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PubMed1999

Catalase and paraoxonase in hypertensive type 2 diabetes mellitus: correlation with glycemic control.

OBJECTIVES: Type 2 diabetes mellitus (DM) is well recognized as being associated with increased prevalence of hypertension. Experimental and epidemiologic studies have shown that oxygen-free radicals are elevated because antioxidant enzyme activities are altered both in uncontrolled essential hypertension and DM itself. Recently paraoxonase (PON) has been recognized as an antioxidant enzyme that hydrolyzes lipid peroxides. The aim of this study is to evaluate simultaneously PON activities and antioxidant status in hypertensive type 2 DM cases and to establish any possible relationship between these parameters and duration of hypertension or diabetes, hemoglobin (Hb) A1c levels, and lipid parameters. DESIGN AND METHODS: Nineteen normotensive subjects with type 2 DM, 37 hypertensive (diastolic blood pressure 90 mm Hg or more) subjects with type 2 DM, and 25 normotensive control subjects with normal glucose tolerance were selected for this study. Superoxide dismutase (SOD), catalase, and basal-stimulated PON activities were measured by the methods of Sun et al.; Goth; and Eckerson, Wyte, and La Du, respectively; other lipid parameters were determined using an autoanalyzer. RESULTS: Catalase activities of either hypertensive patients with type 2 DM or type 2 DM patients without complication were found to be higher than controls (p<0.01), although no significant difference in SOD and basal-stimulated PON activities was observed between these groups. A significant elevation in catalase activity (p = 0.004) of patients with high HbA1c levels (>7.0%) (n = 37) compared with patients with low HbA1c levels (<7.0%) (n = 19) was detected. There was also a positive correlation between the catalase activities and fasting glucose levels and HbA1c concentrations in hypertensive patients with type 2 DM (r = 0.4567, p<0.05 and r = 0.3686, p<0.05, respectively). An increase in catalase activity of patients with B and/or AB phenotype compared with patients with A phenotype was also noted. CONCLUSION: Poor glycemic control in diabetes is strongly associated with an increase in free radicals and consequent diabetic complications. Uncontrolled glucose metabolism may also be the cause of alterations in antioxidant enzymes. Among these, catalase correlates best with poor glycemic control. The current data reveal that B allele carriers of PON are more susceptible to oxidant stress.

Aged↗
PubMed2001

Paraoxonase producing PON1 gene M/L55 polymorphism is related to autopsy-verified artery-wall atherosclerosis.

Paraoxonase (PON) is an antioxidative enzyme, which eliminates lipid peroxides. PON has two common polymorphisms (M/L55 and R/Q192) that influence PON concentration and activity. We studied whether the M/L55 or R/Q192 genotype relates with the severity of atherosclerosis of the abdominal aorta, and the mesenteric and common iliac arteries in 123 consecutive autopsy cases (90 males and 33 females, aged 18-93 years). The severity of atherosclerosis in the arteries was evaluated, and the percentage of stenosis was measured. The intimal thickness in the internal elastic lamina (IEL) of the coeliac (CA), superior mesenteric (SMA) and inferior mesenteric (IMA) arteries were measured by light-microscopy. The LL homozygous men had more atherosclerotic plaques and complicated lesions in the common iliac arteries (56.8%) than the M allele carriers (28.3%, P=0.007). In logistic regression analysis, age (P<0.001) and the PON M/L55 genotype (P=0.015) were associated significantly with the severity of atherosclerosis in the common iliac arteries independent of smoking status, R/Q192 genotype, hypertension, diabetes mellitus, BMI and sex. The mean intima of the IMA was significantly thicker (P=0.035) and the number of stenotic lesions in SMAs significantly higher (P=0.008) in the LL homozygous men than M allele carriers. In turn, the R/Q192 genotype was not statistically significantly associated with plaque type, intimal thickness in the IEL or with the number of stenotic lesions. This study demonstrates that PON L55 homozygosity is an independent risk factor for autopsy-verified atherosclerosis in Finns.

Adult↗
PubMed2002

Dietary determinants of serum paraoxonase activity in healthy humans.

