Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated 190 healthy, unrelated and randomly selected, north-west Indian Punjabis (M:102; F:88) for paraoxonase (PON1) polymorphism by dual substrate method and also determined lipid variables i.e., total cholesterol (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and triglycerides (TG) in them to determine any relationship between PON1 activity, PON1 phenotypes and lipids. The basal plasma paraoxonase (PON) activity, and PON activity in presence of 1 Mol NaCl (salt activated paraoxonase i.e., SAP) were estimated by using paraoxon as substrate whereas the, phenyl acetate esterase (A) activity was estimated by using phenylacetate as substrate. Based on the ratio of SAP/A activity, three distinct phenotypes of PON1 could be determined with gene frequencies of PON*A (low activity) and PON*B (high activity) allele being 0.847 and 0.153 respectively. In the whole population on partial correlation after normalising the variables and after adjusting the lipids for age and body mass index (BMI), a significant negative correlation was observed between SAP/A ratio and TC (r = -0.290; P < 0.01) and LDL (r = -0.154; P < 0.05). However, on analysis of covariance (ANCOVA) after normalizing the lipid variables and adjusting these for age and body mass index (BMI), no significant difference could be observed in lipid profile of these three phenotypes. The lack of a significant relationship between lipids and PON1 phenotypes, suggests that PON phenotype does not significantly influence the lipid profile in north-west Indian Punjabis. However, a significant negative correlation between the PON activity and TC and LDL suggests that low PON activity could be a risk factor for atherosclerosis in these subjects.
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PMID:Paraoxonase (PON1) polymorphism & its relation with lipids in north west Indian Punjabis. 1064 1

Homocysteine thiolactone is formed in all cell types studied thus far as a result of editing reactions of some aminoacyl-tRNA synthetases. Because inadvertent reactions of thiolactone with proteins are potentially harmful, the ability to detoxify homocysteine thiolactone is essential for biological integrity. This work shows that a single specific enzyme, present in mammalian but not in avian sera, hydrolyzes thiolactone to homocysteine. Human serum thiolactonase, a 45-kDa protein component of high density lipoprotein, requires calcium for activity and stability and is inhibited by isoleucine and penicillamine. Substrate specificity studies suggest that homocysteine thiolactone is a likely natural substrate of this enzyme. However, thiolactonase also hydrolyzes non-natural substrates, such as phenyl acetate, p-nitrophenyl acetate, and the organophospate paraoxon. N-terminal amino acid sequence of pure thiolactonase is identical with that of human paraoxonase. These and other data indicate that paraoxonase, an organophosphate-detoxifying enzyme whose natural substrate and function remained unknown up to now, is in fact homocysteine thiolactonase. By detoxifying homocysteine thiolactone, the thiolactonase/paraoxonase would protect proteins against homocysteinylation, a potential contributing factor to atherosclerosis.
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PMID:Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation. 1066 May 50

Obesity is an important risk factor of atherosclerosis; however, the mechanism of proatherogenic effect of obesity is not definitely established. Recent studies suggest an important role of leptin in obesity associated complications. We investigated the effect of chronic hyperleptinemia on two antioxidant enzymes contained in plasma lipoproteins: paraoxonase 1 (PON1) and platelet activating factor-acetylhydrolase (PAF-AH). The study was performed on three groups of male Wistar rats: (1) control, fed ad libitum, (2) leptin treated, receiving leptin (0.25 mg/kg twice daily s.c. for 7 days), (3) pair-fed, in which food intake was identical as in leptin-treated animals. PON1 activity toward paraoxon, phenyl acetate, gamma-decanolactone and homogentisic acid lactone was lower in leptin-treated than in control group by 30.4, 30.8, 34.5 and 62%, respectively. Leptin increased plasma concentration and urinary excretion of isoprostanes by 46.4 and 49.2%, respectively. Leptin treatment had no effect on plasma lipid profile and glucose level. Plasma leptin was 208.8% higher in leptin-treated and 51.5% lower in pair-fed than in control group. These data indicate that hyperleptinemia induced by exogenous leptin administration markedly decreases plasma PON1 activity and induces oxidative stress. These mechanisms may be involved in atherogenesis in hyperleptinemic obese individuals.
Atherosclerosis 2003 Sep
PMID:Leptin decreases plasma paraoxonase 1 (PON1) activity and induces oxidative stress: the possible novel mechanism for proatherogenic effect of chronic hyperleptinemia. 1295 79

HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, -107C/T, -162A/G, -824G/A, and -907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, -107C/T, and -907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03). Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma.
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PMID:Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia. 1557 50

