Gene/Protein Disease Symptom Drug Enzyme Compound
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Organophosphates (OPs) are routinely used as pesticides in agriculture and as insecticides within the household. Our prior work on Reelin and APOE delineated a gene-environment interactive model of autism pathogenesis, whereby genetically vulnerable individuals prenatally exposed to OPs during critical periods in neurodevelopment could undergo altered neuronal migration, resulting in an autistic syndrome. Since household use of OPs is far greater in the USA than in Italy, this model was predicted to hold validity in North America, but not in Europe. Here, we indirectly test this hypothesis by assessing linkage/association between autism and variants of the paraoxonase gene (PON1) encoding paraoxonase, the enzyme responsible for OP detoxification. Three functional single nucleotide polymorphisms, PON1 C-108T, L55M, and Q192R, were assessed in 177 Italian and 107 Caucasian-American complete trios with primary autistic probands. As predicted, Caucasian-American and not Italian families display a significant association between autism and PON1 variants less active in vitro on the OP diazinon (R192), according to case-control contrasts (Q192R: chi2=6.33, 1 df, P<0.025), transmission/disequilibrium tests (Q192R: TDT chi2=5.26, 1 df, P<0.025), family-based association tests (Q192R and L55M: FBAT Z=2.291 and 2.435 respectively, P<0.025), and haplotype-based association tests (L55/R192: HBAT Z=2.430, P<0.025). These results are consistent with our model and provide further support for the hypothesis that concurrent genetic vulnerability and environmental OP exposure may possibly contribute to autism pathogenesis in a sizable subgroup of North American individuals.
Mol Psychiatry 2005 Nov
PMID:Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. 1602 37

Vitamin E and probucol are well-known antioxidants that prevent cells from the oxidative stress, which is a risk factor of atherosclerosis. Male rabbits were fed either 0.03% vitamin E or 0.05% probucol in a 0.5% high-cholesterol (HC) diet for 8 weeks. Vitamin E and probucol significantly suppressed an increase in plasma total-cholesterol (total-C) and low-density lipoprotein cholesterol compared to HC-control group. However, plasma high-density lipoprotein-cholesterol (HDL-C) and HDL-C/total-C ratio levels and plasma paraoxonase activity were only significantly higher in vitamin E group after 8 weeks. Hepatic ACAT activity was significantly lower in both vitamin E and probucol groups than in HC-control group, while HMG-CoA reductase activity was the highest only in the probucol group. Total fecal sterol content was significantly higher in probucol and vitamin E groups than in the two control groups. Some atherogenic signs were discovered in the aortic fatty streak of HC-control group, yet not in other groups. Hepatic mRNA expressions of apo B-100 and apo C-III were significantly lower in probucol group than in other groups. Vitamin E supplementation was found to alter the plasma HDL-C-related factors; meanwhile, probucol supplementation was very effective in enhancing cholesterol metabolism, except for a negative effect that reduced plasma HDL-C concentration.
J Biochem Mol Toxicol 2005
PMID:Vitamin E supplementation alters HDL-cholesterol concentration and paraoxonase activity in rabbits fed high-cholesterol diet: comparison with probucol. 1629 55

Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001< or =P< or =0.04) and two SNPs were associated with AD in Caucasian families (0.01< or =P< or =0.04). Of note, the pattern of association for the PON1 promoter SNP -161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006< or =P< or =0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the -161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.
Hum Mol Genet 2006 Jan 01
PMID:Polymorphisms in the PON gene cluster are associated with Alzheimer disease. 1631 30

We have developed a statistical method named MAP (mutagenesis assistant program) to equip protein engineers with a tool to develop promising directed evolution strategies by comparing 19 mutagenesis methods. Instead of conventional transition/transversion bias indicators as benchmarks for comparison, we propose to use three indicators based on the subset of amino acid substitutions generated on the protein level: (1) protein structure indicator; (2) amino acid diversity indicator with a codon diversity coefficient; and (3) chemical diversity indicator. A MAP analysis for a single nucleotide substitution was performed for four genes: (1) heme domain of cytochrome P450 BM-3 from Bacillus megaterium (EC 1.14.14.1); (2) glucose oxidase from Aspergillus niger (EC 1.1.3.4); (3) arylesterase from Pseudomonas fluorescens (EC 3.1.1.2); and (4) alcohol dehydrogenase from Saccharomyces cerevisiae (EC 1.1.1.1). Based on the MAP analysis of these four genes, 19 mutagenesis methods have been evaluated and criteria for an ideal mutagenesis method have been proposed. The statistical analysis showed that existing gene mutagenesis methods are limited and highly biased. An average amino acid substitution per residue of only 3.15-7.4 can be achieved with current random mutagenesis methods. For the four investigated gene sequences, an average fraction of amino acid substitutions of 0.5-7% results in stop codons and 4.5-23.9% in glycine or proline residues. An average fraction of 16.2-44.2% of the amino acid substitutions are preserved, and 45.6% (epPCR method) are chemically different. The diversity remains low even when applying a non-biased method: an average of seven amino acid substitutions per residue, 2.9-4.7% stop codons, 11.1-16% glycine/proline residues, 21-25.8% preserved amino acids, and 55.5% are amino acids with chemically different side-chains. Statistical information for each mutagenesis method can further be used to investigate the mutational spectra in protein regions regarded as important for the property of interest.
J Mol Biol 2006 Jan 27
PMID:A statistical analysis of random mutagenesis methods used for directed protein evolution. 1632 1

