Plasma Paraoxonase Activity Research Articles

The protective effect of caffeic acid phenethyl ester on cadmium-induced liver toxicity: A histopathological and biochemical study

In this study, the changes caused by caffeic acid phenethyl ester (CAPE) in the histopathological and biochemical parameters in the oxidant / antioxidant balance in mice with experimental cadmium toxicity were investigated. A total of 40 female Swiss albino mice were used, with 10 mice in each group. The mice were divided into four groups (Group I - Control group, Group II - CAPE group, Group III - Cadmium group, Group IV - Cadmium + CAPE group). Plasma paraoxonase (PON) activity, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total sialic acid (TSA), total antioxidant capacity (TAC), total oxidant capacity (TOC), and oxidative stress index (OSI) were analyzed on mice’s blood samples. The results showed that cadmium intoxication triggered oxidative stress in the mice. It also lowered their PON activity alongside TAC and HDL levels (P<0.001, P<0.01, and P<0.01, respectively) and increased their TSA, LDL, TOC, and OSI levels (P<0.05, P<0.01, P<0.01, and P<0.01, respectively). The histopathological examination of the liver tissues revealed focal apoptotic regions, sinusoidal occlusion, and irregularity in the cadmium group and no significant change in the other groups. These results indicated that CAPE can significantly prevent biochemical and histopathological changes due to cadmium damage.

Plasma paraoxonase-1 activity levels in patients with type 2 diabetes mellitus in Lagos State University Teaching Hospital, Lagos, Southwest Nigeria: a cross-sectional study.

paraoxonase 1 (PON1) is a high-density lipoprotein (HDL) associated enzyme that has anti-inflammatory, anti-atherogenic, and antioxidant functions. PON1 is noted to be a determinant of resistance to the development of atherosclerosis through hydrolysis of phospholipid and cholesteryl ester hydroperoxides. This study was designed to assess PON1 activity levels among patients with type 2 diabetes mellitus (T2DM) in Southwest Nigeria. this was a cross-sectional study done over a period of six months. A total of 138 participants; 69 with T2DM and 69 apparently healthy controls were recruited for this study. Fasting plasma glucose (FPG), HDL cholesterol (HDL-c), and PON1 activity were analyzed in the participants. The comparison of the mean between the groups of participants was assessed using the independent student t-test while the Mann-Whitney U test was used to compare two medians. The p-value was set at 0.05. mean age for participants with T2DM was 54.90 ± 8.1 years and the healthy control group was 54.12 ± 8.4 years, with a p-value of 0.549. The male-to-female ratio was 0.47 for both participants with T2DM and healthy controls. Participants with T2DM had significantly higher median glucose concentration of 109.18 mg/dl compared with 82.58 mg/dl among controls, p-value <0.001. Median serum HDL-c was lower in diabetics compared to controls (52.66 mg/dl vs 57.92 mg/dl; p-value < 0.001). PON1 activity was lower in T2DM compared with that of the controls (690.11 pmol/min/ml vs 3379.7 pmol/min/ml; p-value <0.001). Paroxonase 1 showed a non-significant positive correlation with HDL-c and a negative correlation with FPG, and body mass index (BMI). these findings suggest that PON1 activity is lower in T2DM compared to healthy controls and a lower PON1 activity level was seen among female diabetics compared with the male diabetics.

Paraoxonase 1 Ameliorates Renal Lipotoxicity by Activating Lipophagy and Inhibiting Pyroptosis

Several studies in recent years have shown that lipid overload causes lipotoxic damage to the kidney, and oxidative stress, inflammation, and autophagic arrest are all important mechanisms of renal lipotoxicity. However, effective measures with therapeutic effects on renal lipotoxicity are limited. The present study indicated the protective effect of the paraoxonase 1 (PON1) against renal lipotoxicity in high-fat diet-fed scavenger receptor class B type I-deficient (SR-BI-/-) mice. The results showed that SR-BI-/- mice exhibited significant renal pathologic characteristics, such as oxidative stress, inflammation, and fibrosis, under a normal chow diet, and were accompanied by dyslipidemia and reduced plasma PON1 activity and renal PON1 levels. PON1 overexpression significantly attenuated the above pathologic changes in the kidneys of SR-BI-/- mice fed with a high-fat diet. Mechanistically, PON1 may ameliorate renal oxidative stress by reducing reactive oxygen species production, reduce renal lipid accumulation by inhibiting AKT/mechanistic target of rapamycin kinase pathway to activate lipophagy, and reduce the occurrence of inflammation and cell death by inhibiting Nod-like receptor family protein 3 inflammasome-mediated pyroptosis. The present study is the first to show that PON1 overexpression can effectively alleviate renal lipotoxicity injury, and PON1 may be a promising therapeutic strategy for the treatment of renal lipotoxicity-related diseases.