Paraoxonase 1 (PON1) is a serum enzyme closely associated with high-density lipoprotein (HDL), which may protect against atherosclerosis by hydrolyzing lipid peroxides and several organophosphorus compounds. The purpose of the present study was to test the hypothesis that lipid peroxidation modifies the activity and protein mass of PON1 in humans and rats. Our findings revealed that the bulk of the activity monitored by the hydrolysis of paraoxon and phenyl acetate was confined to liver intracellular endoplasmic reticulum-derived microsomes and was mostly recovered in circulating HDL3. Confirmation was obtained by the determination of PON1 expression by Western blot. It is noteworthy that PON1 levels were consistently decreased in human sera, HDL, and liver microsomes compared with rat counterparts. Concomitant with iron-ascorbate-mediated lipid peroxidation, there was a decline in PON1 activity and protein in both HDL3 and microsomes, which was attenuated by butylated hydroxytoluene antioxidant treatment. The current data indicate that PON1 localization in microsomes and HDL3 could represent a selective cellular and lipoprotein response to oxidative stress. This was tested by the iron-ascorbate oxygen-radical generating system. It is also proposed that the increased PON1 level may have a function related to the well-known atherosclerosis resistance of rats.
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PMID:Iron-ascorbic acid-induced oxidant stress and its quenching by paraoxonase 1 in HDL and the liver: comparison between humans and rats. 1605 86

Carotid intima media thickness (IMT), represents an important clinical indicator of early atherosclerosis. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme primarily associated with low-density lipoprotein (LDL) while a small proportion of enzymatic activity is also associated with high-density lipoprotein (HDL). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The authors investigated the possible relationship between carotid IMT and the plasma levels of PAF-AH mass and activity as well as the PON1 activity in hyperlipidemic patients. One hundred unrelated patients with primary hyperlipidemia and 67 age-and sex-matched normolipidemic apparently healthy volunteers participated in the study. The PAF-AH activity in total plasma and in HDL-rich plasma (HDL-PAF-AH activity), the plasma PAF-AH mass, and the serum PON1 activities toward paraoxon and phenyl acetate were determined. The plasma PAF-AH mass and activity were higher in hyperlipidemic patients compared to controls, whereas the HDL-PAF-AH activity, as well as the serum PON1 activities were not significantly different between the studied groups. When hyperlipidemic patients were divided into 2 subgroups according to their IMT values (IMT <0.7 mm and IMT > or =0.7 mm) patients with IMT > or =0.7 mm had significantly higher age, and serum triglyceride concentrations, whereas no difference was found in the plasma PAF-AH mass and activity as well as in the HDL-PAF-AH activity between the 2 studied subgroups. The same phenomenon was observed for serum PON1 activities. In a multivariate analysis, only the age was significantly correlated with IMT values (p<0.05). Neither the total plasma PAF-AH mass and activity nor the HDL-PAF-AH activity are associated with early carotid atherosclerosis.
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PMID:Lack of association between carotid intima-media thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia. 1607 29

Low-density lipoproteins (LDLs), when modified by free radicals derived from artery wall cells, induce atherosclerosis. In contrast to oxidized LDL (ox-LDL), high-density lipoproteins (HDLs) are able to prevent atherosclerosis through a protein with antioxidant properties, paraoxonase 1 (PON1). The purpose of this study was to explore the association between the activity of HDL-associated PON1 and circulating ox-LDL as well as to investigate the relationship between ox-LDL and parameters of lipid profile in thirty Slovaks aged 21-73 years because recent studies have presented controversial results concerning PON1 and its role in LDL oxidation. For determination of circulating ox-LDL sandwich ELISA was used and other lipid parameters were determined by routine laboratory analyses. PON1 activities were assayed by two synthetic substrates - paraoxon and phenyl acetate. Lipid peroxides were determined spectrophotometrically. Of the lipid parameters examined, ox-LDL level correlated positively with total (P < 0.0001) and LDL-cholesterol (P < 0.001). Triacylglycerols (TAG) (P < 0.001), lipid peroxides (P < 0.01) and atherogenic index (AI = total cholesterol/HDL) (P < 0.0001) were also strongly correlated with ox-LDL. No inverse relationships were observed between ox-LDL and HDL-cholesterol or arylesterase/paraoxonase activities of PON1. Furthermore, it was found that ox-LDL (P < 0.01) and lipid peroxides (P < 0.05) were significantly higher in men than in women. PON1 arylesterase activity was marginally affected by sex. The results of this study suggest that the anti-atherogenic properties of HDLs are not directly related to their total concentration and that PON1 activity determined towards synthetic compounds (paraoxon and phenyl acetate) reflects no association with markers of oxidative stress. Furthermore, it follows from our results that men are more susceptible to developing atherosclerosis compared to women.
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PMID:Activity of paraoxonase 1 (PON1) and its relationship to markers of lipoprotein oxidation in healthy Slovaks. 1710 15

