Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prediction of response (or non-response) to anti-TNF treatment for rheumatoid arthritis (RA) is a pressing clinical problem. We conducted a genome-wide association study using the Illumina HapMap300 SNP chip on 89 RA patients prospectively followed after beginning anti-TNF therapy as part of Autoimmune Biomarkers Collaborative Network (ABCoN [Autoimmune Bio-markers Collaborative Network]) patient cohort. Response to therapy was determined by the change in Disease Activity Score (DAS28) observed after 14 wks. We used a two-part analysis that treated the change in DAS28 as a continuous trait and then incorporated it into a dichotomous trait of "good responder" and "nonresponder" by European League Against Rheumatism (EULAR) criteria. We corrected for multiple tests by permutation, and adjusted for potential population stratification using EIGENSTRAT. Multiple single nucleotide polymorphism (SNP) markers showed significant associations near or within loci including: the v-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene on chromosome 20; the type I interferon gene IFNk on chromosome 9; and in a locus on chromosome 7 that includes the paraoxonase I (PON1) gene. An SNP in the IL10 promoter (rs1800896) that was previously reported as associated with anti-TNF response was weakly associated with response in this cohort. Replications of these results in independent and larger data sets clearly are required. We provide a reference list of candidate SNPs (P < 0.01) that can be investigated in future pharmacogenomic studies.
Mol Med
PMID:Genome-wide association scan identifies candidate polymorphisms associated with differential response to anti-TNF treatment in rheumatoid arthritis. 1861 56

Autism spectrum disorders (ASD) comprise a complex and heterogeneous group of conditions of unknown aetiology, characterized by significant disturbances in social, communicative and behavioural functioning. Recent studies suggested a possible implication of the high-density lipoprotein associated esterase/lactonase paraoxonase 1 (PON1) in ASD. In the present study, we aimed at investigating the PON1 status in a group of 50 children with ASD as compared to healthy age and sex matched control participants. We evaluated PON1 bioavailability (i.e. arylesterase activity) and catalytic activity (i.e. paraoxonase activity) in plasma using spectrophotometric methods and the two common polymorphisms in the PON1 coding region (Q192R, L55M) by employing Light Cycler real-time PCR. We found that both PON1 arylesterase and PON1 paraoxonase activities were decreased in autistic patients (respectively, P < 0.001, P < 0.05), but no association with less active variants of the PON1 gene was found. The PON1 phenotype, inferred from the two-dimensional enzyme analysis, had a similar distribution in the ASD group and the control group. In conclusion, both the bioavailability and the catalytic activity of PON1 are impaired in ASD, despite no association with the Q192R and L55M polymorphisms in the PON1 gene and a normal distribution of the PON1 phenotype.
J Cell Mol Med 2010 Mar
PMID:Paraoxonase 1 activities and polymorphisms in autism spectrum disorders. 1862 74

This study was performed to investigate the lipid-lowering, antioxidant, and hepato-protective effects of pinitol in dose-dependent manners in hamsters fed-high fat and high cholesterol (HFHC) diet. Pinitol supplementation (0.05%, P-I and 0.1% pinitol, P-II) with an HFHC diet (10% coconut oil plus 0.2% cholesterol) for 10 wks significantly lowered the white adipose tissue weights, hepatic lipid droplets, plasma glucose, total-cholesterol, nonHDL-cholesterol, total-cholesterol/HDL-cholesterol ratio, and hepatic lipid levels. Whereas it significantly increased the brown adipose tissue weight, plasma HDL-cholesterol, apolipoprotein A-I (apo A-I) concentrations, paraoxonase (PON) activity, and/or mRNA expression, compared to the HFHC control group. Plasma insulin and adiponectin levels were significantly lower and higher, respectively, in both P-I and P-II groups than the HFHC control group. Dietary pinitol significantly inhibited hepatic HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT), and cytochrome P4502E1 (CYP2E1) activities without altering their mRNA expressions compared to the control group. Pinitol significantly elevated the hepatic antioxidant enzyme activities, whereas it also significantly reduced the hepatic lipid peroxide and H2O2 production. Accordingly, these results indicate that both 0.05 and 0.1% pinitol supplementation may improve the lipid and antioxidant metabolism in HFHC diet-fed hamsters. In particular, pinitol supplementation was very effective on the elevation of antiatherogenic factors, including plasma HDL-cholesterol, apo A-I, adiponectin, and PON.
Mol Nutr Food Res 2009 Jun
PMID:Metabolic response of soy pinitol on lipid-lowering, antioxidant and hepatoprotective action in hamsters fed-high fat and high cholesterol diet. 1920 1