Effects of combined physical exercise on plasma lipid variables, paraoxonase 1 activity, and inflammation parameters in adults with obesity: a randomized clinical trial.

We aimed to investigate whether combined physical exercise mayaffect plasma lipid variables, paraoxonase 1 (PON1) activity, and inflammation parameters in adults with obesity. Thirty-six participants were recruited to complete the study protocol. The mean age was 37 ± 1years, and the baseline body mass index was 33.0 ± 0.4kg/m2. Participants were allocated to the control group (CG) and the exercise group (EG). The EG performed three weekly sessions of combined physical exercise for 16weeks. Plasma lipid variables, PON1 activity, and inflammatory profile were determined before and after intervention. Total cholesterol levels decreased in both groups, without intergroup difference (time p = 0.001). Non-high-density lipoprotein cholesterol (HDL-C) levels decreased in both groups (time p = 0.001); however, they were lower in the EG than in the CG (p = 0.038). The EG had increased HDL-C levels, but the CG had decreased HDL-C levels (time*group p = 0.011). PON1 activity was reduced in both groups (time, p = 0.001). The Castelli risk Index I and II reduced in the EG and increased in the CG (time*group, p = 0.008 and p = 0.011, respectively). The inflammatory markers were not modified. Adults with obesity may benefit from regular practice of combined physical exercise training in many metabolic aspects that are related to protection against the development of cardiovascular disease.

Protective effect of astaxanthin on experimental ovarian damage in rats.

This study aimed to investigate the protective effect of astaxanthin (AS) on 3-nitropropionic acid (3-NPA) induced experimental ovarian damage in rats. Thirty two female Wistar rats were divided into four equal groups of eight each: control group (C); phosphate-buffered saline, AS group; AS (80 mg/kg) for 14 days, 3-NPA group; 3-NPA (6.25 mg/kg) twice a day for 7 days, 3-NPA + AS group; administered AS (80 mg/kg) for 14 days and 3-NPA (6.25 mg/kg) for 7 days. All injections were administered intraperitoneally. Rats were fed ad libitum with standard rat chow and tap water. Plasma and ovarian tissue total antioxidant capacity (TAC), total oxidant capacity (TOC) and oxidative stress index (OSI) levels, whole blood reduced glutathione (GSH), plasma paraoxonase 1 (PON1) activity, lipid profile, malondialdehyde (MDA), nitric oxide (NO), total sialic acid (TSA) and total thiol (TT) concentrations were analysed spectrophotometrically. Also, ovarian tissue histopathology was performed. We observed 3-NPA-induced histopathological ovarian damagesignificantly decreased the TAC (p < 0.001), GSH (p < 0.001), high-density lipoprotein (p < 0.01) levels and PON1 activity (p < 0.01), and significantly increased TOC, OSI (p < 0.001), MDA, NO, TSA, cholesterol, low-density lipoprotein (p < 0.01) and triglyceride (p < 0.05) levels. In conclusion, cotreatment with AS restored the negative effect of 3-NPA on all biochemical parameters cited above and improved the histopathological ovarian damage. Ovarian toxicity induced by 3-NPA might be due to oxidative damage. The improvement of AS seems to be related to its antioxidant properties.

Hepatic paraoxonase 1 ameliorates dysfunctional high-density lipoprotein and atherosclerosis in scavenger receptor class B type I deficient mice.

