Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased LDL oxidation is associated with coronary artery disease. The predictive value of circulating oxidized LDL is additive to the Global Risk Assessment Score for cardiovascular risk prediction based on age, gender, total and HDL cholesterol, diabetes, hypertension, and smoking. Circulating oxidized LDL does not originate from extensive metal ion-induced oxidation in the blood but from mild oxidation in the arterial wall by cell-associated lipoxygenase and/or myeloperoxidase. Oxidized LDL induces atherosclerosis by stimulating monocyte infiltration and smooth muscle cell migration and proliferation. It contributes to atherothrombosis by inducing endothelial cell apoptosis, and thus plaque erosion, by impairing the anticoagulant balance in endothelium, stimulating tissue factor production by smooth muscle cells, and inducing apoptosis in macrophages. HDL cholesterol levels are inversely related to risk of coronary artery disease. HDL prevents atherosclerosis by reverting the stimulatory effect of oxidized LDL on monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits the oxidation of LDL. PAF-acetyl hydrolase, which circulates in association with HDL and is produced in the arterial wall by macrophages, degrades bioactive oxidized phospholipids. Both enzymes actively protect hypercholesterolemic mice against atherosclerosis. Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are indeed antagonists in the development of cardiovascular disease.
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PMID:Oxidized LDL and HDL: antagonists in atherothrombosis. 1164 Dec 34

Type I diabetes is associated with a high incidence of coronary heart disease (CHD), despite a normal or even increased concentration of high-density lipoprotein (HDL) cholesterol. This paradox may be explained by changes in the antioxidant capacity of HDL, related to paraoxonase (PON1) activity. HDL compositional changes in subjects with Type I diabetes may result in changes in PON1 activity that are associated with a higher incidence of CHD. Single-vertical-spin density-gradient ultracentrifugation was used to isolate seven HDL fractions from serum according to density. PON1 activity was measured in serum and in the HDL fractions using phenyl acetate as substrate. The mean recovery of PON1 activity in the HDL fractions was 87% (S.D. 12%). CHD risk was assessed using B-mode ultrasound to measure carotid artery intima-media thickness (IMT). Groups of 35 subjects with Type I diabetes [duration of diabetes 18 years (12-32 years) [median (interquartile range)]; glycated haemoglobin 7.67% (1.17%)] and 24 non-diabetic control subjects were studied. Carotid IMT was greater in the diabetic subjects [0.60 (0.55-0.70) compared with 0.55 (0.45-0.64) mm; P=0.042] and HDL cholesterol concentration was higher [1.53 (0.36) compared with 1.32 (0.34) mmol/l; P=0.031]. There were qualitative differences in HDL in subjects with Type I diabetes: HDL particles were triacylglycerol-deplete, and there were greater numbers of the larger, more buoyant HDL particles. These properties were not those found to determine PON1 activity. PON1 activity increased as HDL particle density increased and particle size decreased; the increase in PON1 activity was associated with an increase in the ratio of the two HDL surface lipid components, phospholipid and unesterified cholesterol, as particle density increased. PON1 activity was similar in diabetic and non-diabetic subjects [121 (28) and 120 (36) micromol x min(-1) x ml(-1) respectively; P=0.887]. PON1 activity was not associated with carotid IMT in either group. Our results suggest that the PON1 activities of HDL particles relate to the density, size and composition of the particles. However, PON1 activity does not appear to contribute to the greater risk of CHD in subjects with Type I diabetes.
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PMID:High-density lipoprotein composition and paraoxonase activity in Type I diabetes. 1172 54

The gene of an esterase enzyme, called paraoxonase (PON, EC.3.1.8.1.) is a member of a multigene family that comprises three related genes PON1, PON2, and PON3 with structural homology clustering on the chromosome 7.(1,2) The PON1 activity and the polymorphism of the PON1 and PON2 genes have been found to be associated with risk of cardiovascular diseases such as hypercholesterolaemia, non-insulin-dependent diabetes, coronary heart disease (CHD) and myocardial infaction.(3-8) The importance of cardiovascular risk factors in the pathomechanism of Alzheimer's disease (AD) and vascular dementia (VD)(9-13) prompted us to examine the genetic effect of PON2 gene codon 311 (Cys-->Ser; PON2*S) polymorphism and the relationship between the PON2*S allele and the other dementia risk factor, the apoE polymorphism in these dementias. The PON2*C and PON2*S allele frequencies were similar in both AD (25% and 75%) and VD groups (23% and 77%), respectively, compared with the controls (27% and 73%). The ratio of the PON2*S carriers was significantly higher among the apoE4 allele carrier AD (27%) and VD (25%) groups than in the control (12%). Our results indicate that the PON2*S and apoE4 alleles have interactive effect on the development of the two most common forms of dementias AD and VD, and further support the hypothesis that cardiovascular factors contribute to the development of AD.
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PMID:Codon 311 (Cys --> Ser) polymorphism of paraoxonase-2 gene is associated with apolipoprotein E4 allele in both Alzheimer's and vascular dementias. 1180 56