Serum paraoxonase (PON1) plays an important role in protecting low-density lipoprotein against oxidative modification. In this study, the full-length cDNA sequence (1,416 bp) of porcine PON1 was cloned by reverse transcription polymerase chain reaction and rapid amplification of cDNA ends. It was found to contain a 1,068 bp open reading frame encoding a deduced protein of 355 amino acids with a calculated molecular weight of 40.02 kDa. The genomic structure and sequence of porcine PON1 were also analyzed using a bacterial artificial chromosome clone of a Chinese Erhualian pig. The porcine PON1 gene contained nine exons and eight introns spanning approximately 29 kb, and was located on chromosome nine between microsatellite markers SWR915 and SW944 by IMpRH mapping. Porcine PON1 was highly expressed in kidney, followed by liver, lung and small intestine, expressed at an extremely low level in heart, and was hardly expressed in spleen, lymph, muscle of the anterior limb, cerebrum, fat, cerebellum or hypothalamus.
Mol Biol Rep 2010 Mar
PMID:Sequence identification, chromosomal mapping and tissue specific expression of the porcine paraoxonase 1 (PON1) gene. 1934 7

Human paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that has a role in the detoxification of organophosphorus compounds by hydrolyzing the bioactive oxons. PON1 polymorphims are responsible, at least in part, for the variation in the catalytic activity and expression of the enzyme and have been associated with susceptibility to organophosphorus pesticide toxicity, mainly neurotoxicity. The aim of this study was to determine whether paraoxon induced micronuclei and to examine the role of PON1 polymorphism in paraoxon's genotoxic potential. First, dose finding cytogenetic experiments were performed on lymphocyte cultures from three donors and a range of paraoxon concentration (1-25 microM) were tested. In a second set of experiments, 5 microM paraoxon was added to blood cultures of 11 donors with two different PON1 haplotypes (PON T(-108)M(55)Q(192) with low activity and haplotype PON C(-108)L(55) R(192) with high activity, referred to as PON1QQ and as PON1 RR, respectively). Because PON1 is present in blood, the effect of adding 5 microM paraoxon and 70 microl of autologous plasma to lymphocyte cultures also was examined. Paraoxon had no effect on cell viability, but caused a significant dose-dependent increase in MN frequency. The basal MN frequencies were similar on QQ and RR genotypes. A significant difference was observed in the MN frequency only in lymphocytes from individuals with the QQ genotype treated with 5 microM paraoxon and the autologous plasma did not modify these effects. The results obtained in this study suggest that PON1 genotype might have an important role in the identification of individuals at risk for cancer development due to occupational exposure to pesticides.
Environ Mol Mutagen 2009 Dec
PMID:The role of paraoxonase polymorphisms in the induction of micronucleus in paraoxon-treated human lymphocytes. 1940 56

