PON

Optical transmission is getting more popular in the access network due to the increasing demand for bandwidth. New services like IP television (IPTV) transmission, video on demand (VoD) etc. over Internet together along high speed Internet access are confronting the demand of higher bandwidth at the customer end in today's Ethernet network backbone. Even though today's well deployed XDSL (i.e., VDSL/VDSL2+, SHDSL) solutions can satisfy bandwidth demand but are limited to the restriction regarding distance.

Human serum paraoxonase (PON1, EC 3.1.8.1.) is a high-density lipid (HDL)-associated, calcium-dependent enzyme; its physiological substrates are not known. In this study, a new purification strategy for human PON1 enzyme was developed using two-step procedures, namely ammonium sulfate precipitation and sepharose-4B-L-tyrosine-1-napthylamine hydrophobic interaction chromatography. SDS-polyacrylamide gel electrophoresis of the enzyme indicates a single band with an apparent MW of 43 kDa. Overall purification rate of our method was found 227fold. The V max and K m of the purified enzyme were determined 227.27 EU and 4.16 mM, respectively. The in vitro effects of commonly used antibiotics, namely gentamycin sulfate and cefazolin sodium was also investigated on the purified human serum PON1 enzyme and human liver PON1 enzyme from human hepatoma cell (HepG2). Gentamycin sulfate and cefazolin sodium caused a dose-and time-dependent decrease on PON1 activity in HepG2 cells. Moreover, gentamycin sulfate and cefazolin sodium were effective inhibitors on purified human serum PON1 activity with IC 50 of 0.887 and 0.0084 values, respectively. The kinetics of interaction of gentamycin sulfate and cefazolin sodium with the purified human serum PON1 indicated a different inhibition pattern. Cefazolin sodium showed a competitive inhibition with K i of 0.012 ± 0.00065 mM. However, Gentamycin sulfate was inhibited in non-competitive manner with K i of 0.026 ± 0.015.

Actualmente, las redes de fibra óptica están en proceso de implementación en todo el mundo ya que poseenventajas frente a las redes tradicionales, entre ellas el aumento de la cobertura y altas velocidades de transmisión; sin embargo, las redes de acceso de fibra óptica para largas distancias son ahora un tema de investigación, debido a que el aumento de las distancias involucra factores limitantes como el de la atenuación y la dispersión, los cuales degradan el rendimiento de la red. En este artículo de investigación se propone el diseño de una red óptica de larga distancia con un enfoque PON (Passive Optical Network) y capacidades multicanal, la cual es reconfigurable por medio de switches ópticos y AWG (Arrayed Waveguide Gratings). Se indican los cálculos realizados, así como el diseño de los nodos de distribución. Finalmente, el sistema es simulado y analizado para determinar la viabilidad de la red.

In accordance to increasing demand of access level bandwidth for services such as high definition video streaming and IP television, service providers are moving to fiber-based solutions such as Passive Optical Network (PON) for last mile deployment. A number of automated methods exist to address the planning of these networks, although these methods make the assumption that each fiber is housed in its own duct in separate trenches. By including the sharing of ducts and therefore trenching cost, a more accurate representation of a real world deployment can be achieved as well as providing better estimates of total deployment cost. In this paper, fiber duct sharing and network constraints are incorporated into a basic Mixed Integer Linear Program (MILP) model through the use of network flow optimization techniques and solved using real world Geographic Information System (GIS) data. Experiments indicate that while increasing computational effort, the inclusion of fiber duct sharing results in a significant reduction in total deployment cost.

Every day, the need for high speed reliable data transmission increases more and more. One important option is the passive optical networks which use the optical fiber and provides high data rates and long distance. This work investigates the performance of a four users Optical Time Division Multiplexing OTDM over different length of single mode fibers SMF for different bit rates. The effect of utilizing Eribium Dopped Fiber amplifiers EDFAs was investigated for mitigating effect of performance degradations due to attenuation. In order to increase capacity of the system, A hybrid four Wavelength Division Multiplexing WDM and four OTDM system was proposed Dispersion Compensating Fiber DCF was used for reducing the effect of dispersion distortion. A post dispersion compensation was applied to a four users OTDM each with bite rate of 10 and 40 Gbps in terms of data capacity per Optical Network Unit ONU. A bit rate of 160 Gbps was obtained from the work with an BER of 10-10 over length of 352.89km. The simulation was implemented using optisystem 7 and matlab R2011a.

Motivations, challenges and requirements of optical layer monitoring in PONs are discussed. An exhaustive
review of monitoring systems is given considering both Time-Division Multiplexed PON (TDM-PON) and
Wavelength-Division Multiplexed PON (WDM-PON) cases.

Many studies support a crucial role for oxidative & nitrosative stress (O&NS) in the pathophysiology of unipolar and bipolar depression. These disorders are characterized inter alia by lowered antioxidant defenses, including: lower levels of zinc, coenzyme Q10, vitamin E and glutathione; increased lipid peroxidation; damage to proteins, DNA and mitochondria; secondary autoimmune responses directed against redox modified nitrosylated proteins and oxidative specific epitopes. This review examines and details a model through which a complex series of environmental factors and biological pathways contribute to increased redox signaling and consequently increased O&NS in mood disorders. This multi-step process highlights the potential for future interventions that encompass a diverse range of environmental and molecular targets in the treatment of depression.