The associations between habitual diet and a variety of markers of lipid peroxidation or oxidative stress in a group of 95 healthy comparatively young Finnish volunteers (24 male and 71 females) were investigated. The habitual diet of the subjects was evaluated with a 3-day food record. The following biochemical parameters related to lipid peroxidation or oxidative stress were measured: lagtime of Cu2+ induced LDL oxidation in vitro, lipid hydroperoxides and Schiff bases produced during the LDL oxidation test, malondialdehyde measured as thiobarbituric acid-reactive substances from native LDL and Cu2+ oxidized LDL, serum paraoxonase (PON) activity. Serum PON activity showed most constantly associations with habitual diet. PON activity correlated negatively (r=-0.31 to -0.37) with intake of vegetables, total and water-soluble fiber, as well as intake of beta-carotene. Highly significant difference (P=0.005) in PON activity between lowest (<135 g/day) and highest (>256 g/day) vegetable intake quartiles was found. Malondialdehyde levels showed conflicting associations with diet. The results suggest that the significantly lower PON activity associated with high vegetable intake needs to be studied further.

Adult↗
PubMed1998

Partner of Numb colocalizes with Numb during mitosis and directs Numb asymmetric localization in Drosophila neural and muscle progenitors.

During mitosis of multiple types of precursor cells in Drosophila, Numb is asymmetrically distributed between the two daughter cells and confers distinct daughter cell fates. Here we report the identification of a novel gene product, Partner of Numb (PON), based on its physical interaction with Numb. PON is asymmetrically localized during mitosis and colocalizes with Numb. Loss of pon function disrupts Numb localization in muscle progenitors and delays Numb crescent formation in neural precursors. Moreover, ectopically expressed PON responds to the apical-basal polarity of epithelial cells and is sufficient to localize Numb basally. We propose that PON is one component of a multimolecular machinery that localizes Numb by responding to polarity cues conserved in neural precursors and epithelial cells.

Amino Acid Sequence↗
PubMed2003

Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese.

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.

Amino Acid Substitution↗
PubMed1990

Preoccipital cortex receives a differential input from the frontal eye field and projects to the pretectal olivary nucleus and other visuomotor-related structures in the rhesus monkey.

The bidirectional axonal transport capabilities of the horseradish peroxidase (HRP) technique facilitated the study of the frontal-eye-field (FEF) input and pretectal output of two regions of extrastriate preoccipital cortex (POC). Following horseradish peroxidase (HRP) gel implants into the middle and dorsal POC in two rhesus monkeys, the middle POC implant demonstrated retrograde frontal cortical labeling largely restricted to the inferior frontal eye field (iFEF) and adjacent inferior prefrontal convexity, whereas the dorsal POC implant showed labeling in the caudal ventral bank of the superior ramus of the arcuate sulcus (sas) and middle-to-dorsal region of the rostral bank of the concavity of the arcuate sulcus (dorsal FEF). Prominent anterogradely labeled efferent preoccipital projections were observed to the ipsilateral pretectal olivary nucleus (PON) and to a lesser extent the anterior pretectal nucleus. Although the middle POC case had heavier projections to the lateral PON, the dorsal case projected more heavily to the medial PON. In addition, both implants demonstrated subcortical connections with the lateral and dorsal inferior pulvinar nuclei, central superior lateral thalamic intralaminar nucleus, caudate nucleus, and middle-to-ventral claustrum. However, while the middle POC implant had efferent projections to the superficial superior colliculus (SC), pregeniculate nucleus (PGN), lateral terminal accessory optic nucleus (LTN), and dorsolateral pontine nucleus (DLPN), resembling those previously reported for the middle temporal (MT) visual area (Maunsell & Van Essen, 1982; Ungerleider et al., 1984), the dorsal implant had projections to the lateral intermediate SC, zona incerta (ZI), PGN, a notably lesser projection to the LTN, and basilar pontine projections to the lateral and lateral dorsal pontine subnuclei (not including the extreme dorsolateral DLPN). These preliminary results suggest that the preoccipital cortex, which reportedly functions in pupillary constriction, accommodation, and convergence, entertains connections with the PON and other visuomotor-related structures, and thus could act as an intermediary in the pathway between the iFEF and PON, and provide a possible explanation for pupillary effects that occur with stimulation of the FEF (Jampel, 1960) and within the contex of other oculomotor activities. The findings shed light on certain differences in connections of middle vs. dorsal POC with visuomotor-related nuclei, and appear to suggest that the middle region, which receives input from the iFEF, has greater access to the optokinetic (OKN) system by virtue of its projection to the LTN, and to the smooth-pursuit system b

Afferent Pathways↗
PubMed1998

Interleukin 1beta decreases prostacyclin synthase activity in rat mesangial cells via endogenous peroxynitrite formation.

We have reported that peroxynitrite (PON) selectively inactivated prostacyclin synthase (PGIS) by a mechanism of tyrosine nitration at the active site [Zou, Martin and Ullrich (1997) Biol. Chem. Hoppe-Seyler 378, 707-713]. We have now extended our studies on rat mesangial cells (RMC) and show that nitration can occur under the influence of cytokines. Pretreatment of RMC with interleukin 1beta (IL-1beta), which up-regulated cyclo-oxygenase 2 and inducible nitric oxide synthase (NOS-2), significantly attenuated the conversion of [14C]prostaglandin H2 (PGH2) into the stable prostacyclin (PGI2) metabolite 6-oxo-prostaglandin F1alpha (6-oxo-PGF1alpha). The presence of superoxide dismutase (SOD, 100 units/ml) or the NOS synthase inhibitor Nomega-monomethyl-l-arginine (100 microM) as well as cycloheximide (10 microM) plus actinomycin (10 microM) abolished IL-1beta-mediated down-regulation of 6-oxo-PGF1alpha from PGH2. At the same time, 6-oxo-PGF1alpha production from arachidonate (AA) increased at the expense of prostaglandin E2 (PGE2). Neither NO alone generated from different NO donors nor superoxide from xanthine/xanthine oxidase (1-100 m-units/ml) inhibited PGI2 synthesis, either from PGH2 or from AA. Bolus additions of chemically synthesized PON or the PON generator 3-morpholinosydnonimine N-ethylcarbamide (SIN-1) exhibited a potent inhibition of 6-oxo-PGF1alpha release from both PGH2 and AA. In addition, immunoprecipitation of nitrotyrosine-containing proteins from PON- and SIN-1-treated RMC yielded distinct nitrated PGIS bands but also from IL-1beta-pretreated cells alone, compared with a lack of nitrated PGIS in control cells. Taken together, our results strongly suggest that IL-1beta pretreatment of RMC via NOS-2 leads to the production of PON with the consequence of a partial nitration and inhibition of PGIS.

Animals↗
PubMed1998

A longitudinal analysis of alteration in lecithin-cholesterol acyltransferase and paraoxonase activities following laparoscopic cholecystectomy relative to other parameters of HDL function and the acute phase response.

The composition of high-density lipoprotein (HDL) changes during inflammation; however, potential changes of HDL function during inflammation and the effects of acute phase proteins that are either on the HDL particles or in the serum have not been clarified. The concentrations of C-reactive protein (CRP), serum amyloid A protein (apoSAA) isoforms, lipids and apolipoproteins, and the activities of lecithin-cholesterol acyltransferase (LCAT) and paraoxonase (PON) were measured before and after laparoscopic cholecystectomy, in 12 patients with cholecystolithiasis to clarify the function of acute-phase HDL and the relationship between acute-phase proteins and HDL functions. Both acute-phase apoSAA (A-apoSAA) and CRP increased, reached their maximum levels 3-6 days after the operation, and then returned to preoperative levels after 2 weeks. In contrast, apolipoproteins and LCAT decreased reciprocally, reached their minimum levels 3-6 days after the operation, and returned to preoperative levels after 2 weeks. However, PON decreased 3-6 days after the operation, and remained low even after 2 weeks. At the nadir the mean activities of LCAT and PON were 56 and 76% of the preoperative levels, respectively. HDL-cholesterol or constitutive apoSAA did not change significantly. LCAT has been reported to be involved in reverse-cholesterol transport and PON to be preventive for lipid peroxidation of low-density lipoprotein in vitro. Thus, during the acute phase of inflammation, HDL may be altered to an atherogenic state due to a decrease in LCAT and PON activities. Therefore, this longitudinal analysis was carried out to determine whether HDL function is modified in a single episode of inflammation and thus may contribute to the occurrence of atherosclerotic disease in patients with chronic or recurrent acute inflammation.

Acute-Phase Reaction↗
PubMed2003

Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization.

Serum paraoxonases (PONs) are a group of enzymes that play a key role in organophosphate (OP) detoxification and in prevention of atherosclerosis. However, their structure and mechanism of action are poorly understood. PONs seem like jacks-of-all-trades, acting on a very wide range of substrates, most of which are of no physiological relevance. Family shuffling and screening lead to the first PON variants that express in a soluble and active form in Escherichia coli. We describe variants with kinetic parameters similar to those reported for PONs purified from sera and others that show dramatically increased activities. In particular, we have evolved PON1 variants with OP-hydrolyzing activities 40-fold higher than wild type and a specificity switch of >2,000-fold, producing PONs specialized for OP rather than ester hydrolysis. Analysis of the newly evolved variants provides insights into the evolutionary relationships between different family members.

Aryldialkylphosphatase↗
PubMed2000

Oxidized phospholipids induce changes in hepatic paraoxonase and ApoJ but not monocyte chemoattractant protein-1 via interleukin-6.

In this study, we tested if interleukin-6 (IL-6) plays a role in mediating the effects of oxidized phospholipids (OXPL). Treatment of HepG2 cells with oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphoryl choline (OX-PAPC), or biologically active lipids present in mildly oxidized low density lipoprotein, increased apolipoprotein J (apoJ), and decreased paraoxonase (PON) mRNA levels. Antibodies to IL-6 blocked these changes. IL-6 treatment in the absence of OXPL produced the same pattern of mRNA changes observed with OXPL treatment alone. In vivo, OX-PAPC injected into C57BL/6J mice resulted in a marked reduction in PON activity and an increase in apoJ levels in plasma after 16 h. Injection of OX-PAPC into IL-6-deficient C57BL/6J mice (IL-6 -/-) did not alter either PON activity or apoJ levels. We then tested if other mechanisms involved in fatty streak formation depended upon IL-6. Antibody to IL-6 had no effect on OX-PAPC-induced secretion of MCP-1 by endothelial cells nor on MCP-1 mRNA expression in HepG2 cells. C57BL/6J and IL-6 -/- mice fed an atherogenic diet both demonstrated markedly reduced plasma PON activities and the IL-6 -/- mice developed fatty streaks to a greater degree than wild-type mice. We conclude that IL-6 is critical to short term but not long term regulation of PON and that IL-6 is not required for OXPL regulation of MCP-1.

Animals↗
PubMed1994

Perturbation of cell adhesion and microvilli formation by antisense oligonucleotides to ERM family members.

To examine the functions of ERM family members (ezrin, radixin, and moesin), mouse epithelial cells (MTD-1A cells) and thymoma cells (L5178Y), which coexpress all of them, were cultured in the presence of antisense phosphorothioate oligonucleotides (PONs) complementary to ERM sequences. Immunoblotting revealed that the antisense PONs selectively suppressed the expression of each member. Immunofluorescence microscopy of these ezrin, radixin, or moesin "single-suppressed" MTD-1A cells revealed that the ERM family members are colocalized at cell-cell adhesion sites, microvilli, and cleavage furrows, where actin filaments are densely associated with plasma membranes. The ezrin/radixin/moesin antisense PONs mixture induced the destruction of both cell-cell and cell-substrate adhesion, as well as the disappearance of microvilli. Ezrin or radixin antisense PONs individually affected the initial step of the formation of both cell-cell and cell-substrate adhesion, but did not affect the microvilli structures. In sharp contrast, moesin antisense PONs did not singly affect cell-cell and cell-substrate adhesion, whereas it partly affected the microvilli structures. These data indicate that ezrin and radixin can be functionally substituted, that moesin has some synergetic functional interaction with ezrin and radixin, and that these ERM family members are involved in cell-cell and cell-substrate adhesion, as well as microvilli formation.

Animals↗
PubMed2004

Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury.

The role of reactive oxygen-induced oxidative damage to lipids (i.e., lipid peroxidation, LP) and proteins has been strongly supported in previous work. Most notably, a number of free radical scavengers and lipid antioxidants have been demonstrated to be neuroprotective in traumatic brain injury (TBI) models. However, the specific sources of reactive oxygen species (ROS), the time course of oxidative damage and its relationship to post-traumatic neurodegeneration in the injured brain have been incompletely defined. The present study was directed at an investigation of the role of the ROS, peroxynitrite (PON), in the acute pathophysiology of TBI and its temporal relationship to neurodegeneration in the context of the mouse model of diffuse head injury model. Male CF-1 mice were subjected to a moderately severe head injury and assessed at 1-, 3-, 6-, 12-, 24-, 48-, 72, 96- and 120-h post-injury for neurodegeneration using quantitative image analysis of silver staining and semi-quantitative analysis of PON-mediated oxidative damage to proteins (3-nitrotyrosine, 3-NT) and lipids (4-hydroxynonenal, 4-HNE). Significant evidence of silver staining was not apparent until 24-h post-injury, with peak staining seen between 72- and 120-h. This time-course of neurodegeneration was preceded by intense immunostaining for 3-NT and 4-HNE, which occurred within the first hour post-injury. The time course and staining pattern for 3-NT and 4-HNE were similar, with the highest staining intensity noted within the first 48-h in areas surrounding trauma-induced contusions. In the case of 3-NT, neuronal perikarya and processes and microvessels displayed staining. The temporal and spatial coincidence of protein nitration and LP damage suggests that PON is involved in both. However, lipid-peroxidative (4-HNE) immunoreactivity was broader and more diffuse than 3-NT, suggesting that other reactive oxygen mechanisms, such as iron-dependent LP, may also contribute to the more widespread 4-HNE immunoreactivity. This indicates that optimal pharmacological inhibition of post-traumatic oxidative damage in TBI may need to combine two functionalities: one to scavenge PON or PON-derived radicals, and the second to inhibit LP caused by multiple ROS species.

Aldehydes↗
PubMed2003

Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers.

Pesticides, such as parathion, are metabolized by cytochrome p-450 system to paraoxon, which is a potent cholinesterase inhibitor. Paraoxonase (PON) catalyzes the hydrolysis of these toxic metabolites and protects against pesticide toxicity. A glutamine/arginine (Gln/Arg) polymorphism at amino acid position 192 of PON has been described. The Arg/Arg genotype is associated with higher serum paraoxonase activity compared to Gln/Gln. The Arg/Gln genotype is associated with intermediate serum PON activity. The potential association between PON genotype and symptoms of chronic pesticide toxicity was examined among 100 farm workers. As part of a cross-sectional study of pesticide toxicity among mixed-race farm workers in the Western Cape. South Africa, 100 farm workers were genotyped for polymorphism of the paraoxonase gene at amino acid position 192. Subjects with two or more of the following symptoms were considered to have evidence of chronic toxicity: abdominal pain, nausea, rhinorrhea, dizziness, headache, somnolence, fatigue, gait disturbance, limb numbness, paresthesias, limb pain, or limb weakness. In multivariable logistic regression analysis, the independent predictors of chronic toxicity were previous history of head trauma resulting in loss of consciousness (OR 2.8, 95% CI = 1.7-6.7), having worked as a pesticide applicator (OR 5.4, 95% CI = 3.2-8.9), and having one of the two "slow metabolism" (Gln/Gln or Gln/Arg) genotypes (OR 2.9, 95% CI = 1.7-6.9). Furthermore, the prevalence of chronic toxicity increased in a stepwise fashion from 15% among pesticide nonapplicators with a "fast metabolism" (Arg/Arg) genotype, to 42.9% among pesticide nonapplicators with "slow metabolism" (Gln/Gln or Gln/Arg) genotypes, to 58.8% among pesticide applicators with "fast metabolism" genotype, and 75.0% among pesticide applicators with "slow metabolism" genotypes (P = 0.001). Age, number of years on the job, smoking history, alcohol history, education level, plasma or red blood cell cholinesterase level, or previous history of acute organophosphate poisoning were not statistically significant predictors of chronic toxicity. The PON genotype is an important determinant of a farmworker's susceptibility to chronic pesticide poisoning.

Adult↗
PubMed2005

The paraoxonase-2-310 polymorphism is associated with the presence of microvascular complications in diabetes mellitus.

OBJECTIVE: To investigate the paraoxonase-2 (PON 2)-C/S 310 polymorphism and its relationship to the presence of diabetic complications and glycaemic control. DESIGN: Case-control study. SETTING: One study centre at University hospital. MATERIALS AND METHODS: The subjects were people with type 2 diabetes (n=252), type 1 diabetes (n=152) and healthy controls (n=282). The PON 2-C/S 310 polymorphism was measured by restriction fragment length polymorphism analysis. Lipids and lipoproteins were measured by standard clinical chemistry methods. Diabetes and diabetic complications were defined by World Health Organization criteria. RESULTS: There was an over-representation of the C/C 310 genotype in those with diabetes and microvascular complications (type 2 diabetes P=0.043, type 1 diabetes P=0.052, both populations combined P=0.014). The PON 2-C/S 310 polymorphism was also associated with glycaemic control. C 310/C 310 homozygotes had the highest HbA(1c) concentration (P=0.020 type 2 diabetes, P=0.065 type 1 diabetes, P=0.035 both populations combined). There was no association between the PON 2-310 polymorphism and lipid and lipoprotein concentrations. CONCLUSIONS: PON 2 could be directly involved in protecting critical enzymes or organelles against oxidative damage; PON2 may thus predispose to the development of microvascular complications.

Adult↗
PubMedDate not supplied

Presence of neuropeptide--Y and its C-terminal flanking peptide immuno-reactivity in the seminiferous tubules of human testis.

The presence of neuropeptide Y (NPY) and its C-terminal flanking peptide (C-PON) was described by immunohistochemistry in human testes. The immunopositive material was visualized in the spermatogenic elements of the seminiferous tubules. More NPY occurred in the younger testis and more C-PON in the older ones. NPY positive material was present mainly in the spermatogonia, and in the primary spermatocytes, where C-PON also occurred. The megalospermatocytes, present in aged testis, showed C-PON immunoreactivity. Both NPY and C-PON were present in granular form in the perinuclear zone of the cells. No positive material was detected in the Sertoli cells or in the Leydig cells. It is possible that NPY and its precursor are synthetized within the testis and might play a role in the paracrine and/or autocrine regulation of spermatogenesis.

Adult↗
PubMed2006

Rosiglitazone modulates fasting and post-prandial paraoxonase 1 activity in type 2 diabetic patients.

1. In the present study, we have explored the effect of rosiglitazone on post-prandial paraoxonase (PON)-1, an enzyme with potent anti-oxidant properties that may protect against atherosclerosis because increased post-prandial lipaemia, although sometimes understated, is part of the diabetic dyslipidaemia. 2. A randomized, cross-over, placebo-controlled, double-blind clinical trial was performed. Participants (19 type 2 diabetic patients on oral antihyperglycaemic agents) were randomly assigned to receive either placebo or rosiglitazone 4 mg twice daily for 8 weeks. After a 6 week wash-out, the alternative treatment was implemented. Standardized 6 h oral fat-loading tests were performed after each treatment period. 3. Patients assigned to rosiglitazone had increased fasting PON-1 activity (from 331 +/- 29 to 362 +/- 32 U/L before treatment vs after treatment, respectively; P = 0.015), although the PON-1 mass did not change (68.8 +/- 21.1 vs 64.2 +/- 25.4 mg/L before treatment vs after treatment, respectively). In addition, rosiglitazone significantly decreased fasting plasma peroxides compared with placebo (162 +/- 25 vs 214 +/- 28 mmol/L, respectively; P = 0.019). The post-prandial fall in PON-1 activity, expressed as area under the curve, was attenuated by rosiglitazone (-97 +/- 14 vs-161 +/- 24 Uh/L for rosiglitazone vs placebo, respectively; P = 0.02) and the increase in PON-1 activity caused by rosiglitazone correlated with reductions in fasting plasma glucose (r = -0.42; P < 0.05), homeostatic model assessment index (r = -0.59; P < 0.01) and peroxides (r = -0.40; P = 0.07). 4. The present data indicate that rosiglitazone may convey increased protection against the oxidative modification that represents increased post-prandial lipaemia.