Excessive lipid peroxidation is a major factor of accelerated atherosclerosis, observed in patients with systemic lupus erythematosus (SLE). We aimed at the present study to determine the paraoxonasel (PON1) and arylesterase activities, and lipid-profile in 37 SLE patients and 30 age-/sex-matched controls. Association was analyzed between PON1 activity and SLEDAI, CRP, anti-oxLDL, and antiphospholipid antibody (aPL) levels, steroid dose, and atherothrombotic events. The age of patients was 40.8 +/- 13.9 year, follow-up time 6.7 +/- 6.2 year, SLEDAI 2 (0-15). PON1 and arylesterase activities were measured spectrophotometrically using paraoxon and phenyl acetate as substrates, respectively. Phenotypic distribution of PON1 was determined by dual substrate method. We measured antioxLDL and aPL levels by ELISA, the CRP by automated immunoassay. PON1 activity (121.9 +/- 65.9 U/mL) was reduced significantly (P < 0.001) in SLE as compared to control (188.1 +/- 78.9 U/mL), but arylesterase activity was not different. A negative correlation was found between PON1 activity and age. PON1 activity did not correlate with other measured parameters. Reduced PON1 activity associated with clinical atherothrombotic complications (P < 0.01). High activity BB phenotype was not present in SLE. Lipid parameters (TC, LDL-C, HDL-C, ApoAI, and ApoB) were within normal range in both groups. Results indicated reduced PON1 activity in lupus patients despite long disease duration and low inflammatory activity, and it was evidenced as a risk for atherosclerotic complications. As the arylesterase activity was normal, further examinations are required to find other mechanisms, such as anti-PON1 antibodies, genetic polymorphisms, and difference in distribution of HDL-subfractions or enzyme abnormalities in HDL remodeling.
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PMID:Reduced paraoxonase1 activity is a risk for atherosclerosis in patients with systemic lupus erythematosus. 1789 73

Non-enzymatic glycosylation (glycation) is a spontaneous set of reactions between reducing sugars and free amino groups in proteins or other biomolecules leading to the formation of fluorescent and coloured compounds known as advanced glycation end products (AGEs). AGEs cause structural changes of key proteins in humans, and therefore they are related with a number of physiological processes and diseases such as aging, atherosclerosis, cataract, arthritis, Alzheimer's disease. Two main strategies have been employed to prevent the formation of AGEs: a) low carbohydrate diet and b) pharmacological intervention. The latter includes treatment with reactive compounds which might be either sugar competitors (type A), carbonyl traps (type B) or free radical trapping antioxidants (type C). Acetylsalicylic acid (ASA, aspirin) is a good example of sugar competitor capable of inhibiting glycation by acetylating epsilon-amino groups of lysine residues in proteins. Taking into consideration the inhibiting effect of ASA on glycation we designed to study the antiglycation activity of other acetyl group-containing compounds (acetamides and acetyl esters) using the lysine-rich protein histone H1 as a model. The glycation of the histone H1 was carried out by either fructose or a complex mixture of glycating agents obtained from E. coli and monitored by fluorescent spectroscopy, SDS-PAGE and measurement of the content of reactive carbonyl groups in the target protein. Our results showed that the inhibitory effect of phenyl acetate, acetanilide, 4-acetamidophenylacetic acid and isopropenyl acetate was comparable to that of ASA. Based on the obtained results we conclude that these compounds act as free radical scavengers protecting proteins from the damaging effect of reactive oxygen species produced during the formation of AGEs.
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PMID:Inhibitory effect of some acetyl esters and acetamides on glycation of the histone H1. 1881 Sep 96

Mammalian paraoxonases (PON1, PON2, PON3) are a unique family of calcium-dependent hydrolases, with enzymatic activities toward a broad range of substrates (lactones, thiolactones, carbonates, esters, phosphotriesters). Although PONs physiological substrates were not yet identified, some studies suggest that they could be some lactones, or some specific oxidized phospholipids, or products of both enzymatic and nonenzymatic oxidation of arachidonic and docosahexaenoic acid, as well as N-acyl-homoserine lactones (which are quorum-sensing signals of pathogenic bacteria). Since no endogenous substrates for PONs activity determination are available yet, synthetic substrates such as paraoxon, phenyl acetate, and several lactones are used for PONs activity assays. All three members of the PON family (PON 1/2/3) were shown to protect from atherosclerosis development. Their anti-atherogenic biological activities were studied in vitro using serum or cell cultures, and also in vivo, using PON 1/2/3 knockout or transgenic mice, as well as humans - healthy volunteers and atherosclerotic patients (diabetics, hypercholesterolemics, and hypertensives).
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PMID:Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases. 1908 53


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