Human microsomes from duodenum and ileum/jejunum were used. The toxic metabolite chlorpyrifos-oxon was the only one formed. 10-fold interindividual variability was observed. Bioactivation was confined in the duodenum, declining toward the distal ileum. Intestinal metabolism could play a role in CPF pre-systemic bioactivation. Available online xxx

A physical layer monitoring scheme for detecting more than one fault in tree-structured PONs (Passive Optical Network) is proposed. The method is based on the use of an OTDR (Optical Time Domain Reflectometer) and of variable reflectors located at the end of the branches.

h i g h l i g h t s • TRAP and PON1, 197 healthy, 91 with unipolar depression and 45 with bipolar disorder. • PON1, male gender, RR genotype and body mass index are inversely correlated with TRAP. • PON1 activity, interactions between PON1 Q192R genotypes and smoking influence TRAP.

Optical transmission is getting more popular in the access network due to the increasing demand for bandwidth. New services like IP television (IPTV) transmission, video on demand (VoD) etc. over Internet together along high speed Internet access are confronting the demand of higher bandwidth at the customer end in today’s Ethernet network backbone. Even though today’s well deployed XDSL (i.e., VDSL/VDSL2+, SHDSL) solutions can satisfy bandwidth demand but are limited to the restriction regarding distance. Hereby, the suitable solution for high bandwidth demand with a long reach can be met by reaching optical cable to customer end directly. One of the possible ways would be to install passive optical network (PON). Gigabit PON (GPON) is the far-most advanced PON solution used by European and US providers while providers in Asia predominantly use EPON/GePON. This GPON is the basic technology to support the structure of the next-generation fiber to the home (FTTH) system. This paper p...

Human serum paraoxonase (PON1) is associated with HDL and inhibits oxidative modification of LDL. PON1 enzymatic activity has been shown to decrease in diabetic patients; however, the effect of PON1 status on long-term outcome has not been reported. In this study, we examined the association between baseline PON1 status and the development of cardiovascular disease (CVD) during 10 years of follow-up in 88 type 2 diabetic patients whose enzymatic activities, concentrations, and genetic polymorphisms of PON1 had been determined. A total of 20 CVD events were recorded during the follow-up period. Using Kaplan-Meier survival curves, we found a significantly increased incidence of CVD in patients with a lower concentration or paraoxonase activity of PON1 than each median value (log-rank 7.460; P \ 0.01, and log-rank 4.187; P \ 0.05, respectively). By Cox regression analysis, both concentration and paraoxonase activity were significantly associated with the development of CVD, even after correction for gender, age, and preexisting CVD (P \ 0.05). Low concentration and enzymatic activity of PON1 may be an independent predictor of cardiovascular events in diabetic patients.

Human longevity is at least partly heritable, and the progeroid syndromes of accelerated aging have genetic causes. In addition, there are human homologues to many of these genes that affect lifespan in model organisms. In people, longevity genes might slow the rate of age-related changes in cells, increase resistance to environmental stresses like infection and injury, and reduce the risk of many age-related conditions. This article reviews several genetic pathways that appear to be involved in the aging process and longevity, including genes involved in the progeroid syndromes, telomeres and telomerase, caloric restriction, stress resistance and oxidative damage, mitochondrial DNA, insulin signaling, and inflammation. It concludes with a discussion of the analytic challenges that face investigators in this area.

Wild-type human butyrylcholinesterase (BuChE) has proven to be an efficient bioscavenger for protection against nerve agent toxicity. Human acetylcholinesterase (AChE) has a similar potential. A limitation to their usefulness is that both cholinesterases (ChEs) react stoichiometrically with organophosphosphorus (OP) esters. Because OPs can be regarded as pseudo-substrates for which the dephosphylation rate constant is almost zero, several strategies have been attempted to promote the dephosphylation reaction. Oxime-mediated reactivation of phosphylated ChEs generates a turnover, but it is too slow to make pseudocatalytic scavengers of pharmacological interest. Alternatively, it was hypothesized that ChEs could be converted into OP hydrolases by using rational site-directed mutagenesis based upon the crystal structure of ChEs. The idea was to introduce a nucleophile into the oxyanion hole, at an appropriate position to promote hydrolysis of the phospho-serine bond via a base catalysis mechanism. Such mutants, if they showed the desired catalytic and pharmacokinetic properties, could be used as catalytic scavengers.

An efficient monitoring method having a very short measurement time (a few seconds) is proposed. The equal-length branches can be effectively monitored, but also the information of temperature at any place in the network can be obtained. The feasibility of this technique is experimentally demonstrated.