To elucidate risk factors for cerebral amyloid angiopathy (CAA) in the elderly, we have investigated 201 autopsy cases of elderly Japanese (ages: 62-104 years), including 82 patients with Alzheimer's disease (AD). Severity of CAA showed no relationship with the history of hypertension, hyperlipidemia, or diabetes mellitus, nor with severity of atherosclerosis of cerebral and systemic arteries, indicating that common vascular risk factors would not be related to CAA. Incidence and severity of CAA were significantly higher in the AD cases compared with the non-AD cases (p < 0.0001). Severity of CAA correlated with densities of senile plaques and neurofibrillary tangles in total and non-AD cases, although the correlations were not significant within the AD cases. Associations of genetic polymorphisms with CAA have been investigated for genes of apolipoprotein E (APOE), presenilin 1 (PS1), alpha1-antichymotrypsin (ACT), butyrylcholinesterase, alpha2-macroglobulin, and paraoxonase. Severity of CAA in APOE epsilon4 carriers is significantly higher than that in non-epsilon4 carriers in total cases, although no significant difference was found in the CAA severity between the epsilon4 carriers and non-epsilon4 carriers within the AD or non-AD group. An intronic polymorphism of PS1 was significantly associated with the severity of CAA, indicating that the PS1 2/2 genotype may be related to lower risk of CAA. A polymorphism in the signal peptide sequence of ACT was significantly associated with the CAA severity in the AD group. Our results suggest that CAA shares risk factors with AD and that multiple genetic factors would be associated with the risk of CAA in the elderly.
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PMID:Risk factors for cerebral amyloid angiopathy in the elderly. 1248 Jul 32

Paraoxonase 1 (PON1), an A-esterase with peroxidase-like activity present on the surface of HDL, decreases the peroxidation of LDL. Serum PON1 activity (PON1a) decreases with aging and in disorders associated with a high risk of adverse cardiovascular events (acute myocardial infarction, diabetes mellitus, and chronic renal failure). The implication of vascular factors in Alzheimer-type dementia (ATD) is strongly suspected. We measured PON1a by spectrophotometry using the paraoxon substrate in 180 healthy subjects (controls; mean age: 75.3 +/- 8.9 years; 98 women) and 154 patients admitted for cognitive testing. According to criteria, 45 patients had mild cognitive impairments (MCI; mean age: 75.6 +/- 9.3 years; 28 women), 60 had ATD (mean age: 75.6 +/- 8.3 years; 47 women), and 49 had vascular dementia (VaD; mean age: 77.5 +/- 7.2 years; 33 women). Mean PON1a was lower in VaD (0.25 +/- 0.1 U/mL) than in controls or ATD (both 0.41 +/- 0.2 U/mL, p < 0.01). Mean PON1a values in MCI (0.34 +/- 0.2 U/mL) and ATD (0.41 +/- 0.2 U/mL) were not significantly different. In multiple linear regression, PON1a was negatively correlated with male sex, age, and VaD, and positively correlated with ATD (each correlation p < 0.001). As shown in other high-risk cardiovascular disorders, PON1a seems to be a reliable marker of VaD. Its modification in Alzheimer's disease supports the implication of vascular risk factors in this type of dementia.
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PMID:Paraoxonase 1 activity: a new vascular marker of dementia? 1248 Jul 37

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.
Diabetes Res Clin Pract 2003 Jul
PMID:Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese. 1284 20

The one disease associated with the greatest morbidity and mortality in industrialized countries is coronary heart disease (CHD). High density lipoprotein (HDL) is one of the most important independent protective factors for the arteriosclerosis which underlies CHD. Paraoxonase 1 (PON1) is an enzyme that confers antioxidant properties to HDL. In vitro, PON1 hydrolyzes a large variety of endogenous or exogenous substrates, some of which are clearly involved in the progression of arteriosclerosis. A close relationship between PON1 deficiency and accelerated progression of arteriosclerosis has been found in animal models. Moreover, PON1 activity is reduced in high oxidative stress diseases such as CHD, dyslipoproteinemias, inflammatory processes, diabetes and certain neuropathies. Reduced PON1 enzyme activity is associated with several arteriosclerosis-related diseases. The most thoroughly studied genetic variant of PON1 is PON1-192, in which the R allele is associated with elevated paraoxonase activity. This allele, present in 24.8% of the Italian population, is found in up to 78.9% of the population of Ecuadorian Cayapa Indians. A metaanalysis of studies on the relationship between CHD and the R allele showed the latter to be an independent risk factor for this disease, with an odds ratio of 1.18 (95% confidence interval, 1.10-1.27). The PON1 enzyme is a potentially useful new qualitative indicator in addition to the well known reverse cholesterol transport capacity associated with high plasma levels of HDL.
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PMID:[The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis]. 1522 2

