Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pons”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 631 records · Page 35Linked to original sources
PubMed1995

Clinical and magnetic resonance image correlation in idiopathic cerebellar ataxia.

Sixty-one patients who fulfilled the clinical criteria for idiopathic cerebellar ataxia and who had symptoms at least for 3 years were examined clinically and by magnetic resonance imaging (MRI). Based on the clinical signs, they were divided into patients with pure cerebellar signs (Group 1), patients with additional mild rigidity and/or hyperreflexia (Group 2) and patients with additional severe rigidity and hypokinesia (Group 3). Patients in Group 1 had milder disability and better prognosis than patients in Group 2 or Group 3 (ataxic score: 14.9 vs. 28.6 and 36.0; annual progression ratio: 0.26 vs. 0.65 and 0.70, respectively). We measured the area of the cerebellar vermis, ventral pons and dorsal brainstem on midsagittal T1-weighted MR images for all patients and age- and sex-matched controls. The cerebellar vermis as well as the ventral pons of patients were significantly smaller than corresponding structures in controls (p < 0.001). The ventral pons of patients in Group 2 and Group 3 was significantly smaller than that of patients in Group 1 (p < 0.0001, respectively), and the dorsal brainstem of patients in Group 2 and Group 3 was also significantly smaller than that of patients in Group 1 (p < 0.001, respectively). The ventral pons of patients in Group 3 was significantly smaller than that of patients in Group 2 (p < 0.05) as well. There was a significant correlation between the area of the ventral pons and the annual progression ratio (p < 0.001). With MRI, slight but definite hyperintensities were demonstrated in the pontine base and the medulla of 22 patients on proton density images. In the longitudinal study, patients in Group 2 and Group 3 had atrophy of the ventral pons already at an early stage. The ventral pons of patients in Group 3 was smaller at the initial MR examination than that of patients in Group 2. These observations suggest that patients with smaller ventral pons may have rapid progression and poor prognosis. Thus, even a relatively simple quantitation of the area of the ventral pons may be useful to predict the prognosis of patients, in addition to neurologic assessment at intervals.

Adult↗
PubMed2006

Cytoarchitecture of pneumotaxic integration of respiratory and nonrespiratory information in the rat.

The "pneumotaxic center" in the Kölliker-Fuse and medial parabrachial nuclei of dorsolateral pons (dl-pons) plays an important role in respiratory phase switching, modulation of respiratory reflex, and rhythmogenesis. Recent electrophysiological and neural tracing data implicate additional pneumotaxic nuclei in (and a broader role for) the dl-pons in integrating respiratory and nonrespiratory information. Here, we examined the cytoarchitecture of the greater pneumotaxic center and its integrating function by using combined extracellular recording and juxtacellular labeling of unit respiratory rhythmic neurons in dl-pons in urethane-anesthetized, vagotomized, paralyzed, and servo-ventilated adult Sprague Dawley rats. Perievent histogram analysis identified four major types of neuronal discharge patterns: inspiratory, expiratory (with three subdivisions), inspiratory-expiratory, and expiratory-inspiratory phase spanning, sometimes with mild tonic background activity. Most recorded neurons were localized in the Kölliker-Fuse and medial parabrachial nuclei, but some were also found in lateral parabrachial nucleus, intertrigeminal nucleus, principal trigeminal sensory nucleus, and supratrigeminal nucleus. The majority of labeled neurons had large and spatially extended dendritic trees that spanned several of these dl-pons subnuclei, often with terminal dendrites ending in the ventral spinocerebellar tract. The distal sections of the primary and higher-order dendrites exhibited rich varicosities, sometimes with dendritic spines. Axons of some labeled neurons were traced all the way to the ventrolateral pons (vl-pons). These findings extend and generalize the classical definition of the pneumotaxic center to include extensive somatic-axonal-dendritic integration of complex descending and ascending respiratory information as well as nociceptive and possibly musculoskeletal and trigeminal information in multiple dl-pons and vl-pons structures in the rat.

Action Potentials↗
PubMed2006

Paraoxonase-1 concentrations in end-stage renal disease patients increase after hemodialysis: correlation with low molecular AGE adduct clearance.