Background: Acromegalic patients have increased cardiometabolic risk factors due to an elevation of growth hormone (GH) levels. Human serum paraoxonase (PON), a high-density lipoprotein (HDL)-related enzyme, is one of the major bioscavengers and decreases the oxidation of low-density lipoprotein (LDL), a key regulator in the pathogenesis of atherosclerosis. In this study, we investigated a potential relationship between serum PON levels or PON polymorphisms and acromegaly. Methods: A total of 48 acromegalic patients and 44 healthy controls were included in this study. Serum GH levels, insulin-like growth factor-1 levels and lipid profiles were measured. Serum PON levels, as well as PON 1 L55M and Q192R gene polymorphisms, were examined. Results: No significant differences were found in terms of age, gender, presence of diabetes, serum LDL cholesterol (LDL-C), HDL-C, or triglyceride levels between the case and control groups (P > 0.05). A statistically significant difference was found in serum PON levels between the cases and controls (P = 0.007). The median serum PON level was 101 ± 63.36 U/l in the case group and 63 ± 60.50 U/l in the control group. There was a significant correlation between serum PON levels and IGF-1 levels (P = 0.004, r = 0.319); however, no significant differences were found in PON1 L55M and PON Q192R polymorphisms between the patients and controls (P = 0.607 and P = 0.308, respectively). In addition, no significant differences were found in serum PON levels in acromegalic patients who were and were not in remission (P = 0.385), nor between those with PON1 L55M and Q192R polymorphisms (P = 0.161 and P = 0.336, respectively). Conclusions: Elevated serum PON levels were detected in acromegalic patients, independently of their remission status. This suggests protective effects for cardiometabolic risk parameters.

A two dimensional spectral/spatial cyclic shift (2D-CS) optical code division multiple access (OCDMA) systems is proposed for a potentially next generation passive optical network (NG-PON) implementation called (2D-CS NG-OCDMA-PON) system. The2D-CS proposed code is characterized by a high capacity and a zero cross correlation property leads to completely eliminating the multiple access interference (MAI) effect that is considered as the main OCDMA system drawback. Firstly, the 2D-CScode construction is investigated from 1D-CS code. Secondly, a system description is provided by exhibiting the transmitter and receiver architecture in the PON context. Analytical analysis reveals that our proposed 2D-CScode outperforms similar codes such as perfect difference (2D-PD) and dynamic cyclic shift (2D-DCS) codes in terms of spectral efficiency, simultaneous network subscribers and data bit rate. In addition, based on numerical analysis 2D-CS NG-OCDMA-PON system shows a good system performance by means of avery low BER and a high Qfactor values equal to10 −26 and 10.41 dB, respectively. Likewise, for four users and free-amplification the achievable reach ability distance of the NG-OCDMA-PON system is 63.21 km, 43.57 km and 33.2 km while Q-factor is equal to 6 dB at a bit rate of 622Mb/s, 1Gb/s and 1.5 Gb/s, respectively. On the other side, according to the system setup the number of single mode fiber (SMF) is reduced to the half compared to other 2D-OCDMA-PON systems based on enhanced multi diagonal (EMD) and single weight ZCC (SWZCC) codes.

A two dimensional spectral/spatial cyclic shift (2D-CS) optical code division multiple
access (OCDMA) systems is proposed for a potentially next generation passive optical
network (NG-PON) implementation called (2D-CS NG-OCDMA-PON) system. The2DCS proposed code is characterized by a high capacity and a zero cross correlation property leads to completely eliminating the multiple access interference (MAI) effect that is considered as the main OCDMA system drawback. Firstly, the 2D-CScode construction is investigated from 1D-CS code. Secondly, a system description is provided by exhibiting the transmitter and receiver architecture in the PON context. Analytical analysis reveals that our proposed 2D-CScode outperforms similar codes such as perfect difference (2DPD) and dynamic cyclic shift (2D-DCS) codes in terms of spectral efficiency, simultaneous network subscribers and data bit rate. In addition, based on numerical analysis 2D-CS NG-OCDMA-PON system shows a good system performance by means of avery low BER and a high Q-factor values equal to 10−26 and 10.41 dB, respectively. Likewise, for four users and free-amplification the achievable reach ability distance of the NG-OCDMA-PON system is 63.21 km, 43.57 km and 33.2 km while Q-factor is equal to 6 dB at a bit rate of 622 Mb/s, 1 Gb/s and 1.5 Gb/s, respectively. On the other side, according to the system setup the number of single mode fiber (SMF) is reduced to the half compared to other 2D-OCDMA-PON systems based on enhanced multi diagonal (EMD) and single weight ZCC (SWZCC) codes.

Atorvastatin δ-lactone, a major, pharmacologically inactive metabolite, has been associated with toxicity. In a previous study we showed that polymorphisms of UGT1A3 influence atorvastatin δ-lactone formation. Here we investigated the reverse reaction, atorvastatin δ-lactone hydrolysis, in a human liver bank. Screening of microarray data revealed paraoxonases PON1 and PON3 among 17 candidate esterases. Microsomal δ-lactone hydrolysis was significantly correlated to PON1 and PON3 protein (r s = 0.60; r s = 0.62, respectively; P < 0.0001). PON1 and PON3 were strongly correlated to each other (r s = 0.60) but PON1 was shown to be more extensively glycosylated than PON3. In addition a novel splicevariant of PON3 was identified. Genotyping of 40 polymorphisms within the PON-locus identified PON1 promoter polymorphisms (−108T > C, −832G > A, −1741G > A) and a tightly linked group of PON3 polymorphisms (−4984A > G, −4105G > A, −1091A > G, −746C >T, and F21F) to be associated with changes in atorvastatin δ-lactone hydrolysis and expression of PON1 but not PON3. However, carriers of the common PON1 polymorphisms L55M or Q192R showed no difference in δ-lactone hydrolysis or PON expression. Haplotype analysis revealed decreased δ-lactone hydrolysis in carriers of the most common haplotype *1 compared to carriers of haplotypes *2, *3, *4, and *7. Analysis of non-genetic factors showed association of hepatocellular and cholangiocellular carcinoma with decreased PON1 and PON3 expression, respectively. Increased C-reactive protein and γ-glutamyl transferase levels were associated with decreased protein expression of both enzymes, and increased bilirubin levels, cholestasis, and presurgical exposure to omeprazole or pantoprazole were related to decreased PON3 protein. In conclusion, PON-locus polymorphisms affect PON1 expression whereas non-genetic factors have an effect on PON1 and PON3 expression. This may influence response to therapy or adverse events in statin treatment.