BackgroundHigh-density lipoprotein (HDL) plays an antiatherogenic role by mediating reverse cholesterol transport (RCT), antioxidation, anti-inflammation, and endothelial cell protection. Recently, series of evidence have shown that HDL can also convert to proatherogenic HDL under certain circumstances. Plasma paraoxonase 1 (PON1) as an HDL-bound esterase, is responsible for most of the antioxidant properties of HDL. However, whether PON1 can serve as a therapeutic target of dysfunctional HDL-related atherosclerosis remains unclear.MethodsIn this study, scavenger receptor class B type I deficient (Scarb1−/−) mice were used as the animal model with dysfunctional HDL and increased atherosclerotic susceptibility. Hepatic PON1 overexpression and secretion into circulation were achieved by lentivirus injection through the tail vein. We monitored plasma lipids levels and lipoprotein profiles in Scarb1−/− mice, and measured the levels and activities of proteins associated with HDL function. Meanwhile, lipid deposition in the liver and atherosclerotic lesions was quantified. Hepatic genes relevant to HDL metabolism and inflammation were analyzed.ResultsThe results showed the relative levels of PON1 in liver and plasma were increased by 1.1-fold and 1.6-fold, respectively, and mean plasma PON1 activity was increased by 63%. High-level PON1 increased the antioxidative and anti-inflammatory properties, promoted HDL maturation and macrophage cholesterol efflux through increasing HDL functional proteins components apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and lecithin-cholesterol acyltransferase (LCAT), while decreased inflammatory protein markers, such as serum amyloid A (SAA), apolipoprotein A4 (APOA4) and alpha 1 antitrypsin (A1AT). Furthermore, hepatic PON1 overexpression linked the effects of antioxidation and anti-inflammation with HDL metabolism regulation mainly through up-regulating liver X receptor alpha (LXRα) and its downstream genes. The pleiotropic effects involved promoting HDL biogenesis by raising the level of APOA1, increasing cholesterol uptake by the liver through the APOE-low density lipoprotein receptor (LDLR) pathway, and increasing cholesterol excretion into the bile, thereby reducing hepatic steatosis and aorta atherosclerosis in Western diet-fed mice.ConclusionsOur study reveals that high-level PON1 improved dysfunctional HDL and alleviated the development of atherosclerosis in Scarb1−/− mice. It is suggested that PON1 represents a promising target of HDL-based therapeutic strategy for HDL-related atherosclerotic cardiovascular disease.

Influence of phospholipase A2 and paraoxonase activity on endothelial function changes in various forms of coronary artery disease

Abstract Funding Acknowledgements Type of funding sources: None. High phospholipase A2 activity is associated with atherosclerotic disorders of the arteries, while paraoxonase activity decreases with increasing atherogenic plasma activity. The purpose is to study the relationship between the combined effect of phospholipase A2 and paraoxonase activity on vascular endothelial dysfunction in various forms of coronary artery disease. We examined 152 men 52.5 ± 0.8 years, including 53 - STEMI, 32 - NSTEMI, 67 - chronic chronic coronary syndromes (CCS). Methods. All patients were examined for endothelial function of the brachial artery with a test for reactive hyperemia and vasodilation with exogenous NO, as well as determination of phospholipase A2 activity and plasma paraoxonase activity. All studiies conform to the principles of the Declaration of Helsinki of the World Medical Association. Results. Dynamics evaluation of endothelial function indicates a significant increase in blood flow in the brachial artery after compression in the NSTEMI group, but a decrease in the STEMI group after vasodilation of exogenous NO. Analysis of phospholipase A2 activity and paraoxonase showed an increasing the first in STEMI group compared to NSTEMI one and CCS while decreasing the second in the corresponding groups (Tab. 1). The results of the study confirm the association of increased activity of phospholipase A2 with vascular disorders severity, the correction of which should be considered a priority in prospective studies. The fact of reducing the activity of paraoxonase should be considered in the correction treatment of vascular disorders. Tab. 1 CCS NSTEMI STEMI LSD criteria D% 7,48 ± 0,39 6,65 ± 0,54 6,77 ± 0,62 {1-2} V% 54,71 ± 1,01 51,13 ± 1,92 42,16 ± 3,29 p1 &amp;lt; 0,0001 p2 = 0,010 {3} / {1, 2} D% (NO) 10,35 ± 0,47 8,24 ± 0,96 10,28 ± 0,98 {1, 2} V% (NO) 55,60 ± 1,12 37,71 ± 3,72 p1 &amp;lt; 0,0001 28,12 ± 3,94 p1 &amp;lt; 0,0001 {1} / {2, 3} sPA2 1,12 ± 0,03 1,25 ± 0,04 p1 &amp;lt; 0,0001 1,34 ± 0,04 p1 &amp;lt; 0,0001 {1} / {2, 3} PAO 0,54 ± 0,01 0,50 ± 0,01 0,44 ± 0,01 p1 &amp;lt; 0,0001 p2 &amp;lt; 0,0001 {1} / {2,3} D% - diameter of brachial artery after compression. V% - blood flow velocity after compression. sPA2 -phospholipase A2. PAO - paraoxanase. p - reliability on Sheffe"s criteria.

Chronic nandrolone decanoate administration effects on antioxidant parameters in Wistar rats

Chronic nandrolone decanoate exposure is associated with a modified redox status in the favor of oxidants. Paraoxonase and myeloperoxidase activities are considered sensitive biomarkers of oxidative stress and inflammation, being also predictors for coronary artery disease. The aim of our study was to investigate the impact of chronic nandrolone administration on paraoxonase and myeloperoxidase activities in Wistar rats. 16 Wistar rats were divided into two groups (n=8 for each of them): nandrolone decanoate (A) treated group and control group (C). After 12 weeks of nandrolone decanoate administration we analyzed several plasma oxidative stress parameters: TROLOX Equivalent Antioxidant Activity, paraoxonase and myeloperoxidase activities, total thiols, and advanced oxidation protein products. Our results showed a significant decreased total antioxidant activity in nandrolone treated group compared with controls, while paraoxonase activity and total thiols levels were significantly increased. Myeloperoxidase activity and advanced oxidation protein products were not significantly different between the two studied groups. In conclusion decreased plasma total antioxidant activity suggested increased oxidative stress induced by chronic high doses of nandrolone. Despite oxidative stress presence high doses of nandrolone induced also increased plasma paraoxonase activity.

Paraoxonase-1 (PON1) Status Analysis Using Non-Organophosphate Substrates.

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme with antioxidant, anti-inflammatory, and antiapoptotic roles. The ability of PON1 to hydrolyze specific organophosphate (OP) compounds and prevent accumulation of oxidized lipids in lipoproteins has prompted a large number of studies investigating PON1's role in modulating toxicity and disease. Most of these studies, however, have only focused on PON1 single nucleotide polymorphism analyses and have ignored PON1 activity levels, arguably the most important parameter in determining protection against exposure and disease. We developed a two-substrate activity assay termed "PON1 status" that reveals both the functional PON1192 genotype and plasma PON1 activity levels. While our previous studies with PON1 status demonstrated that both PON1192 functional genotype and enzymatic activity levels obtained exclusively by determining PON1 status are required for a proper evaluation of PON1's role in modulating OP exposures and risk of disease, the original PON1 status assay requires the use of highly toxic OP metabolites. As many laboratories are not prepared to handle such toxic compounds and the associated waste generated, determination of PON1 status has been limited to rather few studies. Here, we describe a PON1 status protocol that uses non-OP substrates with a resolution equivalent to that of the original PON1 status approach. We have also included useful suggestions to ensure the assays can easily be carried out in any laboratory. The protocols described here will enable a proper examination of the risk of exposure or susceptibility to disease in PON1 epidemiological studies without the need to handle highly toxic substrates. © 2021 Wiley Periodicals LLC. Basic Protocol: Determining PON1 status using non-organophosphate substrates Support Protocol 1: Experimental pathlength determination Support Protocol 2: PON1 DNA genotyping for the Q192R (rs662) polymorphism.

Paraoxonase-1 enzyme activity in rheumatoid arthritis patients: association with carotid intima-media thickness?