BACKGROUND: Hemorrhagic stroke and ischemic heart disease continue to be key problems in patients with end stage renal failure. Reduced serum paraoxonase (PON-1) activity has been described in these patients, which could contribute to the accelerated development of atherosclerosis. We hypothesized that retention of uremic toxins and or "middle molecules" including advanced glycation (AGE) free adducts and peptides could play a mechanistic role in decreasing PON-1 activity. METHODS: We enrolled 22 ESRD patients undergoing hemodialysis in whom paired pre- and post-dialysis samples were studied along with 30 age-matched control subjects. RESULTS: ESRD patients showed a 76% decrease in PON-1 activity. As expected, ESRD patients had an increase in lipoperoxides and advanced oxidation protein products (AOPP). Our patients had a 3-fold increase in serum AGEs and a striking 10-fold increase in low molecular weight (<10 kDa) AGEs. Post-dialysis samples in all patients displayed an increase in PON-1 activity, which ranged from 4 to 40% of the predialysis value. HDL-cholesterol, apoAI, free cholesterol (as a LCAT surrogate), HDL-subclasses and TG did not change significantly after dialysis. Changes in PON-1 activity display a good correlation (r=0.66, p<0.001) with rates in which creatinine and urea are cleared. Clearance of low molecular weight AGEs after hemodialysis explains 79% of the changes in PON-1 activity and are hence a much better predictor than creatinine changes (r=0.89, p<0.00). In vitro incubation of paraoxonase with serum ultrafiltrates show a time and concentration dependent inhibition of PON-1 by the ultrafiltrates, an inhibition that is up to 3 times higher (from 8 to 24%) when chronic renal failure patients are the source of the ultrafiltrate. CONCLUSION: We showed that HD results in a significant, consistent increase in the activity of the antioxidant enzyme PON-1. The effect, correlates with the effectiveness of dialysis to clear creatinine and urea, and with the clearance of AGE adducts of low molecular weight. This effect was replicated in vitro, showing time and dose dependency. Our results suggest that another cause for the observed lower PON-1 concentrations in CRF are the retention of low-middle molecules and demonstrate a positive effect of hemodialysis in the delicate oxidant-antioxidant state of these patients, that should be weighted against other pro-oxidant effects that have also been shown to occur previously. If the hypothesis that AGEs are the main culprits is proved in further research, this opens a putative therapeutic avenue for AGE blockers in ESRD.

Aryldialkylphosphatase↗
PubMed2005

Correlation between the activities of lipoprotein lipase and paraoxonase in type 2 diabetes mellitus.

UNLABELLED: In type 2 diabetes mellitus the decreased catabolism of triglyceride-rich lipoproteins as a consequence of mainly the decreased lipoprotein lipase activity results in hypertriglyceridaemia and other lipoprotein alterations promoting atherosclerosis. The high-density lipoprotein-associated enzyme, paraoxonase, prevents the oxidation of low-density lipoprotein, which is an antiatherogenic effect. AIM: to examine the relation between the activities of enzymes influencing HDL remodelling- LPL and PON- in type 2 diabetes mellitus. METHODS: 56 newly diagnosed type 2 diabetic patients and 39 healthy controls were involved in the study. The serum PON activity was measured spectrophotometrically using paraoxone as substrate. PON phenotype was determined by the dual substrate method, PON mass was measured by ELISA. The determination of lipoprotein lipase activity was performed using 3H-triolein. RESULTS: We noticed smaller PON activity decrease in our newly diagnosed diabetic subjects compared to the previous studies which investigated the alteration of enzyme activity after a longer duration of diabetes mellitus. The lipoprotein lipase activity showed a positive correlation with PON activity (r=0.43; P<0.02). Interestingly, the PON activity of the homozygous-low activity group did not correlate with the LPL activity, while in the heterozygous and homozygous-high activity groups there was a significantly positive correlation (r=0.51; P<0.05) between PON and LPL activity. CONCLUSION: Besides lipid alterations, the metabolic changes of type 2 diabetes mellitus influence the reduction of the antioxidant capacity of HDL by remodelling HDL and decreasing PON activity via modification of lipoprotein lipase activity, which might contribute to accelerated atherosclerosis.

Aryldialkylphosphatase↗
PubMed2002

Killing of spores of Bacillus subtilis by peroxynitrite appears to be caused by membrane damage.