An efficient monitoring method having a very short measurement time (a few seconds) is proposed. The equal-length branches can be effectively monitored, but also the information of temperature at any place in the network
can be obtained. The feasibility of this technique is experimentally demonstrated.

A number of new nitric oxide (NO)-precursors were synthesized by grafting nitrate-containing moieties on the structures of the benzyloxy isonipecotanilide derivatives 1 and 2 already reported as moderately potent antiplatelet agents. Various nitrooxy (ONO2)-alkyl side chains were covalently linked to the piperidine nitrogen of the parent compounds through carbamate and amide linkage, and the synthesis of a benzyl nitrate analog (15) of compound 1 was also achieved. The in vitro vasodilatory activities, as well as platelet anti-aggregatory effects, of the newly synthesized organic nitrates were assessed. The (ONO2)methyl carbamate-based derivative 5a and the benzyl nitrate analog 15, which on the other hand retain activity as inhibitors of ADP-induced platelet aggregation, exhibited strong NO-mediated vasodilatory effects on pre-contracted rat aorta strips, with EC50 values in the low nanomolar range (13 and 29nM, respectively). Experiments carried out with the selectively inhibited ...

Human microsomes from duodenum and ileum/jejunum were used. The toxic metabolite chlorpyrifos-oxon was the only one formed. 10-fold interindividual variability was observed. Bioactivation was confined in the duodenum, declining toward the distal ileum. Intestinal metabolism could play a role in CPF pre-systemic bioactivation.

Objective: Epidemiological and experimental studies indicate that kidney disease is associated with increased oxidative stress. Our aim was to determine whether paraoxonase 1 (PON1) activity is altered in patients with moderately decreased glomerular filtration rates (GFRs) compared to healthy controls. Material and methods: Forty-eight patients showing relatively low GFRs upon renal scintigraphy with 99m Tc-DTPA were compared to 40 age-matched healthy subjects. Serum PON1 activity was measured spectrophotometrically. Lipid hydroperoxide levels were measured via iodometric assay. Results: The mean ages of the patient and control groups were 32.09 ± 6.10 (range 23-50) and 31.30 ± 5.30 (range 20-46) years, respectively. Serum PON1 (p = 0.949) and high-density lipoprotein (p = 0.473) levels did not differ between groups. Significant differences were detected between groups in terms of mean triglyceride (p = 0.009), very-low-density lipoprotein (p = 0.010), lipid hydroperoxide (p = 0.026), urea (p = 0.012), and creatinine (p = 0.001) levels, whereas total cholesterol (p = 0.520) and low-density lipoprotein (p = 0.161) were similar between groups. Mean GFR was significantly lower in the low GFR group compared to the control (p = 0.000). Conclusion: Our results indicate that PON1 activity and high-density lipoprotein levels may not be determining factors in premature vascular aging in patients with moderately decreased GFRs. Instead, some other undetermined factor(s) may be involved in modulating enzymatic activity.

Diabetes Mellitus (DM) is a multisystemic disorder with serious complications and these patients may also have serious problems with their oral cavity probably because of the microangiopathic and neuropathic complications. In diabetic patients, there may be several problems of the oral cavity such as gingivitis, periodontitis, candidiasis, glossitis, oral ulcerations, loss of taste sensations, opportunistic infections and several other conditions dependent on these. One of the recent theories about complications in DM is the contribution of reactive oxygen radicals. Paraoxonase (PON1) is an enzyme that is synthesized in liver and having the capability of hydrolasing the active metabolite of an insectisid, parathion. Previously it was shown that there are two polymorphic areas on the PON1 gene: one causing a Leu --&gt; Met substitution at 55th position, the other causing Gln --&gt; Arg at the 192nd position. We investigated the differences in PON activities related to the oral lesion...

High-density lipoprotein-associated paraoxonase 1 (PON1) enzyme can retard the oxidation of lipids. The methionine for leucine substitution at position 55 (M/L55) of the PON1 protein is associated with lower (MM genotype) or higher (ML or LL genotype) expression of the gene affecting serum level of PON1. We studied the association of the PON1 M/L55 genotype with the extent of atherosclerosis in an autopsy series of Finnish males. Areas of the coronary arteries and the aorta covered with fatty streaks and fibrotic and complicated lesions were measured from a total of 700 cases. Carriers of the MM genotype (14.4% of subjects) had larger percentual areas of fatty streaks in their left anterior descending coronary artery (P = 0.014) and right coronary artery (P = 0.004), as well as in thoracic (P < 0.001) and abdominal aorta (P = 0.010) compared to carriers of the LL or ML genotype. A PON1 genotype-by-smoking interaction was observed on the area of fatty streaks in left anterior descending coronary artery (P = 0.011) and right coronary artery (P = 0.005); the association between fatty streaks and MM genotype was evident only among non-smokers, whereas in smokers this association was abolished. The areas of more advanced atherosclerotic lesions did not vary significantly between the genotype groups. These data suggest that the genetic variation of PON1 affects the formation of early atherosclerotic lesions and that the effect is modified by smoking.

h i g h l i g h t s • TRAP and PON1, 197 healthy, 91 with unipolar depression and 45 with bipolar disorder. • PON1, male gender, RR genotype and body mass index are inversely correlated with TRAP. • PON1 activity, interactions between PON1 Q192R genotypes and smoking influence TRAP.

