 8.82; p value = .012). With binary logistic regression model, adjusting for age and sex, RR genotype is independently associated with CHD. Adjusted odds ratio of RR was 5.24 with 95 % confidence interval (CI) 1.41 - 19.47 for developing CHD (p &lt; 0.05). CONCLUSIONS The RR genotype is more frequently seen in CAD patients than in controls. The QR genotype is more frequent than QQ or RR in both cases and controls. KEYWORDS Coronary Artery Disease, Paraoxonase, Gene Polymorphism

Impact of some metal ions on activity of purified human enzyme paraoxonase (hPON1)

Inhibition of enzymes has a great influence on various metabolism activity in the body. The objective of this research has been to assess the impact of some metals and the drug statin on the activity of purified enzyme paraoxonase extracted from human sera (hPON1). The enzyme was purified in consecutive four steps using Ammonium Sulphate, Dialysis, Ion exchange and Gel filtration chromatography, respectively. These four purification steps have approved their credence in obtaining a maximum purification state of the enzyme. The inhibitory impact of some metals ions, i.e. Mg+2, K+1, Mn+2, Na+1, EDTA, and Zn+2, on the activity of purified hPON1 has also been assessed. The result showed the highest inhibitory impact of 10 mMol/L of Sodium Nitrate (NaNO3) on the activity of purified hPON1 while medication atorvastatin had significantly increased the activity of hPON1. It is concluded that any subtle change in the enzyme PON-1 could consequently lead to various diseases. More assessments are required for type two (PON-2) and type three (PON-3) to be explored. Atorvastatin is recommended to regulate cholesterol metabolism by the intestine and to lower the risk of diseases for elder ages.

A Multi-Omics Analysis of PON1 Lactonase Activity in Relation to Human Health and Disease.

Paraoxonase 1 (PON1) enzyme has antioxidative properties and is present in mammalian blood and several other body fluids. In blood, PON1 is usually integrated into the high-density lipoprotein (HDL) cholesterol. PON1 is a highly versatile enzyme displaying diverse functions such as arylesterase, lactonase, and paraoxonase, among others. PON1 activities are usually investigated with artificial substrates, for example, dihydrocoumarin and thiobutyl butyrolactone for lactonase activity. The PON1 enzyme activities measured with different substrates tend to be falsely assumed as being equivalent in the literature, although there are poor or weak correlations among the PON1 enzyme activities with different substrates. In addition, and despite our knowledge of the factors influencing PON1 paraoxonase and arylesterase activities, there is little knowledge of PON1 lactonase activity variations and attendant mechanisms. This is important considering further that the lactonase activity is the native activity of PON1. We report here a multi-omics analysis of PON1 lactonase activity. The influence of genetic variations, particularly of single nucleotide polymorphisms and epigenetic, proteomic, and lipidomic variations on PON1 lactonase activity are reviewed. In addition, the influence of various environmental, clinical, and demographic variables on PON1 lactonase activity is discussed. Finally, we examine the associations between PON1 lactonase activity and health states and common complex diseases such as atherosclerosis, dementias, obesity, and diabetes. To the best of our knowledge, this is the first multi-omics analysis of PON1 lactonase activity with an eye to future applications in basic life sciences and translational medicine and the nuances of critically interpreting PON1 function with lactones as substrates.

Relationship between PON-1 enzymatic activity and risk factors for pesticide poisoning in farmers from the Cienega, Jalisco, Mexico

Paraoxonase-1 (PON-1) is an enzyme that hydrolyzes organophosphate pesticides. The presence of polymorphisms in PON-1 (L55M and Q192R) decreases its enzyme activity and increases the risk of central nervous system (CNS) toxicity in occupationally exposed farmers, leading to chronic degenerative diseases and death. We studied 103 farmers in the region of Cienega Jalisco, Mexico, which were exposed mainly to organophosphate pesticides. We used serum and plasma samples to assay PON-1 activity and perform polymorphism analysis (L55M and Q192R) using qPCR and TaqMan probes, respectively. For both polymorphisms, there was high percentage of heterozygosity (55 LL = 0.19, LM = 0.75, MM = 0.06; 192 QQ = 0.12, QR = 0.72, RR = 0.16), while the allelic frequencies were more balanced (L = 0.56, M = 0.44; Q = 0.48, R = 0.52). There were no significant differences in enzyme activity of L55M polymorphism genotypes (LL = 179.27; LM = 192.11; MM = 122.11; QQ = 135.74; QR = 187.90; RR = 209; p > 0.05). But there was a slight decrease in enzyme activity for the Q192R polymorphism genotypes. The genotype and alcohol consumption associated with slight increases in enzyme activity. However, genotype and tobacco consumption did not have a significant effect on PON-1 activity (µU/mL) (p > 0.05). Overall, alcohol and tobacco consumption affected PON-1 enzyme activity (µU/mL) up to 21.1%. The data obtained in this study reveal that PON-1 activity is affected by genetic variants such as Q192R and alcohol consumption. This may influence the susceptibility of populations to organophosphate poisoning.