During an infection of a higher eukaryote, dormant spores of a Bacillus species have been previously shown to be present in cells that can generate the toxic agent peroxynitrite (PON). Dormant spores of Bacillus subtilis were much more resistant to killing by PON than were growing cells, and spore-coat alteration or removal greatly decreased PON resistance. Spores were not killed by PON through DNA damage and lost no dipicolinic acid (DPA) during PON treatment. However, PON-killed spores lost DPA during subsequent heat treatments that caused much less DPA release from untreated spores. Although dead, the PON-killed spores germinated and initiated metabolism but never went through outgrowth; the great majority of germinated PON-killed spores also took up propidium iodide, indicating that they had suffered significant membrane damage and were dead. Together these data suggest that spore killing by PON is through some type of damage to the spore's inner membrane.

Bacillus subtilis↗
PubMed2000

A sandwich enzyme-linked immunosorbent assay for human serum paraoxonase concentration.

Serum paraoxonase (PON) is associated with plasma high density lipoproteins, and prevents the oxidative modification of low density lipoproteins. We have developed a sensitive sandwich enzyme-linked immunosorbent assay (ELISA), using two monoclonal antibodies against PON, to measure serum PON concentration. The concentration of PON in healthy Japanese subjects was 59.3 +/- 1.3 microgram/mL (mean +/- SEM; n = 87). Serum PON concentrations in relation to the PON 192 genetic polymorphism were: 69.5 +/- 2.9 microgram/mL in the QQ genotype; 63.0 +/- 1.9 microgram/mL in the QR genotype; and 52.8 +/- 1.7 microgram/mL in the RR genotype. Concentrations were significantly lower in the RR than in the QQ genotype (P < 0.01). Serum paraoxonase specific activity was higher in RR than in QQ subjects (18.6 +/- 0.40 vs. 2. 56 +/- 0.05 nmol/min/microgram, P < 0.01), but arylesterase specific activity was unrelated to genotype. PON concentration was positively associated (P < 0.001) with both serum arylesterase activity and, after adjusting for the effect of the position 192 polymorphism, with serum paraoxonase activity. Subjects with angiographically verified coronary heart disease had significantly lower PON concentrations than the healthy controls (52.0 +/- 2.3 microgram/mL; n = 35, P < 0.01). This association was independent of the position 192 genotype. Our new ELISA should be of value for epidemiologic and clinical studies of serum PON concentration. immunosorbent assay for human serum paraoxonase concentration.

Aged↗
PubMed1986

Two converging brainstem pathways mediating circling behavior.

Ipsiversive circling results from stimulation of the rostromedial tegmentum (RMT) or medial pons (PONS), and contraversive circling results from stimulation of the superior colliculus (SC). To determine whether these sites are functionally connected, the collision method of Shizgal, Bielajew, Corbett, Skelton and Yeomans (1980) was used in rats. Pairs of stimulation pulses were presented to two sites, and the degree of collision between stimulation-evoked action potentials was assessed by measuring the frequency required for circling at short and long intrapair conditioning-testing (C-T) intervals. Collision was evidenced when the required frequencies were higher at short C-T intervals than at long C-T intervals. Collision of 46-62% was observed between RMT and PONS, and collision of 15-29% was observed between SC and PONS. Sites from which collision was obtained were located along the trajectories of the medial tegmental tract and the crossed tectospinal pathway. Refractory periods in all sites were similar, ranging from 0.3 to 1.7 ms. Conduction velocities of axons connecting RMT and PONS and SC and PONS were comparable, ranging from 0.8 to 13.3 m/s and 1.7 to 13.8 m/s, respectively, with lower conduction velocities associated with more ventral pontine sites. Thus, RMT and PONS, and SC and PONS are connected by myelinated axons that mediate circling.

Animals↗
PubMed2004

The human basis pontis: motor syndromes and topographic organization.