En el presente estudio se determinó la actividad y fenotipos de Paraoxonasa-1 (PON1) en 89 estudiantes universitarios de Lima-Perú, debido a que estudios previos reportan que el polimorfismo 192 Q/R de PON1, afecta el metabolismo de diversos insecticidas organofosforados (OPs) y de ciertas drogas; así como, su rol protector contra el desarrollo de la aterosclerosis. Se encontró que la actividad media de PON1 en la población estudiada fue 167.01 ± 60.84 U /L. Los fenotipos AA, AB Y BB de la actividad PON1 presentaron las frecuencias de 0.236, 0.573 Y 0.191 respectivamente. La actividad de PON1 en la población estudiada sigue una distribución unimodal y existe un predominio de los heterocigotos AB sobre los homocigotos AA y BB. El conocimiento de la actividad y los fenotipos de PON1 en esta población ayudaría a identificar individuos susceptibles a la toxicidad por organofosforados y/o con mayor riesgo a desarrollar aterosclerosis y predecir que individuos no responderán favorablement...

a b s t r a c t Paraoxonase 1 (PON1) protects the oxidative modification of low-density lipoprotein (LDL) and is a major anti-atherosclerotic protein component of high-density lipoprotein (HDL). Quercetin, a ubiquitous plant flavonoid, has been shown to have a number of bioactivities and may offer a variety of potential thera-25 peutic uses. We explored the roles of quercetin in the regulation of PON1 expression, serum and liver 26 activity and protective capacity of HDL against LDL oxidation in rats. Compared to the pair-fed control 27 group, feeding quercetin (10 mg/L) in the liquid diet for 4 weeks increased (a) hepatic expression of 28 PON1 by 35% (p < 0.01), (b) serum and liver PON1 activities by 29% (p < 0.05) and 57% (p < 0.01), respec-29 tively, and (c) serum homocysteine thiolactonase (HCTL) activity by 23% (p < 0.05). Correspondingly, the 30 lag time of low-density lipoprotein (LDL) oxidation was increased by >3-fold (p < 0.001) with plasma HDL 31 from quercetin-fed group compared to the HDL from control group. Our data suggest that quercetin has 32 antiatherogenic effect by up regulating PON1 gene expression and its protective capacity against LDL 33 oxidation. 34 Ó 2009 Published by Elsevier Inc. 35 36 37 The paraoxonase 1 (PON1) is a calcium-dependent ester hydro-38 lase tightly associated with high-density lipoprotein (HDL) parti-39 cles [1,2]. Experimental evidences have shown that PON1 40 functions as an antioxidative enzyme that inhibits the oxidation 41 of low-density lipoprotein (LDL) [3-5], which prevents the devel-42 opment of atherosclerosis [6,7]. It also hydrolyses thiolactone to 43 homocysteine, which alters the proteins in the arterial wall [8]. 44 PON1 knock-out mice are more susceptible to atherosclerosis than 45 wild-type littermates and clinical studies have linked PON1 to the 46 prevention of cardiovascular disease [9,10]. 47 Even though the PON1 gene polymorphism may play certain 48 roles in the development of coronary artery disease (CAD) [11-49 13], its phenotypic expression is more closely related to CAD 50 [14]. It is known that PON1 inhibits cholesterol biosynthesis [15] 51 and stimulates HDL-mediated cholesterol efflux from macrophages 52 [3,16-18] thus preventing CAD development. Therefore, it is more 53 important to investigate possible dietary supplements that could 54 influence PON1 activity and/or its expression. Quercetin, an ubiq-55 uitous flavonoid present in all fruits and vegetables, has been 56 shown to have free radical-scavenging property and to reduce 57 low-density lipoprotein (LDL) oxidation [19,20], and thus may ben-58 efit with respect to cardiovascular disease (CVD) and certain can-59 cers [21]. In this communication, we demonstrate that dietary 60 quercetin significantly up regulates PON1 expression, activity and 61 its HCTL activity and significantly increases protective capacity of 62 HDL against LDL oxidation. 63 Materials and methods 64 Animal feeding. Male Wistar rats weighing between 130 and 65 150 g. were purchased from Charles River Laboratories, Inc. (Wil-66 mington, MA). The rats were housed in groups of 2 per cage in plas-67 tic cages (40 Â 24 Â 18 cm), in a temperature-controlled room at 68 25°C with 12-h light: dark cycles. All rats were fed a pelleted com-69 mercial diet (Purina Rodent Chow, #500, TMI Nutrition, St. Louis, 70 MO) for 1 week after arrival. They were then randomly divided into 71 2 groups (6 animals/group) and pair-fed the control Lieber-DeCarli 72 liquid diet [22] or quercetin liquid diet for 4 weeks. The concentra-73 tion of quercetin used in the diet was 10 mg/liter, which was iso-74 energetic to control Lieber-DeCarli diet. At the end of the 75 experimental period, all the animals in each group were exangui-76 nated via abdominal aorta under pentobarbital anesthesia 77 (50 mg/kg, ip), and the blood serum and livers were saved for fur-78 ther analyses as described below: 79 Protein extracts from liver. Livers from control and quercetin-fed 80 rats were harvested and washed three times with ice-cold phos-81 phate-buffered saline (PBS). The tissues were then homogenized 0006-291X/$ -see front matter Ó