Kiwifruit Supplementation Increases the Activity of the Paraoxonase Enzyme and decreases Oxidized Low-Density Lipoprotein in High-Fat Diet Fed Hamsters

Background: It is shown that kiwifruit elevates serum high-density lipoprotein cholesterol (HDL-C) levels and exhibits beneficial effects on human health due to its antioxidant potential. Objectives: This study aimed to investigate the impact of kiwifruit on the activity of the paraoxonase 1 (PON1) enzyme, as a main antioxidant enzyme in HDL functionality, in a high-fat diet (HFD). Methods: To this end, 42 male Syrian hamsters were divided into 6 groups including hamsters receiving a normal diet (the control normal group), a regular diet supplemented with kiwifruit at two concentrations (i.e., 1.86 g/kg and 3.73 g/kg), a HFD comprised of 15% butterfat + 0.05% cholesterol (the control high-fat group), and a HFD supplemented with kiwifruit at two concentrations (i.e., 1.86 and 3.73 g/kg) for 8 weeks. Results: The results showed that supplementation of kiwifruit to the HFD increased the levels of HDL-C and remarkably reduced the concentrations of oxidized low-density lipoprotein (ox-LDL) and malondialdehyde (MDA) compared with the control-HF group. In addition, the paraoxonase activity of PON1 significantly increased in HFD supplemented with kiwifruit (1.86 g/kg), and finally, arylesterase (ARE) activity increased in all treated groups when compared with untreated groups. Conclusion: Our findings suggested that kiwifruit can improve the lipid profile and prevent oxidative stress-induced by lipid peroxidation in hamsters receiving HFD, thus increasing the ARE and paraoxonase activities of PON1.

Paraoxonase Role in Human Neurodegenerative Diseases.

The human body has biological redox systems capable of preventing or mitigating the damage caused by increased oxidative stress throughout life. One of them are the paraoxonase (PON) enzymes. The PONs genetic cluster is made up of three members (PON1, PON2, PON3) that share a structural homology, located adjacent to chromosome seven. The most studied enzyme is PON1, which is associated with high density lipoprotein (HDL), having paraoxonase, arylesterase and lactonase activities. Due to these characteristics, the enzyme PON1 has been associated with the development of neurodegenerative diseases. Here we update the knowledge about the association of PON enzymes and their polymorphisms and the development of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Evaluation of carbonic anhydrase and paraoxonase inhibition activities and molecular docking studies of highly water-soluble sulfonated phthalocyanines.

The investigation of carbonic anhydrase and paraoxonase enzyme inhibition properties of water-soluble zinc and gallium phthalocyanine complexes ( 1 and 2 ) are reported for the first time. The binding of p-sulfonylphenoxy moieties to the phthalocyanine structure favors excellent solubilities in water, as well as providing an inhibition effect on carbonic anhydrase (CA) I and II isoenzymes and paraoxonase (PON1) enzyme. According to biological activity results, both complexes inhibited hCA I, hCA II, and PON1. Whereas 1 and 2 showed moderate hCA I and hCA II (off-target cytosolic isoforms) inhibitory activity (Ki values of 26.09 µM and 43.11 µM for hCA I and 30.95 µM and 33.19 µM for hCA II, respectively), they exhibited strong PON1 (associated with high-density lipoprotein [HDL]) inhibitory activity (Ki values of 0.37 µM and 0.27 µM, respectively). The inhibition kinetics were analyzed by Lineweaver–Burk double reciprocal plots. It revealed that 1 and 2 were noncompetitive inhibitors against PON1, hCA I, and hCA II. These complexes can be more advantageous than other synthetic CA and PON inhibitors due to their water solubility. Docking studies were carried out to examine the interactions between hCA I, hCA II, and PON1 inhibitors and metal complexes at a molecular level and to predict binding energies.