Objectives The aim was to find the relationship of biochemical determinants of paraoxonase-1 (PON1) enzyme activity with carotid intima-media thickness (IMT) as a surrogate marker of atherosclerotic cardiovascular (CV) disease risk in patients with rheumatoid arthritis (RA). Background There is strong correlation between patients with RA and CV morbidity and mortality that cannot be explained by traditional risk factors alone. And this could be due to abnormal function of high-density lipoproteins (HDL). HDL promotes cholesterol efflux, as well as protects low-density lipoprotein (LDL) against oxidation, and this ability has been referred to as an 'anti-inflammatory' function because the lipid oxidation products derived from LDL are highly proinflammatory. PON1 is an HDL-associated enzyme that promotes antioxidant and anti-inflammatory properties of HDL by preventing the formation of oxidized LDL and inactivating oxidized phospholipids. Patients and methods The authors conducted a case–control study, including 30 RA patients and 20 controls, enrolled in Menoufia, Egypt. B-mode Doppler ultrasound imaging to measure carotid IMT, C-reactive protein (CRP), erythrocyte sedimentation rate, lipid profile, and PON1 activity were measured. Results RA patients tended to be more dyslipidemic as evidenced by decreased HDL and increased total cholesterol, tryglycerides (TGD), and LDL, which showed increased carotid IMT and decreased PON1 activity than the control group. Patients with carotid plaque tended to be more dyslipidemic and plasma PON1 activity tended to be lower than in patients without carotid plaque. A significant correlation between plasma PON1 activity and systemic inflammation as measured by the erythrocyte sedimentation rate and hsCRP level was noted. Conclusion Our data suggest that the lower the activity of PON1, the higher the atherosclerotic CV disease risk in RA patients, as assessed by the presence of carotid plaque. There is a significant correlation between plasma PON1 activity and systemic inflammation in RA patients. Higher hsCRP levels were associated with lower PON1 activity.

Plasma paraoxonase1 activity in rats treated with monocrotophos: a study of the effect of duration of exposure.

We have earlier demonstrated the potential of monocrotophos (MCP), a highly toxic organophosphorus insecticide (OPI), to elicit insulin resistance in rats after chronic exposure. Given the understanding of role of paraoxonase1 (PON1) in OPI toxicity and diabetes pathology, this study was envisaged to understand the effect of duration of exposure to MCP on plasma PON1 activity in rats. Rats were administered MCP per os at 1/20 and 1/10th LD50 as daily doses for 180 days. Interim blood samples were collected at 15, 30, 45, 90 and 180 d for analysis of plasma parameters. Exposure to MCP for 45 resulted in persistent trend of hyperinsulinemia, while significant increase in fasting glucose levels was observed after 180 days. MCP caused suppression of plasma cholinesterase activity though the study period, albeit extent of inhibition was more severe during the early phase of the study. Exposure to MCP for 180 d resulted in hypertriglyceridemia and marginal decrease in HDL-C levels. MCP failed to modulate PON1 activity in plasma during the early phase of the study (up to 45 d). However, prolonged exposure resulted in significant increase in the plasma PON1 activity. This suggests that manifestation of insulin resistance in rats subjected to chronic exposure to MCP is associated with increase in PON1 activity. Our work provides rationale for studying whether the increase in PON1 activity observed in the present study serves to counter the deleterious effect of long term exposure to organophosphorus insecticides on metabolic homeostasis.

Polymorphisms in the anti-oxidant paraoxonase-1 (PON1) gene associated with fertility of postpartum dairy cows

Paraoxonase 1 (PON1) is a negative acute phase plasma protein synthesized by the liver that has anti-oxidant activity. The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the PON1 promoter region with plasma PON1 activity and fertility in Holstein dairy cows. Sixty-eighty Holstein cows were used in this initial investigative study. Blood samples were collected weekly beginning 28 days prior to expected calving, twice weekly in week 1 and 2 postpartum, and then once weekly through 6 weeks postpartum for plasma PON1 activity analysis. Cows were synchronized for ovulation and timed AI at 63–70 DIM using an Ovsynch program. Pregnancy diagnosis was confirmed by rectal palpation and reproductive performance data was recorded until 210 DIM. DNA was extracted from blood of each cow and a fragment of proximal PON1 gene promoter was sequenced. Seven single nucleotide polymorphisms (SNPs) were identified in the promoter region of the PON1 gene at positions −22, −105, −176, −221, −392, −611 and −676, six of which were significantly associated with plasma PON1 activity level. The SNPs −221 and −392 were significantly associated with both plasma PON1 activity and the calving to conception interval (P < 0.05) with no significant effect on calving to first ovulation interval. In conclusion, the genotypes associated with higher plasma PON1 activity in SNP locations −221 and −392 were also associated with a reduced calving to conception interval in this study set of cows. These SNPs may provide novel genetic markers for improved fertility in future larger studies in dairy cows.