Objectives: Paraoxonase-1 (PON1) deficiency is related to increased susceptibility to low density lipoprotein oxidation and development of atherosclerosis. The aim of this study was to investigate paraoxonase and arylesterase activities along with oxidative status parameters, and to find out if there is any increased susceptibility to atherogenesis, which might be reflected with increased oxidative stress and decreased serum PON1 activity in beta-thalassemia minor (BTM) subjects.

The Brazil nut (Bertholletia excelsa) of the Amazon region is consumed worldwide. It is rich in both monounsaturated fatty acids and polyunsaturated fatty acids and is known for its high selenium content. This study tested the hypothesis whether the consumption of this nut could affect the plasma lipids and apolipoproteins and some functional properties of the antiatherogenic high-density lipoprotein (HDL). Fifteen normolipidemic subjects aged 27.3 ± 3.9 years and with body mass index of 23.8 ± 2.8 kg/m 2 consumed 45 g of Brazil nuts per day during a 15-day period. On days 0 and 15, blood was collected for biochemical analysis, determination of HDL particle size, paraoxonase 1 activity, and lipid transfer from a lipoprotein-like nanoparticle to the HDL fraction. Brazil nut ingestion did not alter HDL, low-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I, or apolipoprotein B concentrations. HDL particle diameter and the activity of antioxidative paraoxonase 1, mostly found in the HDL fraction, were also unaffected. Supplementation increased the reception of cholesteryl esters (P b .05) by the HDL yet did not alter the reception of phospholipids, free cholesterol, or triacylglycerols. As expected, plasma selenium was significantly increased. However, the consumption of Brazil nuts for short duration by normolipidemic subjects in comparable amounts to those tested for other nuts did not alter serum lipid profile. The only alteration in HDL function was the increase in cholesteryl ester transfer. This latter finding may be beneficial because it would improve the nonatherogenic reverse cholesterol transport pathway.

Purpose: Major depressive disorder (MDD) is a devastating disease that afflicts large populations and has also been accepted to be an independent risk factor for cardiovascular disease (CVD). Oxidative stress seems to play an essential role in the relationship of MDD and CVD. We aimed to determine the level of oxidative stress in patients with MDD and to investigate the effects of long-term antidepressant (AD) treatment on the oxidativeantioxidative system parameters and CVD risk factors. Method: Fifty patients who fully met the fourth Diagnostic and Statistical Manual of Mental Disorders criteria for MDD and 44 healthy control subjects were included in the study. Control visits of the patients were repeated 6 weeks, 12 weeks and 24 weeks after beginning of the AD treatment. Lipid profiles, oxidation and oxidizability of apolipoprotein B-containing lipoproteins (expressed as apo B-b-MDA and apo B-Δ-MDA, respectively), levels of plasma malondialdehyde (p-MDA), total antioxidative capacity (TAOC), antioxidant molecules and antioxidant enzyme activities including paraoxonase/arylesterase, red blood cell superoxide dismutase (RBC-SOD) and glutathione peroxidase were determined during 24-week of follow-up period. Results: According to the results of the study, p-MDA, apo B-b-MDA and RBC-SOD activity were increased and arylesterase activity was decreased in MDD patients. Body mass index (BMI), vitamin A and total cholesterol levels in MDD patients increased after 24-weeks of AD treatment. RBC-SOD activity, TAOC, p-MDA and apo B-b-MDA levels were decreased; paraoxonase/arylesterase activities and apo B-Δ-MDA were increased at the end of 24th week. Conclusion: Oxidative stress, demonstrated in MDD patients, was partly improved during 24 weeks of AD treatment. Increase in paraoxonase/arylesterase activities and decrease in p-MDA and apo B-b-MDA levels after 24 weeks seem to be beneficial for reduction of CVD risk in MDD patients. However increased BMI and apo B-Δ-MDA levels are negative cardiovascular effects of long-term AD treatment.

Objectives: Paraoxonase-1 (PON1) deficiency is related to increased susceptibility to low density lipoprotein oxidation and development of atherosclerosis. The aim of this study was to investigate paraoxonase and arylesterase activities along with oxidative status parameters, and to find out if there is any increased susceptibility to atherogenesis, which might be reflected with increased oxidative stress and decreased serum PON1 activity in beta-thalassemia minor (BTM) subjects.