Identification of Protein Carbonyls (PCOs) in Canine Serum by Western Blot Technique and Preliminary Evaluation of PCO Concentration in Dogs With Systemic Inflammation.

In people, serum Protein Carbonyls (PCOs) increase during oxidative stress (OS) due to oxidative damage to proteins. OS is often associated with inflammation and especially with sepsis, a condition hard to diagnose in veterinary medicine because reliable markers are lacking. The aim of this study was to assess whether PCOs in canine serum may be detected by antibody-based methods such as Western Blotting (WB), and to preliminarily investigate the possible utility of this marker in dogs with inflammation. A serum sample oxidized in vitro was used to set up the method; the coefficient of variation obtained by repeated analysis varied from 24 to 36%. In order to assess whether the technique may cover the range of PCOs concentration detectable in routine practice, PCOs were measured in 4 healthy dogs and in 15 with inflammatory diseases, in some cases potentially associated with sepsis, as suggested by the results of other inflammatory markers such as C-Reactive Protein (CRP) and the anti-oxidant enzyme Paraoxonase 1 (PON-1): the concentration of PCOs was low in dogs with normal PON-1 activity, moderately increased in the majority of dogs with low-normal PON-1 activity, and severely increased in dogs with very low PON-1 activity. In conclusion this study demonstrates that PCOs, may be detected in canine serum, using antibody-based techniques such as WB. The preliminary results in dogs with and without systemic inflammation encourage further studies on the possible role of PCOs as inflammatory markers.

Antioxidant paraoxonase 1 activity in children with celiac disease. Impact of gluten free diet

Background and Aims: There is evidence, that celiac disease (CD) could be associated with non-traditional atherogenic risk factors. High density lipoproteins (HDL) constitute the only antiatherogenic fraction, being the inhibition of low density lipoprotein (LDL) oxidation one of its main functions. This capacity depends on different HDL-associated components, such as the antioxidant enzyme paraoxonase (PON1). To assess the relationship between CD and the activity of PON1 in recently diagnosed children compared to healthy controls, and the effect of gluten-free diet (GFD).

Simultaneous Cross-Linking and Cross-Polymerization of Enzyme Responsive Polyethylene Glycol Nanogels in Confined Aqueous Droplets for Reduction of Low-Density Lipoprotein Oxidation.

A key initiating step in atherosclerosis is the accumulation and retention of apolipoprotein B complexing lipoproteins within the artery walls. In this work, we address this exact initiating mechanism of atherosclerosis, which results from the oxidation of low-density lipoproteins (oxLDL) using therapeutic nanogels. We present the development of biocompatible polyethylene glycol (PEG) cross-linked nanogels formed from a single simultaneous cross-linking and co-polymerization step in water without the requirement for an organic solvent, high temperature, or shear stress. The nanogel synthesis also incorporates in situ noncovalent electrostatically driven template polymerization around an innate anti-inflammatory and anti-oxidizing paraoxonase-1 (PON-1) enzyme payload-the release of which is triggered because of matrix metalloproteinase responsive elements instilled in the PEG cross-linker monomer. The results obtained demonstrate the potential of triggered release of the PON-1 enzyme and its efficacy against the production of ox-LDL, and therefore a reduction in macrophage foam cell and reactive oxygen species formation.

519 Poster - Genetic variability of PON1 and NT-proBNP levels after breast cancer radiotherapy

Background: Radiotherapy enables good long-term local control and survival in early breast cancer patients. However, some patients experience acute or late adverse events that may decrease their quality of life. Cardiotoxicity of radiotherapy represents one of the important late adverse events. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is one of the biomarkers for the evaluation of suspected heart failure. Genetic factors can also contribute to the interindividual variability in the occurrence of adverse events. Because radiation leads to increased production of reactive oxygen species and oxidative stress, our aim was to evaluate the association of polymorphisms in antioxidant enzyme paraoxonase 1 (PON1) with NT-proBNP levels after radiotherapy, as a marker of cardiotoxicity in breast cancer patients.

Developmental and social deficits and enhanced sensitivity to prenatal chlorpyrifos in PON1-/- mouse pups and adults.

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12–15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects.