对氧磷酶与妊娠期高血压疾病关系研究进展

对氧磷酶由355个氨基酸组成,它与高密度脂蛋白中的载脂蛋白结合,能保护低密度脂蛋白免受氧化修饰,降低体内氧化型低密度脂蛋白水平,并且能破坏氧化型低密度脂蛋白中的溶血磷脂,与脂代谢有密切关系.因其具有血管保护作用,故与妊娠期高血压疾病关系日益受到重视.     

手机辐射促进氧化低密度脂蛋白诱导的泡沫细胞形成

目的 探讨手机辐射对氧化低密度脂蛋白诱导的泡沫细胞形成的影响。方法 将鼠源性单核巨噬细胞RAW 264.7细胞分为三个组:对照组织、氧化低密度脂蛋白组和氧化低密度脂蛋白+手机辐射组。氧化低密度脂蛋白组以50 mg/L氧化型低密度脂蛋白培育细胞48 h诱导巨噬细胞泡沫化,而氧化低密度脂蛋白+手机辐射组细胞在50 mg/L氧化型低密度脂蛋白培育的同时接受定期的手机辐射。结果 与氧化低密度脂蛋白组相比,氧氧化低密度脂蛋白+手机辐射组细胞中总胆固醇、游离胆固醇、胆固醇脂显著性增加(P<0.05),有更多的脂滴存在。结论 手机辐射能促进氧化低密度脂蛋白诱导的泡沫细胞形成。     

护心食品,呵护你的心血管

当过量摄入肥甘厚腻之品时,血液中胆固醇的含量就会升高,若其在动脉血管内皮、平滑肌细胞内一旦被氧化“锈蚀”为氧化型低密度脂蛋白,便会被血液中的巨噬细胞迅速吞噬,变成粘乎乎的泡沫细胞,沉积在血管壁上,这就是造成动脉粥样硬化,引起冠心病的“祸根”。现代医学研究认为,能防止低密度脂蛋白氧化“锈蚀”的天然抗氧化剂,具有保护冠状动脉血管、维护心血管供血的功效。科学家近 10年来研究发现,含有天然抗氧化剂最多的食物主要有以下几类： 番茄红素 从 500多种类胡萝卜素中“脱颖而出”,其抗氧化功效是β胡萝卜素的 2倍,能阻…     

糖基化低密度脂蛋白、氧化低密度脂蛋白和2型糖尿病合并下肢血管病变的关系

[目的]探讨血清糖基化低密度脂蛋白、氧化低密度脂蛋白在T2DM合并下肢血管病变中的作用,同时说明在血管病变防治中抗糖化、抗氧化治疗同样重要.[方法]测定178例糖尿病患者和60例对照组(健康体检)的血清,糖基化低密度脂蛋白和氧化低密度脂蛋白水平,血清GLDL采用氯化硝基四氮唑蓝比色法,血浆OXLDL采用酶联免疫吸附法测定.[结果]①2型糖尿病患者血清糖基化低密度脂蛋白(0.396±0.079)mmol/L,与正常对照组相比增高(0.266±0.072)mmol/L,2型糖尿病血浆氧化低密度脂蛋白(58.266±24.203)μg/dl明显高于对照组(33.349±8.340 μg/dl,差异均有统计学意义(P＜0.01).②2型糖尿病并发周围血管病组的血清糖基化低密度脂蛋白(0.415±0.073)mmol/L,较无血管病组(0.372±0.084)mmol/L增高,血浆氧化低密度脂蛋白水平2型糖尿病并发周围血管病组(GLDL、)(59.017±24.854)μg/dl,显著高于无周围血管病组(48.356±24.429)μg/dl,差异有统计学意义(P＜0.01).③2型糖尿病患者血清糖基化低密度脂蛋白与血浆氧化低密度脂蛋白正相关(r=0.712,P＜0.01).[结论]糖基化低密度脂蛋白、氧化低密度脂蛋白和2型糖尿病合并下肢血管病变有关.     