Clinical-anatomic correlations were performed in 25 patients with focal infarcts in the basilar pons to determine whether pontine lacunar syndromes conform to discrete clinical entities, and whether there is topographic organization of the motor system within the human basis pontis. Twelve clinical signs were scored on a 6-point scale, neuroimaging lesions were mapped and defined with statistical certainty, and structure-function correlation was performed to develop a topographic map of motor function. Clinical findings ranged from major devastation following extensive lesions (pure motor hemiplegia) to incomplete basilar pontine syndrome and restricted deficits after small focal lesions (ataxic hemiparesis, dysarthria-clumsy hand syndrome, dysarthria-dysmetria and dysarthria-facial paresis). The syndromes are not absolutely discrete, and are distinguished from each other by the relative degree of involvement of each clinical feature. Structure-function correlations indicate that strength is conveyed by the corticofugal fibres destined for the spinal cord, whereas dysmetria results from lesions involving the neurons of the basilar pons that link the ipsilateral cerebral cortex with the contralateral cerebellar hemisphere. Facial movement and articulation are localized to rostral and medial basilar pons; hand coordination is medial and ventral in rostral and mid-pons; and arm function is represented ventral and lateral to the hand. Leg coordination is in the caudal half of the pons, with lateral predominance. Swallowing is dependent upon the integrity of a number of regions in the rostral pons. Gait is in medial and lateral locations throughout the rostral- caudal extent of the pons. Dysmetria ipsilateral to the lesion constitutes a disconnection syndrome, as it occurs when the hemipontine lesion is extensive and interrupts pontocerebellar fibres traversing from the opposite, intact side of the pons. The heterogeneity of manifestations reflects the well-organized topography of motor function in the human basis pontis, in agreement with the anatomic organization of the motor corticopontine projections in the monkey. Higher order impairments including motor neglect, paraphasic errors and pathological laughter result from rostral and medial pontine lesions, and may result from disruption of the pontine component of associative corticopontocerebellar circuits.

Adult↗
PubMed2002

Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome.

OBJECTIVE: To determine the prevalence of anti-high-density lipoprotein (anti-HDL) antibodies and to establish a possible relationship between anti-HDL, anticardiolipin antibodies (aCL), anti-beta(2)-glycoprotein I (anti-beta(2)GPI), and paraoxonase (PON) activity in patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). METHODS: Thirty-two patients with SLE and 36 with primary APS were enrolled in a cross-sectional study. Twenty age- and sex-matched healthy subjects were used as controls. Serum levels of IgG and IgM aCL, anti-beta(2)GPI, and antiprothrombin antibodies and IgG anti-HDL were measured by enzyme-linked immunosorbent assay. Total cholesterol, HDL cholesterol, HDL(2), and HDL(3) were determined by standard enzymatic techniques. PON activity was assessed by quantification of nitrophenol formation, and total antioxidant capacity (TAC) by chemiluminescence. RESULTS: Levels of total HDL, HDL(2), and HDL(3) were reduced in patients with SLE compared with controls (mean +/- SD 0.51 +/- 0.3, 0.37 +/- 0.3, and 0.14 +/- 0.1 mmoles/liter, respectively, versus 1.42 +/- 0.9, 1.01 +/- 0.7, and 0.40 +/- 0.2). Patients with SLE and primary APS had higher titers of anti-HDL antibodies and lower PON activity than controls. In the SLE population, PON activity was inversely correlated with IgG anti-HDL titers (r = -0.48, P = 0.005) whereas in the primary APS population, IgG anti-beta(2)GPI was the only independent predictor of PON activity (r = -0.483, P = 0.003). In the SLE group, anti-HDL was inversely correlated with TAC (r = -0.40, P < 0.02), and PON activity was positively correlated with TAC (r = 0.43, P < 0.02). CONCLUSION: IgG anti-HDL and IgG anti-beta(2)GPI antibodies are associated with reduced PON activity in patients with SLE and primary APS. Since the physiologic role of PON is to prevent low-density lipoprotein oxidation with its attendant atherogenic effects, the reported interactions may be relevant to the development of atherosclerosis in SLE and primary APS.

Adult↗
PubMed1996

Multiple intracellular signal transduction pathways mediating inward current produced by the neuropeptide, achatin-I.