We examined the effects of subchronic exposure to malathion, an organophosphorous (OP) insecticide, on plasma glucose and hepatic enzymes of glycogenolysis and gluconeogenesis in rats in vivo. Malathion was administered orally at doses of 100, 200 and 400 ppm for 4 weeks. At the end of the specified treatment (18 h fasting after the last dose of malathion), the liver was removed. The activities of glycogen phosphorylase (GP) and phosphoenolpyruvate carboxykinase (PEPCK) were analyzed in the homogenate. Four weeks administration of malathion at doses of 100 ppm, 200 ppm, and 400 ppm increased plasma glucose concentrations by 25% (P < 0.01), 17% (P < 0.01), and 14% (P < 0.01) of control, respectively. Malathion also increased hepatic PEPCK activity by 25% (100 ppm, P < 0.01), 16% (200 ppm, P < 0.01), and 21% (400 ppm, P < 0.01) of control, respectively. In addition, malathion increased hepatic GP by 22% (100 ppm, P < 0.01), 41% (200 ppm, P < 0.01), and 32% (400 ppm, P < 0.01) of controls. We conclude that exposure of rats to malathion as a widely used OP in subchronic exposure, which resembles human exposure, may induce diabetes associated with stimulation of hepatic gluconeogenesis and glycogenolysis in favor of glucose release into the blood. The possible mechanisms including increased energy production to detoxification, depressed paraoxonase activity, and increased production of cyclic nucleotides are discussed.
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PMID:Hyperglycemia associated with increased hepatic glycogen phosphorylase and phosphoenolpyruvate carboxykinase in rats following subchronic exposure to malathion. 1522 52

The high incidence of atherosclerosis in women after menopause is associated with a risk pattern including an increase in low density lipoprotein (LDL), even though high density lipoprotein (HDL) cholesterol levels tend to be maintained or slightly decreased. Since estrogens are considered potent antioxidants, an increase in lipid peroxidation and formation of reactive oxygen species would be expected after menopause. If HDL becomes oxidized, the ability to protect LDL against oxidation may be impaired. In postmenopausal women there are scarce reports concerning HDL oxidability and no data about its antioxidant activity. We studied copper-induced oxidation and conjugated dienes formation in HDL isolated from 58 women, 30 postmenopausal (PMW) and 28 premenopausal (PreMW). None presented diabetes or cardiovascular disease and none was receiving hormonal, hypolipidemic or antioxidant therapy either. In order to evaluate the effect of HDL on LDL oxidation we isolated LDL and HDL from the same subject and assessed copper-induced LDL oxidation in the presence of HDL, followed by thiobarbituric acid-reactive substances determination. Relationships with HDL chemical composition, alpha-tocopherol content, cholesteryl ester transfer protein (CETP) and paraoxonase activity (PON) were investigated. HDL chemical composition in PMW exhibited triglyceride enrichment when compared to PreMW (p <0.05). alpha-Tocopherol content and CETP activity were similar in both groups. However, CETP activity correlated positively with HDL triglyceride and negatively with HDL cholesterol percentage (r=0.44, p <0.01 and r=-0.32, p <0.05, respectively). Paraoxonase activity did not show differences between PMW and PreMW. When evaluating HDL oxidability, PMW revealed a shorter lag time in comparison to PreMW, even after adjustment for age, p <0.05. Moreover, when the effect of HDL on LDL oxidation was evaluated, HDL from PMW showed a reduction in its ability to inhibit LDL oxidation, compared to PreMW (p <0.05). In addition, the extent of inhibition of LDL oxidation by HDL was positively correlated with HDL resistance to oxidation (r=0.27, p <0.05). After women classification by paraoxonase phenotype, HDL ability to protect LDL against oxidation remained reduced only in PMW belonging to the PON QR phenotype, in comparison to PreMW QR. These results suggest that HDL from PMW exhibits impairment in its antioxidant ability, which is associated to a decreased HDL resistance to oxidation. In turn, this was related to triglyceride enrichment of HDL particles. All these alterations were independent from HDL cholesterol plasma levels.
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PMID:Impaired high density lipoprotein antioxidant activity in healthy postmenopausal women. 1548 85

The effect of various doses (0, 10, 20, 40, or 80 mg/kg body weight) of naringin (a citrus flavonone) was studied on streptozotocin (STZ)-induced hyperglycaemic rats to evaluate the possible hypoglycaemic and antioxidant activity of naringin in diabetes. In comparison to the normoglycaemic group the treatment of rats with a single dose of STZ (65 mg/kg body weight) only revealed a significant increase (P < 0.05) in plasma hydrogen peroxide (H2O2) by 230%, increased the thiobarbituric acid reactive substances (TBARS) as index of the lipid peroxidation level by 69%, while total antioxidant activity was decreased by 36%, with a consistent significant decrease (P < 0.05) in the activity of erythrocytes antioxidative enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and paraoxonase (PON). Exogenous administration of individual gradual doses of naringin to hyperglycaemic rats causes a dose-dependent decrease of the glucose level, an increase of the insulin concentration, a decrease of the H2O2 and TBARS levels, as well as the increase of the total antioxidant status with an increase of antioxidant enzyme activities (CAT, SOD, GPx, and PON). From this study, it may be concluded that all doses of naringin provided a significant amelioration of hypoglycaemic and antioxidant activity in STZ-induced diabetic rats, however, the greatest effect of naringin was observed at 80 mg/kg body weight.
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PMID:The influence of naringin on the oxidative state of rats with streptozotocin-induced acute hyperglycaemia. 1554 Jun 7


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