The effect of several metal ions and calcium on purified paraoxonases (PON1 and PON3) from rat liver was studied. PON1 and PON3 were also inhibited by EDTA and both enzyme activities were restored by the addition of free calcium. The reactivation by calcium was a time-dependent effect for PON1; however, this was not the case for PON3. We also studied the response of PON1 and PON3 to several inhibitors: Co, Cu, Mn, Hg and p-hydroxymercurybenzoate (pOHMB), and determined the type of inhibition and the inhibition constants. Among all the compounds tested, mercurials (Hg and pOHMB) were the most potent inhibitors of PON1. For PON3 mercurials and copper showed the highest inhibitory potency. Purified PON3 also showed different inhibition patterns as compared to PON1. A comparison of PON1 and PON3 shows qualitative and quantitative differences in the sensitivity against the inhibitors tested, showing major differences in the case of cobalt, copper and pOHMB, which may be related to structural differences of both PONs. These results increase our knowledge of the biochemical properties of PON1 and PON3 and may help in the understanding of their physiological role as a potential detoxification mechanism against environmental metal ions.

Because systemic vasculitis (SV) predisposes to atherosclerosis, and high-density lipoprotein (HDL) prevents atherosclerosis by "reverse cholesterol transport" and by inhibiting low-density lipoprotein (LDL) oxidation thanks to apolipoprotein A-I (Apo-AI) and paraoxonase 1 (PON1), we assessed whether LDL oxidation was increased in SV and associated with less PON1 activity. Methods: The sera of 33 patients with active SV (ASV), 32 in full remission of SV (RSV) and 20 healthy subjects (HS) were analyzed for C-reactive protein (CRP), high-sensitivity-CRP, lipids, lipoproteins, apolipoproteins, PON1 activity, LDL-immune complexes (LDL-IC), and autoantibodies to oxidized-LDL (ox-LDL), and anticardiolipin antibodies. Results: CRP was higher in ASV than RSV and HS, and negatively correlated with HDL-cholesterol and Apo-AI. Autoantibodies to ox-LDL and highly oxidized malondialdehyde-LDL were higher in RSV than ASV and HS (P Ͻ 0.05). LDL-IC titers were higher in ASV than RSV and HS (P Ͻ 0.05). PON1 activity was lower in ASV and RSV than HS (P ϭ 0.02). A trend toward a negative correlation between basal PON1 activity and anti-MDA-LDL antibodies (P ϭ 0.06) was observed. Conclusion: Inflammatory markers in SV were associated with a modified lipoprotein profile, which could lower PON1 activity and contribute to increased ox-LDL titers and accelerated atherosclerosis development.

Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37±2.15 vs. 6.24±1.37 tail% DNA, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Further, the workers with CYP2D6*3PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes…

Organophosphate pesticides (OPs) are primarily metabolized by several xenobiotic metabolizing enzymes (XMEs). Very few studies have explored genetic polymorphisms of XMEs and their association with DNA damage in pesticide-exposed workers. The present study was designed to determine the role of genetic polymorphisms of CYP1A1, CYP3A5, CYP2C9, CYP2D6, and PON1 in the modulation of DNA damage in workers occupationally exposed to OPs. We examined 284 subjects including 150 workers occupationally exposed to OPs and 134 normal healthy controls. The DNA damage was evaluated using the alkaline comet assay and genotyping was done using PCR-RFLP. The results revealed that the PONase activity toward paraoxonase and AChE activity was found significantly lowered in workers as compared to control subjects (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Workers showed significantly higher DNA damage compared to control subjects (14.37±2.15 vs. 6.24±1.37 tail% DNA, p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Further, the workers with CYP2D6*3PM and PON1 (QQ and MM) genotypes were found to have significantly higher DNA damage when compared to other genotypes…

The origins of enzyme specificity are well established. However, the molecular details underlying the ability of a single active site to promiscuously bind different substrates and catalyze different reactions remain largely unknown. To better understand the molecular basis of enzyme promiscuity, we studied the mammalian serum paraoxonase 1 (PON1) whose native substrates are lipophilic lactones. We describe the crystal structures of PON1 at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 structures and the analysis of active-site mutants guided the generation of docking models of the various substrates and their reaction intermediates. The models suggest that promiscuity is driven by coincidental overlaps between the reactive intermediate for the native lactonase reaction and the ground and/or intermediate states of the promiscuous reactions. This overlap is also enabled by different active-site conformations: the lactonase activity utilizes one active-site conformation whereas the promiscuous phosphotriesterase activity utilizes another. The hydrolysis of phosphotriesters, and of the aromatic lactone dihydrocoumarin, is also driven by an alternative catalytic mode that uses only a subset of the active-site residues utilized for lactone hydrolysis. Indeed, PON1's active site shows a remarkable level of networking and versatility whereby multiple residues share the same task and individual active-site residues perform multiple tasks (e.g., binding the catalytic calcium and activating the hydrolytic water). Overall, the coexistence of multiple conformations and alternative catalytic modes within the same active site underlines PON1's promiscuity and evolutionary potential.