114 维生素E与动脉粥样硬化的形成及其流行病学研究进展

低密度脂蛋白(LDL)被氧化修饰形成氧化型低密度脂蛋白(oxLDL)是动脉粥样硬化形成的重要原因。维生素E作为自由基的清除剂抑制oxLDL的形成，保护机体免受氧化损伤。描述性流行病学研究提示，维生素E是动脉粥样硬化的保护因素，近年来的分析性流行病学研究及补充维生素E的人群干预实验结果不一致，且有些与动物实验结果矛盾，因此需更加严密和特异的实验设计来证实维生素E对动脉粥样硬化进程的影响。     

维生素E与动脉粥样硬化的形成及其流行病学研究进展

低密度脂蛋白（LDL）被氧化修饰形成氧化型低密度脂蛋白（oxLDL)是动脉粥样硬化形成的重要原因。维生素E作为自由基的清除剂抑制oxLDL的形成，保护机体免疫受氧化损伤。描述性流行病学研究提示，维生素E是动脉粥样硬化的保护因素，近年来的分析性流行病学研究及补充维生素E的人群干预实验结果不一致，且有些与动物实验结果矛盾，因此需更加严密和特异的实验设计来证实维生素E对动脉粥样硬化进程的影响。     

氧化型低密度脂蛋白诱导内皮细胞基因表达

目的 通过研究氧化型低密度脂蛋白(Oxidized low density lipoprotein。Ox-LDL)诱导血管内皮细胞基因表达谱的改变，为阐明氧化型低密度脂蛋白致内皮细胞功能障碍及动脉粥样硬化形成的分子机制提供科学依据。方法 采用含有4000条全长已知人类基因cDNA，以及96条参照基因cDNA克隆制作的基因表达谱芯片，筛查氧化型低密度脂蛋白(100mg／L)作用6h对人脐静脉血管内皮细胞的基因表达谱改变的影响。结果 Ox-LDL可诱导3条基因表达下调，5条基因表达上调。结论 氧化型低密度脂蛋白的早期作用即可诱导内皮细胞相关基因的表达改变；首次发现氧化型低密度脂蛋白可诱导内皮细胞H731蛋白，ST2蛋白，CyclinB1(细胞周期蛋白B1)和KDRF(KM-102-derived reductase-like factor。KM-102源性还原酶样因子)等基因表达的改变，为揭示氧化型低密度脂蛋白引起血管内皮细胞功能障碍的机制提供线索。     

葛根素对糖尿病P-选择素及主动脉血管细胞粘附分子mRNA表达调节的实验研究

目的观察葛根素对糖尿病大鼠P-选择素及主动脉血管细胞粘附分子(VCAM)mRNA表达的调节。方法利用链脲佐菌素腹腔注射法诱导建立1型糖尿病大鼠模型,将实验用SD大鼠随机分正常对照组、糖尿病组、葛根素3个剂量组[20、40和80mg/(kg.d)ip]。处理16周,观察处理后大鼠的胆固醇、低密度脂蛋白、高密度脂蛋白、P-选择素、糖化低密度脂蛋白、氧化低密度脂蛋白,分离主动脉,HE染色观察主动脉病理形态改变及原位杂交检测主动脉内膜VCAMmRNA表达。结果(1)造模4组大鼠均出现血脂异常及主动脉病理形态改变。(2)葛根素能降低糖尿病大鼠的P-选择素、胆固醇、低密度脂蛋白、氧化低密度脂蛋白(P<0.05),升高高密度脂蛋白(P<0.05);葛根素降低主动脉VCAMmRNA(P<0.05)表达,且呈一定的剂量-反应关系。结论葛根素通过降低黏附分子的表达,起到确切的主动脉保护作用。     