Abstract 16673: Exposure to Ambient Polycyclic Aromatic Hydrocarbons Results in Lipoxygenase Activation and Decreased Paraoxonase-1 Activity

Introduction: There is cumulative evidence in support of causal associations between exposure to air pollution, atherosclerosis and cardiovascular mortality. However, the mechanisms for responsible for those associations are not known. Animal studies have found that exposure to ambient particulate matter (PM) promotes lipoprotein oxidation, together with decreased paraoxonase 1 (PON-1) activity, and activation of 5- and 12/15-lipoxygenase pathways but evidence on human subjects is lacking. Hypothesis: Exposure to polycyclic aromatic hydrocarbon (PAHs), a group of airborne chemicals originated from combustion sources highly prevalent in ambient PM, inhibit PON-1 activity and induce oxidative stress. Methods: We recruited 26 healthy non-smoking young adults traveling from Los Angeles to Beijing in summer. Paired urine and plasma samples were collected before (LA 1 ), during (BJ) and after (LA 2 ) the travel. Urinary monohydroxylated metabolites of five PAHs (i.e. naphthalene, dibenzofuran, fluorene, phenanthrene and pyrene) were measured as indicators of PAHs exposure. We also assessed plasma levels of PON-1 enzymatic activities, 5-, 12- and 15- hydroxyeicosatetraenoic (HETE) acids as well as 9- and 13-hydroxyoctadecadienoic acid (HODE) acids, which are oxidative products of polyunsaturated arachidonic and linoleic acid. Data was analyzed by a mixed-effect model with random intercepts. Results: Four out of five PAHs metabolites (all except for naphthalene) were elevated by 1.6-9.0 folds ( p &lt;0.001) in BJ as compared with levels in LA 1 or LA 2 indicating increased exposure to PAHs in BJ. On the contrary, there was a significant decrease in plasma paraoxonase and arylesterase activities ( p&lt; 0.05) without changes in plasma PON-1 concentration, indicating functional alteration of PON-1. There was also a significant increase in plasma levels of all HETEs and HODEs ( p&lt; 0.05) indicating elevated oxidative stress. The increase in 5-, 12- and 15-HETEs observed in BJ remained statistically significant after normalization by arachidonic acid ( p&lt; 0.05), indicating activation of 5 and 12/15 lipoxygenases. In addition, there were strong associations ( p &lt;0.05) between changes in all PAHs (except naphthalene), with HETEs, HODEs and changes in PON-1-associated paraoxonase and arylesterase enzymatic activities, after adjusting city’s effects. Conclusion: PM promotes atherosclerosis likely by its high content in PAHs, and their concomitant pro-oxidative effects resulting in activation of lipoxygenases and inhibition of PON-1 activity.

32 - Hypobromous acid and loss of cardio-protective paraoxonase-1 activity from human plasma

Paraoxonase-1 (PON1) is a cardio-protective enzyme associated with plasma high-density lipoprotein (HDL). In this study we investigated effects of HOBr, a pro-inflammatory mediator, on plasma PON1 activity. In initial studies, HOBr or HOCl was added to 5-fold diluted human plasma and PON1 phosphotriesterase activity was assayed. Consistent with prior reports, addition of HOCl (2000 uM) to plasma caused loss of PON1 activity, which declined to 71 ± 3 % normal (P 0.05). In conclusion, our results demonstrate HOBr and brominated amines, such as taurine may be important mediators of PON1 activity during inflammation. Supported by Midwestern University.

Sympathomimetic Effects of Acute E-Cigarette Use: Role of Nicotine and Non-Nicotine Constituents.

BackgroundChronic electronic (e) cigarette users have increased resting cardiac sympathetic nerve activity and increased susceptibility to oxidative stress. The purpose of the present study is to determine the role of nicotine versus non‐nicotine constituents in e‐cigarette emissions in causing these pathologies in otherwise healthy humans.Methods and ResultsThirty‐three healthy volunteers who were not current e‐cigarette or tobacco cigarette smokers were studied. On different days, each participant used an e‐cigarette with nicotine, an e‐cigarette without nicotine, or a sham control. Cardiac sympathetic nerve activity was determined by heart rate variability, and susceptibility to oxidative stress was determined by plasma paraoxonase activity. Following exposure to the e‐cigarette with nicotine, but not to the e‐cigarette without nicotine or the sham control, there was a significant and marked shift in cardiac sympathovagal balance towards sympathetic predominance. The decrease in high‐frequency component and the increases in the low‐frequency component and the low‐frequency to high‐frequency ratio were significantly greater following exposure to the e‐cigarette with nicotine compared with exposure to the e‐cigarette without nicotine or to sham control. Oxidative stress, as estimated by plasma paraoxonase, did not increase following any of the 3 exposures.ConclusionsThe acute sympathomimetic effect of e‐cigarettes is attributable to the inhaled nicotine, not to non‐nicotine constituents in e‐cigarette aerosol, recapitulating the same heart rate variability pattern associated with increased cardiac risk in multiple populations with and without known cardiac disease. Evidence of oxidative stress, as estimated by plasma paraoxonase activity, was not uncovered following acute e‐cigarette exposure.

Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport.

This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport.

Mercury, eicosapentanoic acid and docosahexaenoic acid demonstrate limited effect on plasma paraoxonase-1 activity and blood pressure among avid seafood consumers in the Long Island Study of Seafood Consumption, NY, USA.

Moderate fish consumption is recommended for prevention of coronary heart disease (CHD) as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have known beneficial effects on risk factors such as reducing blood pressure (BP) and increasing paraoxonase-1 (PON-1) activity. However concomitant methylmercury (MeHg) exposure from fish consumption may mitigate these benefits and the net effect on BP and PON-1 activity has not been extensively studied in western populations consuming diverse seafood types. We studied the correlation between EPA, DHA and Hg levels with BP and PON-1 activity in a population of avid seafood consumers. Two hundred and eighty-eight avid seafood consumers from Long Island, NY had blood samples drawn for total blood mercury (THg), plasma EPA and DHA levels, and plasma PON-1 activity. Average systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were measured. Subjects' mean EPA+DHA was 4.9% total fatty acids, mean THg was 7.6mcg/L. Mean SBP was 122.5mmHg, mean DBP 70.3mmHg, mean PP 52.2mmHg and mean PON-1 activity 421.2U/L. THg was not associated with any of the BP measures in adjusted linear regression models; EPA+DHA was significantly inversely associated with PP (p=0.02). THg was associated with a significant increase in PON-1 activity (p=0.04), while EPA+DHA was associated with a significant decrease in PON-1 activity (p=0.007); although the size of the effects was small. Our findings suggest blood THg and serum DHA+EPA levels have limited relationship to BP and PON-1 activity, and may not be important modulators of these known CHD risk factors in this population of avid seafood consumers.

Strawberries Added to the Usual Diet Suppress Fasting Plasma Paraoxonase Activity and Have a Weak Transient Decreasing Effect on Cholesterol Levels in Healthy Nonobese Subjects

Objective: Strawberries can improve oxidants–antioxidants balance and reduce some cardiovascular risk factors in obese subjects. Paraoxonase-1 (PON-1) is a high-density lipoprotein–associated enzyme with antioxidant properties that can protect from coronary artery disease in humans. We examined the effect of strawberry consumption on plasma PON-1 activity and lipid profile in healthy nonobese subjects.Methods: Thirty-one subjects (body mass index [BMI] 24.4 ± 4.0 kg/m2) on their usual diet consumed 500 g of strawberry pulp daily for 30 days (first course) and after a 10-day washout the cycle was repeated (second course). Fasting blood and spot morning urine samples were collected before, during, and after each strawberry course (8 time points) for determination of paraoxonase and arylesterase PON-1 activities and lipid profile. Twenty subjects served as controls with respect to cholesterol and PON-1 activities changes over the study period.Results: Strawberries decreased mean plasma paraoxonase PON-1 activity and this effect was more evident after the second course (by 11.6%, p < 0.05) than after the first course (5.4%, p = 0.06), whereas arylesterase activity was constant. Strawberries altered total cholesterol levels (p < 0.05) with a tendency to transiently decrease it (by 5.1%) only after 15 days of the first course. Triglycerides and high- and low-density lipoprotein cholesterol did not change in response to fruit consumption. No changes in PON-1 activities and lipid profile were noted in controls. Paraoxonase correlated with arylesterase activity (ƿ from 0.33 to 0.46 at the first 7 time points, p < 0.05). This association disappeared at the end of study (ƿ = 0.07) when the strongest inhibition of paraoxonase was noted.Conclusions: Supplementation of the usual diet with strawberries decreased paraoxonase PON-1 activity and did not improve lipid profiles in healthy nonobese subjects. Further studies are necessary to establish the clinical significance of paraoxonase suppression and to define a group of healthy subjects who can benefit from strawberry consumption with respect to cholesterol levels.