The effects of intracellular signal transduction system inhibitors on the inward current (Iin) caused by achatin-I (Gly-D-Phe-Ala-Asp), an Achatina endogenous tetrapeptide having a D-phenylalanine residue, applied locally onto the neurone tested, were examined under voltage clamp using two identifiable Achatina giant neurone types, v-RCDN (ventral-right cerebral distinct neurone) and PON (periodically oscillating neurone). H-89 (N-[2-(p-bromocinnamylamino)-ethyl]-5-isoquinolinesulfonamide) (adenosine-3',5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase inhibitor) markedly suppressed the achatin-I-induced Iin on PON, whereas this drug was ineffective on the Iin of v-RCDN. Dose (pressure duration)-response study of achatin-I on PON in a physiological solution and in the presence of H-89, and Lineweaver-Burk plot of these data, indicated that H-89 inhibited the Iin in a noncompetitive manner. KT5823 (N-methyl-(8R*,9S*,11S*)-(-)-9-methoxy-9-methoxycarbonyl-8-methyl-2,3,9, 10-tetrahydro-8,11-epoxy-1H,8H,11H-2, 7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]-trinden-1-on e) (guanosine-3',5'-cyclic monophosphate (cyclic GMP)-dependent protein kinase inhibitor) suppressed the achatin-I-induced Iin of v-RCDN in mainly noncompetitive and partly uncompetitive manners, but this drug had no effect on the Iin of PON. W-7 (N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide) (calmodulin inhibitor) suppressed noncompetitively the Iin of PON, but this drug had no effect on the Iin of v-RCDN. IBMX (3-isobutyl-1-methylxanthine) (cyclic nucleotide phosphodiesterase inhibitor) enhanced the achatin-I-induced Iin of v-RCDN, but this drug was ineffective on the Iin of PON. However, IBMX might have effects on the achatin-I receptor sites on v-RCDN. These findings suggest multiple intracellular signal transduction pathways mediating the achatin-I-induced Iin: the Iin of PON is via cyclic AMP-dependent and probably Ca2+/calmodulin-dependent protein kinases, and that of v-RCDN via cyclic GMP-dependent protein kinase. Other signal transduction system inhibitors including calphostin C (2-[12-[2-(benzyloxy)-propyl]-3, 10-dihydro-4,9-dihydroxy-2,6,7,11-tetramethoxy-3,10-dioxo-1-per yleny]-1 -methylethyl carbonic acid 4-hydroxyphenyl ester) (protein kinase C inhibitor) did not significantly affect the Iin of both v-RCDN and PON.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Kinetics of HDL cholesterol and paraoxonase activity in moderate alcohol consumers.

BACKGROUND: The inverse association between moderate drinking and coronary heart disease mortality is well established. This study was performed to investigate the kinetics of the alcohol-induced increases in apo A-1, HDL cholesterol, and paraoxonase (PON) activity, as well as to study whether the alcohol-induced increases in PON activity differ within different PON polymorphisms, and to investigate whether moderate alcohol consumption has similar effects on the outcome measures in postmenopausal women as in middle-aged men. METHODS: In a randomized, diet-controlled, crossover study, 10 middle-aged men and 9 postmenopausal women, all apparently healthy, nonsmoking, and moderate alcohol drinkers, consumed beer or no-alcohol beer (control) with evening dinner during two successive periods of 3 weeks. During the beer period, alcohol intake equaled 40 and 30 g/day for men and women, respectively. The total diet was supplied to the subjects and had essentially the same composition during these 6 weeks. Before each treatment was a 1-week washout period, in which the subjects were not allowed to drink alcoholic beverages. RESULTS: Moderate alcohol consumption significantly increased serum apo A-I level after 5 days (3.7%, p < 0.05); after 10 days, serum HDL cholesterol level was increased (6.8%, p < 0.001), and after 15 days serum PON activity was increased (3.7%, p < 0.05), all compared with no alcohol consumption. Gene polymorphisms did not modulate the alcohol effect on PON. CONCLUSIONS: Serum apo A-I, HDL cholesterol, and PON activity were significantly increased during 3 weeks of moderate alcohol consumption as compared with no alcohol consumption. Moreover, the results suggest that there is a sequence in induction of these parameters. After an increase in apo A-I, HDL cholesterol is increased followed by an increase in PON activity. Increased serum HDL cholesterol level and PON activity may be a mechanism of action not only in healthy middle-aged men but also in postmenopausal women, underlying the reduced coronary heart disease risk in moderate drinkers.

Alcohol Drinking↗
PubMed2004

The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant-antioxidant system in patients with dyslipidemia.