This report compares statistical models based on molecular and inferred haplotypes of the human paraoxonase-1 gene (PON1). In a study of 402 women comprising three race/ethnicities, 137 women had ambiguous inferred haplotypes. The inferred haplotypes (the one with highest posterior probability) for 20 of these women differed from molecular haplotypes, while based on the posterior distribution from the imputation method, 30 discrepancies were expected. We examined the proportion of the variance in PON1 enzymatic activity (phenotype) explained by genotype, and by inferred and molecular haplotype information. For Caucasians, there was an improvement in adjusted R(2) from 16% for the genotype count model, to 29% for imputed haplotypes, and a further improvement to 33% for molecular haplotypes. For Hispanics and African-Americans, there was no indication that haplotypes helped in explaining PON1 activity, and the imputed model gave essentially the same R(2) as the molecular model. For African-Americans, none of the models had adjusted R(2) that exceeded 4%, while for Hispanics they were all about 21-22%. We propose a new parsimonious model which uses all the genotype information and selected haplotype information. For PON1, this model achieves essentially the same adjusted R(2) as the all-haplotype model, with a potential cost savings and without giving the extreme predictions for uncommon haplotype combinations that the all-haplotype models provides.
Mol Genet Metab 2006 Nov
PMID:Comparison of statistical models for analyzing genotype, inferred haplotype, and molecular haplotype data. 1678 80

Accumulating evidence suggests that the oxidative modification of low-density lipoprotein (LDL) plays an integral role in the initiation and progression of atherosclerosis. We have previously reported that human paraoxonase (PON)2 possesses antioxidant properties and is capable of preventing LDL oxidation in vitro. The objective of this study was to determine whether elevated levels of PON2 could protect against the development of atherosclerosis in vivo. Six-month-old apolipoprotein E-deficient mice (apoE(-/-)) were injected intravenously with either PBS or 3 x 10(11) particles of adenovirus expressing GFP (AdGFP) or human PON2 (AdPON2). Three weeks post-injection, lesion area was significantly lower in mice treated with AdPON2 compared to their control counterparts. Serum from AdPON2 treated mice contained significantly lower levels of lipid hydroperoxides and exhibited an enhanced potential to efflux cholesterol from cholesterol-loaded macrophages. In addition, LDL from AdPON2 treated mice was less susceptible to oxidation, while HDL from these same mice was significantly more capable of protecting LDL against oxidation. These results demonstrate for the first time that elevated levels of PON2 can enhance the efflux potential and antioxidant capacity of serum, increase the anti-inflammatory properties of HDL, and protect against the development of atherosclerosis in vivo.
Mol Genet Metab 2006 Dec
PMID:Adenovirus mediated expression of human paraoxonase 2 protects against the development of atherosclerosis in apolipoprotein E-deficient mice. 1693 14

Homocysteine (Hcy)-thiolactonase (HTase) activity of the paraoxonase-1 (PON1) protein detoxifies Hcythiolactone in human blood and could thus delay the development of atherosclerosis. We investigated a hypothesis that HTase activity is associated with coronary heart disease. We studied HTase activities and PON1 genotypes in a group of 475 subjects, 42.5% of whom were healthy and 57.5% had coronary heart disease (CHD). We found that HTase activity was positively correlated with total cholesterol (r=0.254, P<0.0001), LDL cholesterol (0.149, P=0.016), ApoB (r=0.167, P=0.006), ApoA1 (0.140, P=0.023), and HDL cholesterol (0.184, P=0.002) in a group of CHD cases (n=270) but not in controls (n=202). Mean HTase activity was significantly higher in CHD cases than in controls (4.57 units vs. 3.30 units, P <10(-5)). The frequencies of the PON1-192 genotypes in CHD cases were similar to those in controls. HTase activity was not different between patients receiving statins and those not treated with statins. Multiple regression analysis shows that CHD status, PON1 genotype, and total cholesterol are determinants of HTase activity in humans. Our results suggest that HTase activity of the PON 1 protein is a predictor of CHD.
Cell Mol Biol (Noisy-le-grand) 2006 Dec 31
PMID:The correlation of homocysteine-thiolactonase activity of the paraoxonase (PON1) protein with coronary heart disease status. 1754 99