Paraoxonases were originally discovered as enzymes hydrolyzing exogenous toxic organophosphate compounds such as insecticide paraoxon. There are three members of paraoxonases family currently known: Paraoxonase 1 (PON1), Paraoxonase 2 (PON2), and Paraoxonase 3 (PON3), which are encoded by three separate genes on the same chromosome 7 (human) or chromosome 6 (mouse). PON1 protein consists of 354 amino acids with molecular mass 43 kDa. [1] All three human members of the family are 70% identical at nucleotide level and 60% identical at the amino acid level. [2] Studies on enzymatic activity of paraoxonases revealed esterase and lactonase/lactonizing activities in addition to organophosphatase activity. [3,4] Despite of the large number of compounds that can be hydrolyzed by paraoxonase, the biologically relevant substrates are still not determined for certain. In many cases arylesterase activity is measured to access PON1 level in biological samples. Based on kinetic parameters of paraoxonases toward different substrates, it is assumed that lactones are the likely physiological substrates. [4] Hydrolysis of homocysteine thiolactone by PON1 is considered to be protective against coronary artery disease (CAD). [5] After the introduction of the oxidative stress hypothesis of atherosclerosis and the discovery of antioxidant effect of high-density lipoprotein (HDL), [6,7] PON1 attracted significant interest as a protein that is responsible for the most of antioxidant properties of HDL. [8] Purified PON1 protects HDL and low-density lipoprotein (LDL) from oxidation catalyzed by copper ions. [9,10] PON1 inhibits copper-induced HDL oxidation by prolonging oxidation lag phase, and reduces peroxide and aldehyde content in oxidized HDL. Remarkably, PON1 inhibitors

Hypercholesterolemia is characterized with changes in lipid profile, nitric oxide pathway and oxidative stress markers. This study is designed to evaluate the effects of hypercholesterolemic diet and atorvastatin therapy on oxidative stress, lipid peroxide and thiobarbituric acid reactive substances (TBARS), NO pathway markers, nitric oxide(NO) and asymmetric dimethylarginine (ADMA), homocysteine, and paraoxonase activity (PON1) in rabbits. Twenty rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into 2 groups on the fourth week of the hypercholesterolemic diet. First group was fed with high-cholesterol diet alone, whereas the second group with the same cholesterol diet plus atorvastatin (0.3 mg/kg/day) for 4 weeks. High-cholesterol diet increased total cholesterol, low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), ADMA, TBARS and lipid peroxide levels and reduced PON1 activity and NO levels in rabbits. Four weeks of atorvastatin therapy signi...

The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21 -q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81 -2.06) while M-allele carriers had a HR of 1.76 (1.17 -2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM + PON2 311 CC, had HR of 3.54 (1.81 -6.93) compared to PON1 LL + PON2 SS/SC men (interaction P = 0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis. D

The Brazil nut (Bertholletia excelsa) of the Amazon region is consumed worldwide. It is rich in both monounsaturated fatty acids and polyunsaturated fatty acids and is known for its high selenium content. This study tested the hypothesis whether the consumption of this nut could affect the plasma lipids and apolipoproteins and some functional properties of the antiatherogenic high-density lipoprotein (HDL). Fifteen normolipidemic subjects aged 27.3 ± 3.9 years and with body mass index of 23.8 ± 2.8 kg/m 2 consumed 45 g of Brazil nuts per day during a 15-day period. On days 0 and 15, blood was collected for biochemical analysis, determination of HDL particle size, paraoxonase 1 activity, and lipid transfer from a lipoprotein-like nanoparticle to the HDL fraction. Brazil nut ingestion did not alter HDL, low-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A-I, or apolipoprotein B concentrations. HDL particle diameter and the activity of antioxidative paraoxonase 1, mostly found in the HDL fraction, were also unaffected. Supplementation increased the reception of cholesteryl esters (P b .05) by the HDL yet did not alter the reception of phospholipids, free cholesterol, or triacylglycerols. As expected, plasma selenium was significantly increased. However, the consumption of Brazil nuts for short duration by normolipidemic subjects in comparable amounts to those tested for other nuts did not alter serum lipid profile. The only alteration in HDL function was the increase in cholesteryl ester transfer. This latter finding may be beneficial because it would improve the nonatherogenic reverse cholesterol transport pathway.

Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120fold. Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Thus, we stress that interest for hPON1 must not fade away, and in particular, the 3D structure of the hPON1 eventually in complex with OP has to be solved.

Because systemic vasculitis (SV) predisposes to atherosclerosis, and high-density lipoprotein (HDL) prevents atherosclerosis by "reverse cholesterol transport" and by inhibiting low-density lipoprotein (LDL) oxidation thanks to apolipoprotein A-I (Apo-AI) and paraoxonase 1 (PON1), we assessed whether LDL oxidation was increased in SV and associated with less PON1 activity. Methods: The sera of 33 patients with active SV (ASV), 32 in full remission of SV (RSV) and 20 healthy subjects (HS) were analyzed for C-reactive protein (CRP), high-sensitivity-CRP, lipids, lipoproteins, apolipoproteins, PON1 activity, LDL-immune complexes (LDL-IC), and autoantibodies to oxidized-LDL (ox-LDL), and anticardiolipin antibodies. Results: CRP was higher in ASV than RSV and HS, and negatively correlated with HDL-cholesterol and Apo-AI. Autoantibodies to ox-LDL and highly oxidized malondialdehyde-LDL were higher in RSV than ASV and HS (P Ͻ 0.05). LDL-IC titers were higher in ASV than RSV and HS (P Ͻ 0.05). PON1 activity was lower in ASV and RSV than HS (P ϭ 0.02). A trend toward a negative correlation between basal PON1 activity and anti-MDA-LDL antibodies (P ϭ 0.06) was observed. Conclusion: Inflammatory markers in SV were associated with a modified lipoprotein profile, which could lower PON1 activity and contribute to increased ox-LDL titers and accelerated atherosclerosis development.