BACKGROUND: Atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is used for lipid-lowering therapy, is an effective statin modulating process involved in atherosclerosis. Paraoxonase (PON) associated with high-density lipoprotein (HDL) has been postulated to have a role in protecting low-density lipoprotein (LDL) against oxidative modification. Oxidation of serum LDL is an important early step in the development of atherosclerosis and auto-antibodies against oxidized LDL (AuAb-oxLDL) reflect in-vivo LDL oxidation. DESIGN AND METHODS: To examine the effect of atorvastatin (10 mg/day) therapy on PON activity in serum and HDL, the study group included 40 patients with dyslipidemia (19 women and 21 men), 25 of whom had hypercholesterolemia and of 15 of whom had mixed-type hyperlipidemia. By taking blood samples from the patients, levels of serum lipids, lipid peroxidation product as malondialdehyde (MDA), total antioxidant status (TAS) and AuAb-oxLDL and the activities of PON in serum and isolated HDL were determined. RESULTS: The mean levels of total cholesterol, triglyceride, LDL-cholesterol, MDA and AuAb-oxLDL were decreased while HDL-cholesterol and TAS were increased significantly after lipid-lowering therapy in patients with dyslipidemia. On the other hand, PON activities in serum and HDL were increased significantly. The percentage increase in serum PON activity was associated significantly with the percentage decrease in serum AuAb-oxLDL (r=-0.32, P=0.047) and that of HDL PON activity was associated with the percentage increase in HDL-cholesterol level after atorvastatin therapy (r=0.52, P=0.001). The therapy was more effective in increasing PON activity in patients with HDL levels above 35 mg/dl. CONCLUSION: It was concluded that atorvastatin therapy in dyslipidemic patients decreases the level of oxidative stress and increases PON activity, especially in patients with HDL levels above 35mg/dl.

Adult↗
PubMed1991

Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins.

One hundred and sixty-three healthy Chinese subjects of both sexes were studied for serum paraoxonase (PON) polymorphism, and levels of lipids and apolipoproteins in order to examine effects of PON alleles on these parameters. The level of serum triglyceride was significantly higher in high activity allele (PON*B) compared with that in low activity allele (PON*A) in both sexes (P less than 0.01). The subjects with PON A had significantly higher LDL cholesterol (P less than 0.05) and lower Apo A-II and ApoB levels. The influence of serum paraoxonase on serum lipids was estimated further by Spearman's rank correlation. In the males, there was a significant negative correlation of serum paraoxonase activity with total (P less than 0.05) and LDL (P less than 0.01) cholesterol levels, and positive correlation with HDL cholesterol and Apo A-II levels (P less than 0.05). Serum paraoxonase activity had a high positive correlation with serum triglyceride levels in both sexes (P less than 0.001). Serum ApoB level had a positive correlation with the enzyme activity only in females (P less than 0.01). The allelic effect of PON on these parameters was studied by multiple regression analysis. The high activity allele (PON*B) was associated with higher serum triglyceride level (P less than 0.001) and ApoB (P less than 0.001), while it had lowering influence on total cholesterol (P less than 0.05) and LDL cholesterol (P less than 0.005) in men. The average allelic effect of PON was found to be about 22% for serum triglycerides, 11% for LDL cholesterol, 14% for Apo A-II and 19% for Apo B in the present study. This study suggests a possible significant role of serum paraoxonase alleles in the metabolism of serum lipids and apolipoproteins.

Adult↗
PubMed1999

Serum paraoxonase activity changes in uremic and kidney-transplanted patients.

Serum paraoxonase (PON) is a high-density lipoprotein (HDL)-associated hydrolase, which inhibits low-density lipoprotein oxidation. Uremic and kidney-transplanted patients have an increased risk of atherosclerosis, to which an increased lipoprotein oxidation may contribute. The aim of our study was to determine whether the PON activity or phenotype is altered in uremic and kidney-transplanted patients, and to compare the values with those of healthy controls. 117 uremic patients on long-term hemodialysis treatment, 115 renal-transplanted patients, and 110 healthy controls were involved in the study. The PON activity was significantly reduced in the uremic patients compared to controls (PON 101.36+/-30. 12 vs. control 188.05+/-58.96 U/ml; p < 0.001), while in kidney-transplanted patients the values were almost identical to those of controls (PON 161.5+/-35.39 U/ml). The different immunosuppressive drug combinations did not influence PON activity. To assess whether the altered PON activity was due to a decrease HDL level, we standardized the enzyme activity for the HDL concentration (PON/HDL ratio). We found that the standardized enzyme activity was lower in the uremic (102.7+/-54.8) and kidney-transplanted patients (144.5+/-32.7) when compared to controls (194.5+/-94.5; p < 0.001). The phenotypic distribution of PON in uremic, renal transplant and control patients are as follows: AA 66.67, 56.48 and 66.67%; AB 31. 62, 33.3 and 26.67%; BB 1.71, 10.19 and 6.67%. We conclude that the decreased PON/HDL and PON/apoA-1 ratios may lead to a reduction in the antioxidant capacity of HDL, which might contribute to the accelerated development of atherosclerosis in uremic and kidney-transplanted patients.