The present study was designed to investigate the effects of benzyloxicarbonyl-L-phenylalanyl-alanine-fluoromethylketone (Z-FA.FMK), an inhibitor of cathepsin B on lung injury that occurs concurrently with liver injury induced by D-galactosamine/tumor necrosis factor-alpha (D-GalN/TNF-alpha). Four groups of BALB/c male mice were treated as follows: Group 1--mice receiving intravenous (iv) injections of physiological saline; Group 2--administered with 8 mg/kg Z-FA.FMK by iv injection; Group 3--mice treated with 700 mg/kg D-GalN and 15 microg/kg TNF-alpha by sequential intraperitoneal (ip) injection; Group 4--treated with 700 mg/kg D-GalN and 15 microg/kg TNF-alpha by sequential ip injection 1 h after administration with 8 mg/kg Z-FA.FMK. Mice from Groups 3 and 4 were sacrificed 4 h after D-GalN/TNF-alpha injections. The mice treated with D-GalN/TNF-alpha showed lung damage; increased TNF receptor-associated factor immunoreactivity, lipid peroxidation, protein carbonyl content, and lactate dehydrogenase activity; decreased catalase, superoxide dismutase, and paraoxonase activities. Treatment with Z-FA.FMK resulted in an improvement of these alterations in D-GalN/TNF-alpha-administered mice. The apoptotic index of type-II pneumocytes was the almost same in the four study groups, but pneumocytes labeled with proliferating cell nuclear antigen antibody was more numerous in Group 4 mice. Our results show that D-GalN/TNF-alpha results in lung damage without induction of apoptosis. Treatment with Z-FA.FMK stimulates proliferation of type-II pneumocytes and improves degenerative alterations in injured lung occurred with liver injury induced by D-GalN/TNF-alpha.
Mol Cell Biochem 2010 Jan
PMID:Cathepsin B inhibition improves lung injury associated to D-galactosamine/tumor necrosis factor-alpha-induced liver injury in mice. 1962 48

To compare the molecular composition and functional differences at the lipoprotein level, we analyzed individual lipoprotein fractions from male patients with metabolic syndrome (MetS) (n=10) and gender- and age-matched healthy controls (n=14). The MetS group had significantly higher obesity, blood pressure, serum cholesterol, triglyceride (TG), adiponectin, and uric acid levels than the control group, while the serum blood urea nitrogen and creatinine levels of the MetS group were in the normal range. The MetS group had much weaker serum antioxidant ability and were more susceptible to copper-mediated low-density lipoprotein (LDL)-oxidation. TG and apoC-III co-accumulated with LDL, high density lipoprotein (HDL)2, and HDL3 in the MetS group. The MetS group had serum amyloid A (SAA)-enriched HDL2 and HDL3, although the serum level of SAA was not higher than in controls. The MetS group had significantly deprived paraoxonase (PON) activity in the serum and HDL, while the MetS group had 38% higher serum cholesteryl ester transfer protein (CETP) activity than that of the control group. Many serum parameters, such as TG, apoC-III, and uric acid, were elevated in the MetS group, and most of these measures were enriched in the LDL and HDL fractions rather than the very low density lipoprotein (VLDL) fraction. The lipid and apolipoprotein composition of HDL was severely altered and its beneficial functions were severely diminished. ApoA-I level was more readily detected in lipoprotein-deficient serum of the MetS group, indicating that the apoA-I exists in a lipid-free state. These results suggest that the MetS group had dysfunctional HDL that enriched TG, apoC-III, CETP, and SAA without antioxidant activity.
Int J Mol Med 2010 Jan
PMID:The functional and compositional properties of lipoproteins are altered in patients with metabolic syndrome with increased cholesteryl ester transfer protein activity. 1995 11

Decreased paraoxonase-1 (PON1) activity has been associated with rheumatoid arthritis. There are two polymorphisms in serum PON1; one differs in the amino acid at position 192 (Q192R) and the other one differs at position 55 (L55M). We looked for a possible association between Q192R polymorphism and rheumatoid arthritis. The Q192R polymorphism in 88 rheumatoid arthritis patients and 78 healthy subjects was determined using tetra amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and PCR-restriction fragment length polymorphism (RFLP) methods. We found no significant differences between rheumatoid arthritis patients and control subjects regarding PON1 Q192R polymorphism. PON1 Q192R polymorphism was not found to be correlated with increased risk for rheumatoid arthritis in this Iranian population.
Genet Mol Res 2010 Feb 23
PMID:Lack of association between paraoxonase-1 Q192R polymorphism and rheumatoid arthritis in southeast Iran. 2019 89