Four classes of agents capable of producing human illness have been identified: toxicity, heredity, infection and deficiency. Examples of how members of these classes of etiologic agents can cooperate to produce illness were shown. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis were examined using concepts about cooperation. The Western diet so closely associated with these illnesses often is low in copper. Copper deficiency decreases the activity of methionine synthase which contributes to elevation of homocysteine, and of paraoxonase which impairs hydrolysis of homocysteine thiolactone, an inhibitor of lysyl oxidase. This copper-dependent enzyme initiates the cross-linking of collagen and elastin in arteries and bone. High homocysteine also impairs superoxide dismutase, a copper-dependent enzyme important in oxidative defense. Some genes affecting paraoxonase activity may respond to dietary copper. The copper deficiency theory of ischemic heart disease and the homocysteine theory of arteriosclerosis are inextricably entwined.
Cell Mol Biol (Noisy-le-grand) 2006 Dec 31
PMID:How dietary deficiency, genes and a toxin can cooperate to produce arteriosclerosis and ischemic heart disease. 1754

Cholinergic Status, the total soluble circulation capacity for acetylcholine hydrolysis, was tested for putative involvement in individual variabilities of the recruitment of immune cells in response to endotoxin challenge. Young (average age 26) and elderly (average age 70) volunteers injected with either Escherichia coli endotoxin or saline on two different occasions were first designated Enhancers and Suppressors if they showed increase or decrease, respectively, in plasma acetylcholinesterase (AChE) activity 1.5 h after endotoxin administration compared to saline. Enhancers showed significant co-increases in plasma butyrylcholinesterase (BChE) and paraoxonase (PON1) activities, accompanied by rapid recovery of lymphocyte counts. Young Enhancers alone showed pronounced post-exposure increases in the pro-inflammatory cytokine interleukin-6 (IL-6), and upregulation of the normally rare, stress-induced AChE-R variant, suggesting age-associated exhaustion of the cholinergic effects on recruiting innate immune reactions to endotoxin challenge. Importantly, IL-6 injected to young volunteers or administered in vitro to primary mononuclear blood cells caused upregulation of AChE, but not BChE or PON1, excluding it from being the sole cause for this extended response. Interestingly, Suppressors but not Enhancers showed improved post-exposure working memory performance, indicating that limited cholinergic reactions may be beneficial for cognition. Our findings establish Cholinergic Status modulations as early facilitators and predictors of individual variabilities in the peripheral response to infection.
J Mol Med (Berl) 2007 Nov
PMID:Cholinergic status modulations in human volunteers under acute inflammation. 1765 67

Paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) that prevents low-density lipoprotein (LDL) oxidation. PON1Q192R polymorphism is associated with a risk of coronary heart disease and low HDL levels in case-control studies, but the issue is yet unresolved. Mexico has shown an increase in cardiovascular diseases, and some genetic factors may play a role. Our purpose was to evaluate the association between PON1Q192R and L55M polymorphisms and serum lipid profile in a healthy Mexican population. Ninety unrelated male inhabitants from southeastern Mexico with Mayan ascendancy agreed to participate. Demographic characteristics, lifestyle and medical history were obtained by questionnaire. Lipid profile was determined by enzymatic methods, PON1 activity by using paraoxon and phenylacetate and PON1 genotype by real-time PCR. HDL-cholesterol (HDL-C) levels were associated with genotype: 192RR homozygote subjects had lower HDL-C levels than 192QQ homozygotes, and individuals with 192RR and 192QR genotypes had an odds ratio (OR)=7.05 (95% confidence interval (CI)=1.29-38.34) of having HDL-C <60 mg/dL. Individuals with higher paraoxonase activity (>600.18 U/L) had a slight risk (OR=4.9, 95% CI=0.83-22.02) of having HDL-C <60 mg/dL. PON155LM polymorphism was associated with higher LDL-cholesterol. PON1Q192R polymorphism showed a role in modulating lipid profile: 192RR homozygotes showed the least favorable lipoprotein levels.
Exp Mol Pathol 2008 Oct
PMID:PON1Q192R polymorphism is associated with lipid profile in Mexican men with Mayan ascendancy. 1858 59


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