Adult↗
PubMed2005

Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities.

The paraoxonase (PON) gene family in humans has three members, PON1, PON2, and PON3. Their physiological role(s) and natural substrates are uncertain. We developed a baculovirus-mediated expression system, suitable for all three human PONs, and optimized procedures for their purification. The recombinant PONs are glycosylated with high-mannose-type sugars, which are important for protein stability but are not essential for their enzymatic activities. Enzymatic characterization of the purified PONs has revealed them to be lactonases/lactonizing enzymes, with some overlapping substrates (e.g., aromatic lactones), but also to have distinctive substrate specificities. All three PONs metabolized very efficiently 5-hydroxy-eicosatetraenoic acid 1,5-lactone and 4-hydroxy-docosahexaenoic acid, which are products of both enzymatic and nonenzymatic oxidation of arachidonic acid and docosahexaenoic acid, respectively, and may represent the PONs' endogenous substrates. Organophosphates are hydrolyzed almost exclusively by PON1, whereas bulky drug substrates such as lovastatin and spironolactone are hydrolyzed only by PON3. Of special interest is the ability of the human PONs, especially PON2, to hydrolyze and thereby inactivate N-acyl-homoserine lactones, which are quorum-sensing signals of pathogenic bacteria. None of the recombinant PONs protected low density lipoprotein against copper-induced oxidation in vitro.

Aryldialkylphosphatase↗
PubMed2001

Decreased stability of the M54 isoform of paraoxonase as a contributory factor to variations in human serum paraoxonase concentrations.

There are considerable variations in serum concentrations of the high density lipoprotein (HDL)-associated enzyme, paraoxonase (PON), which is an important determinant of the antioxidant capacity of HDL. The present study examined the hypothesis that differences in the stability of isoforms arising from the coding region L54M polymorphism could contribute to such variations. A model system was developed using transfected Chinese hamster ovary cells to secrete recombinant PON corresponding to human L or M isoforms. The recombinant peptides exhibited the molecular properties of human serum PON. They formed complexes with lipoproteins in culture medium, notably binding to apolipoprotein A-I-containing particles. The enzymatic properties of the recombinant isoforms were comparable to those of human serum PON. The recombinant M isoform lost activity more rapidly and to a greater extent than the recombinant L isoform [26.0 +/- 3.0% vs. 14.0 +/- 1.0% (phenylacetate substrate) and 36.1 +/- 2.0% vs. 19.3 +/- 2.0% (paraoxon substrate) over 96 h (P < 0.01)] in medium containing fetal calf serum or PON-free human serum. Addition of a protease inhibitor resulted in retention of activity by both isoforms. Parallel results were obtained in incubation studies of human serum from donors homozygous LL or MM for the L54M polymorphism. Enzyme activity was lost more rapidly and to a greater extent from MM than LL sera (P < 0.01). A parallel loss of PON peptide mass was also observed, with a significantly greater loss from MM homozygotes (P < 0.001). It corresponded to the appearance of a smaller molecular mass band on SDS-PAGE analysis. Direct analysis of the proteolytic effect using HDL isolated from homozygotes and incubated with purified kallikrein confirmed the greater loss of activity from MM homozygotes and the protective effect of proteolysis inhibitor. The results provide evidence for lesser stability of the M54 isoform of PON, apparently involving greater susceptibility to proteolysis. It provides one mechanism to explain variations in serum levels of PON and has implications for the antioxidant capacity of HDL.

Animals↗
PubMed2001

Serum lipid levels and M/L55 allele distribution of HDL paraoxonase gene in Saami and Finnish men.