A female patient (64 years of age; body mass index, 26) had a markedly and relatively low low-density lipoprotein-cholesterol (LDL-C) level (97 mg/dl) despite high serum total cholesterol (TC) (331 mg/dl) and triacylglyceride levels (307 mg/dl). Since the expected LDL-C was 222 mg/dl, there was a significant difference between the calculation and measurement based on direct enzyme assay. Only 30% of serum cholesterol was associated with LDL-C in this patient. To determine the basis for the markedly low LDL-C/TC ratio, we isolated and analyzed lipoproteins from the patient as well as age- and gender-matched controls. The patient had lowered serum CETP activity and elevated paraoxonase activity with GOT and GPT values in the normal range. The very low-density lipoprotein particles from the patient were larger than those of the controls and enriched with lipid and protein, while the LDL from the patient (LDL-P) had a lower particle number and protein content than the controls. The LDL-P was more resistant to cupric ion-mediated oxidation. HDL2 from the patient (HDL2-P) had highly enhanced paraoxonase activity and antioxidant ability. The patient had a 1.5-fold higher level of apolipoprotein (apo) A-I expression in HDL2. ApoA-I in HDL2 and HDL3 from the patient showed no fragmentation, while the control had fragmented bands (17 and 21 kDa) in the HDL. The HDL2-P also had a larger particle size and greater protein content with less lipid content. HDL3-associated cholesteryl ester transfer protein was reduced in the patient, although the particle size was similar to the controls. In conclusion, a patient who had a markedly lower LDL-C/TC ratio despite hyperlipidemia associated with higher paraoxonase activity, higher apoA-I level and lower CETP activity without fragmentation of apoA-I in the HDL fraction is presented. The enhanced antioxidant and anti-inflammatory activity of HDL might contribute to the low LDL-C/TC ratio in this patient.
Int J Mol Med 2010 Jun
PMID:Elevated HDL2-paraoxonase and reduced CETP activity are associated with a dramatically lower ratio of LDL-cholesterol/total cholesterol in a hypercholesterolemic and hypertriglyceridemic patient. 2042

Paraoxonase 1 (PON1) prevents oxidation of low-density lipoproteins and inactivates toxic oxon derivatives of organophosphate pesticides (OPs). More than 250 SNPs have been previously identified in the PON1 gene, yet studies of PON1 genetic variation focus primarily on a few promoter SNPs (-108, -162) and coding SNPs (192, 55). We sequenced the PON1 gene in 30 subjects from a Mexican-American birth cohort and identified 94 polymorphisms with minor allele frequencies >5%, including several novel variants (six SNPs, one insertion, and two deletions). Variants of the PON1 gene and three SNPs from PON2 and PON3 were genotyped in 700 children and mothers from the same cohort. PON1 phenotype was established using two substrate-specific assays: arylesterase (AREase) and paraoxonase (POase). Twelve PON1 and two PON2 polymorphisms were significantly associated with AREase activity, and 37 polymorphisms with POase activity; however, only nine were not in strong linkage disequilibrium (LD) with either PON1(-108) or PON1(192) (r(2) > 0.20), SNPs with known effects on PON1 quantity and substrate-specific activity. Single tagSNPs PON1(55) and PON1(192) accounted for similar ranges of AREase variation compared to haplotypes comprised of multiple SNPs within their haplotype blocks. However, PON1(55) explained 11-16% of POase activity, while six SNPs in the same haplotype block explained threefold more variance (36-56%). Although LD structure in the PON cluster seems similar between Mexicans and Caucasians, allele frequencies for many polymorphisms differed strikingly. Functional effects of PON genetic variation related to susceptibility to OPs and oxidative stress also differed by age and should be considered in protecting vulnerable subpopulations.
Environ Mol Mutagen 2011 Mar
PMID:Effects of PON polymorphisms and haplotypes on molecular phenotype in Mexican-American mothers and children. 2083 25


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