Correlation of Paraoxonase Status with Disease Activity Score and Systemic Inflammation in Rheumatoid Arthritic Patients.

Despite, various preventive efforts on conventional cardiovascular disease (CVD) risk factors, the incidence of CVD in rheumatoid arthritis (RA) patients increases continuously. To solve this conundrum one needs more investigations. The present study was conducted to evaluate the plasma paraoxonase (PON) activity along with the markers of systemic inflammation, oxidative stress and disease activity score-28 (DAS28) in RA patients and clarify their role in determining the probability of RA patients to develop future CVD risk. Plasma PON, total antioxidant activity (TAA), C-reactive protein (CRP), synovial interleukin-6 (IL-6) and erythrocyte malondialdehyde (MDA) levels were estimated in 40 RA patients aged 40-55 years aged and 40 age-matched healthy controls. The data obtained were compared statistically by using Student's t-test and Pearson correlation test. Besides dyslipidaemia, marked reduction in plasma PON and TAA (p< 0.05) were observed in RA patients as compared with that of healthy controls. Erythrocyte MDA, plasma CRP and synovial IL-6 levels were increased significantly (p<0.05) in RA patients. PON was negatively correlated with MDA (r = - 0.672; p < 0.001), CRP (r = -0.458; p<0.05), IL-6 (r = -0.426; p<0.05) and DAS28 (r = -0.598; p < 0.001), and positively correlated with HDL cholesterol (r = 0.648; p<0.001) and TAA (r = 0.608; p< 0.001) levels in RA patients. Alteration in PON activity might contribute to the progression of future CVD risk in RA patients, which may result from interplay of several confounding factors, such as inflammation, oxidative stress and dyslipidaemia. Furthermore, plasma PON activity, CRP and TAA levels could be considered as non-traditional factors to predict CVD risk. Thus, it is suggested that future drugs could be developed to target the non-traditional risk factors in RA patients.

PEP-1-MsrA ameliorates inflammation and reduces atherosclerosis in apolipoprotein E deficient mice

BackgroundMethionine sulfoxide reductase A (MsrA) is a potent intracellular oxidoreductase and serves as an essential factor that protects cells against oxidative damage. However, therapeutic use of exogenous MsrA in oxidative stress-induced diseases is limited, because it cannot enter the cells. The aim of this study is to investigate whether MsrA with PEP-1, a cell penetrating peptide, fused to its N-terminus can protect against oxidative stress in macrophages and can attenuate atherosclerosis in apolipoprotein E deficient (apoE−/−) mice.MethodsMsrA and the fusion protein PEP-1-MsrA were expressed and purified using a pET28a expression system. Transduction of the fusion protein into macrophages was confirmed by Western blot and immunofluorescence staining. Intracellular reactive oxygen species (ROS) and apoptosis levels were measured by flow cytometry. In in vivo study, MsrA or PEP-1-MsrA proteins were intraperitoneally injected into apoE−/− mice fed a Western diet for 12 weeks. Plasma lipids levels, inflammatory gene expression, and paraoxonase-1 (PON1) and superoxide dismutase (SOD) activities were assessed. Atherosclerotic lesions were analyzed by Oil Red O staining and immunohistochemistry.ResultsPEP-1-MsrA could penetrate the cells and significantly reduced intracellular ROS levels and apoptosis in H2O2-treated macrophages. It also decreased TNFα and IL-1β mRNA levels and increased the IL-10 mRNA level in lipopolysaccharide-treated macrophages. In in vivo study, PEP-1-MsrA injection significantly increased plasma PON1 and SOD activities and decreased plasma monocyte chemoattractant protein 1 (MCP-1) level compared to the injection of vehicle control or MsrA. In PEP-1-MsrA injected mice, hepatic PON1 levels were increased, while the expression of TNFα and IL-6 mRNA in the liver was suppressed. Although plasma total cholesterol and triglyceride levels did not change, the aortic atherosclerosis in PEP-1-MsrA treated mice was significantly reduced. This was accompanied by a reduction of total and apoptotic macrophages in the lesions.ConclusionOur study provides evidence that PEP-1-MsrA may be a potential therapeutic agent for atherosclerosis-related cardiovascular diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0677-8) contains supplementary material, which is available to authorized users.