Adult↗
PubMedDate not supplied

Decreased dopamine and increased norepinephrine levels in the spontaneously epileptic rat, a double mutant rat.

Dopamine (DA) and norepinephrine (NE) brain levels and turnover rate were examined in the spontaneously epileptic rat (SER: zi/zi, tm/tm), a double mutant rat obtained by mating tremor heterozygotes (tm/+) with zitter homozygotes associated with epileptic seizures composed of spontaneously occurring tonic convulsion and absence-like seizure. DA and NE levels were also determined in age-matched male zitter, tremor and Kyo: Wistar rats. DA levels in caudate nucleus were significantly lower in adult age (10-12 weeks) SER, which showed epileptic seizures, and zitter rats than in adult Kyo: Wistar and tremor rats. DA levels in other areas such as thalamus-hypothalamus, midbrain, and pons medulla were not different among SER, zitter, tremor, and Kyo: Wistar rats at age 10-12 weeks. Except in cerebral cortex and hippocampus, there were no differences in brain DA levels between young seizure-free SER (age 5 weeks) and young Kyo: Wistar rats. Furthermore, the turnover rate of DA was significantly lower in caudate nucleus of adult SER than of Kyo: Wistar rat, whereas in pons-medulla there was no difference between the two strains. In contrast, NE levels in the thalamus-hypothalamus, midbrain, cerebellum and pons-medulla were higher in SER and zitter rats at age 10-12 weeks than in age-matched tremor and Kyo: Wistar rats. Higher NE levels were also observed in midbrain, cerebellum, and pons-medulla of young SER as compared with young Kyo: Wistar rats. Turnover rates of NE were significantly lower in pons-medulla and cerebellum of the adult SER than in those of Kyo: Wistar rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed2006

Paraoxonase gene polymorphisms and haplotype analysis in a stroke population.

BACKGROUND: Paraoxonase (PON) has anti-atherogenic activity due to its protective function against low density lipoprotein (LDL) oxidation. Alteration of enzyme activity due to polymorphisms in the PON genes may influence the development of atheroma and thus affect stroke risk. Three PON genes (PON1, PON2 and PON3) have been identifiedand mapped to chromosome 7. METHODS: We looked at the distribution of paraoxonase polymorphisms and haplotype arrangement in 397 Caucasian ischaemic stroke patients and 405 controls. We investigated 6 different common single nucleotide polymorphisms (SNP) in PON genes; two substitutions in PON1 ["A/G": Gln (Q)/Arg (R)] at codon 192 and ["T/A": Leu (L)/Met (M)] at codon 55, two in PON2 at codon 311 ["G/A": Cys (C)/Ser (S)] and codon 148 ["C/G": Ala (A)/Gly (G)] and two SNPs, both "A" to "G" substitutions, in PON3--intronic rs2074353, which we designated PON3-1 and [Ala (A)/Ala (A)] at codon 99, designated as PON3-3. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay. Haplotype analysis was performed using both PHASE and EHPLUS programs. RESULTS: Genotype and allele frequencies were similar in cases and controls. Lipid profiles were not influenced by PON genotype. Haplotype frequencies for the six loci (PON2-148, PON2-311, PON3-3, PON3-1, PON1-55 and PON1-192) were estimated. Comparison of the two programs showed a significant difference in haplotype arrangements with EHPLUS (p-value = 0.005) but not with PHASE Ver.2 (p-value = 0.12). The 112211 (1 = frequent allele, 2 = rare allele) haplotype arrangement was commoner in cases than controls (p = 0.015), and the 111121 haplotype was commoner in controls (p = 0.006). CONCLUSION: Our study did not identify a role for individual paraoxonase gene polymorphisms in the pathogenesis of ischaemic stroke. Findings of haplotype differences should be confirmed in large scale studies. The importance of using a well-validated haplotype analysis program is also underlined.

Aged↗