Paraoxonase (PON) is an antioxidative enzyme, which eliminates lipid peroxides. The mutation in codon 55 of PON1 gene causes a change of methionine (M-allele) to leucine (L-allele) and influences PON activity. The Saami are a population living in the northern part of Fennoscandia. In previous studies their death rate from coronary artery disease (CAD) was found to be low. We compared PON M/L55 allele frequencies of 68 Saami and 68 Finnish men and related the PON genotypes to plasma lipid levels and to the levels of autoantibodies against oxidized LDL. The M/L55 genotypes were determined by PCR and restriction enzyme digestion. ELISA was used to measure antibodies against oxidized LDL. The L- and M-allele frequencies were 64% and 36% in Saami population and 64% and 36% in Finnish men, respectively (p = NS, Fisher's exact test). There were also no significant differences in plasma lipid levels or in antibody levels against oxidized LDL between PON genotypes or between Saami and Finnish men. Our results indicate that the PON M/L55 genotype is not associated with plasma lipid levels or the levels of autoantibodies against oxidized LDL in these populations. The Saami men have the same PON M/L55 allele distribution as the Finnish men and the PON genotype might thus not be one factor protecting Saami against CAD.

Analysis of Variance↗
PubMed2006

[Relationship between paraoxonase 1 55 Met/Leu, paraoxonase 2 148 Ala/Gly genetic polymorphisms and coronary artery disease].

OBJECTIVE: To study the relationships between paraoxonase 1 55 Met/Leu (PON1 55Met/Leu), paraoxonase 2 148 Ala/Gly(PON2 148Ala/Gly) genetic polymorphisms and coronary artery disease(CAD), plasma activities of paraoxonase (PON), total superoxide dismutase (T-SOD), as well as plasma concentration of maleic dialdehyde (MDA). METHODS: The PCR-RFLP method was applied to identify the genetic polymorphisms of PON1 55Met/Leu and PON2 148Ala/Gly, and the colorimetry way was used to detect plasma activities of PON, T-SOD and plasma MDA concentration of 262 CAD patients and 100 controls. RESULTS: Comparing with control, the CAD patient had the obviously lower activities of enzymes PON (349.27+/- 138.36 nmol/min.mL vs 454.75+/- 166.00 nmol/min.mL, P< 0.001) and T-SOD (23.61+/- 16.51 U/mL vs 44.01+/- 22.68 U/mL, P< 0.001) while getting the plasma MDA concentration increased markedly(2.47+/- 0.73 nmol/mL vs2.15+/- 0.55 nmol/mL, P< 0.01). The CAD patient had more LM genotype and M allele of PON1 55Met/Leu(24.8% vs 1.4%, P< 0.001 and 12.4% vs 0.5%, P was 0.001 respectively), GG and AG genotype and G allele of PON2 148 Ala/Gly(11.8% vs 5.0%, P< 0.001; 48.1% vs 24.0%, P< 0.001 and 36.0% vs 17.0%, P< 0.001 respectively) than control did. The activities of plasma PON and T-SOD were lower in individuals with PON??1 55 LM genotype than those with LL genotype(304.73+/- 125.04 vs 394.84+/- 154.87 nmol/min.mL and 24.89+/- 16.14 vs 30.22+/- 21.29 U/mL, P< 0.001 and P< 0.05 respectively). The activity of plasma PON was also lower in individuals with PON2 148 GG/AG genotype than that with AA genotype(281.47+/- 84.70 vs 356.00+/- 145.95 vs 417.34+/- 159.00 nmol/min.mL, P< 0.001). Logistic regression analysis showed that PON1 55 LM genotype (OR 29.08, 95%CI 2.88-294.04, P was 0.004) and M allele(OR 15.17, 95%CI 1.32-174.29, P was 0.029), PON2 148 GG/AG genotype (OR 2.32, 95%CI 1.52-3.54, P< 0. 001) and G allele (OR 3.24, 95%CI 1.38-7.61, P was 0.007) were independent risk factors for CAD. CONCLUSION: The CAD patient has the obviously low activities of plasma PON and T-SOD but on the contrary, get the plasma MDA concentration increased markedly. PON1 55 LM genotype and M allele, PON2 148 GG/AG genotype and G allele are the risk factors for coronary artery disease, and the activity of plasma PON is also markedly reduced in individuals with above genotypes.

Adult↗