维生素C在低密度脂蛋白氧化修饰中作用的体外实验

目的：研究维生素C（VC）在预防低密度脂蛋白（LDL）氧化修饰中的作用。方法：在Cu^2 介导的无细胞体系中分别加入VC10,50,100,200μmol/L,巨噬细胞体中分别加入VC50,100,200μmol/L,以维生素（200μmol/L）为阳性对照,不添加维生素C组（VC0）为阴性对照,测定荧光物质（lipofusin),硫代巴比妥酸反应物质（TBARS）,LDL电泳迁移率（Rf),氧化型低密度脂蛋白（Ox-LDL),LDL氧化过程中的停滞时间等LDL的氧化修饰情况。结果：Cu^2 介导的无细胞体系中,高剂量VC（100,200μmol/L）在3,6,9h均能发挥其抗氧化作用,抑制TBARS,Ox-LDL生成,而VC低剂量（10,50μmol/L）则无此作用,相反在3h表现出促Ox-LDL生成作用,在巨噬细胞体系中,高剂量组（100,200μmol/L)能显著降低荧光物质,TBARS和LDL电泳迁移率（Rf),延长LDL氧化过程中的停滞时间,并存在剂量反应关系。结论：VC在LDL氧化修饰中具有双重作用,低剂量时能促进LDL氧化,高剂量时表现出抗氧化作用。     

丹参素保护内皮祖细胞炎症损伤的机制研究

目的观察丹参素对氧化低密度脂蛋白（ox-LDL）损伤后外周血内皮祖细胞（EPCs）功能的影响,并探讨其可能的保护机制。方法密度梯度离心法获取外周血单个核细胞,通过流式细胞仪鉴定内皮祖细胞。培养7 d后,收集贴壁细胞并随机分为对照组、氧化低密度脂蛋白组（100 mg/L）及丹参素干预组（氧化低密度脂蛋白100 mg/L加丹参素,浓度分为2、10和50 mg/L）,干预24 h后分别采用MTT比色法、黏附能力测定实验观察EPCs的增殖能力、黏附能力,并取各组细胞上清液行白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）的含量检测。应用SPSS 13.0软件进行单因素方差分析,P〈0.05为差异有统计学意义。结果氧化低密度脂蛋白损伤后,EPCs的增殖能力、黏附能力显著受损,细胞培养液IL-6及TNF-α含量显著增高;丹参素干预24 h后,显著改善了外周血EPCs的功能,且丹参各组IL-6及TNF-α含量显著减少。结论丹参素对氧化低密度脂蛋白损伤后内皮祖细胞的功能有显著保护作用,其机制可能与抑制炎症因子释放有关。     

血清对氧磷酯酶联合氧化低密度脂蛋白在缺铁性贫血的临床意义

目的探讨血清对氧磷酯酶1（PON1）在缺铁性贫血中的意义。方法测30例缺铁性贫血（IDA）患者血清PON1和氧化低密度脂蛋白（OX-LDL）的水平，并与33例健康对照组比较。结果30例IDA患者PON1值为78．9±6．4U／L，明显低于对照组PON1（147．1±8．2U／L）；而OX-LDL水平为640．1±168．9μg/L，明显高于健康对照组（390．9±199．6μg／L），差别具有统计学意义（P〈0．01）。相关性分析发现，IDA组PON1活性与OX-LDL含量存在明显的负相关（r=-0．598，P〈0．01）。结论PON1活性下降，OX-LDL升高．提示IDA患者体内抗氧化防御体系缺陷，脂质发生过氧化反应，存在动脉粥样硬化的高风险。     

Arylesterase activity and antioxidant status depend on PON1-Q192R and PON1-L55M polymorphisms in subjects with increased risk of cardiovascular disease consuming walnut-enriched meat

Human paraoxonase (PON1) exists in 2 major polymorphic forms and has been shown to protect LDL and HDL against oxidation. The aim of this study was to assess the differences between subjects at increased risk of cardiovascular disease (CVD), taking into account the effects of PON1-Q192R and PON1-L55M polymorphisms on 1) basal serum arylesterase activity, lipid peroxidation (LPO), and LDL-cholesterol (LDL-C), HDL-C, total cholesterol (TC), and oxidized-LDL (ox-LDL) concentrations; 2) the relations between arylesterase activity and lipid variables; and 3) the effect of walnut-enriched meat (WM) consumption on arylesterase activity and lipid variables. Twenty-three Caucasians at increased risk of CVD were randomly assigned to diet order groups in a crossover, nonblinded, placebo-controlled trial, consisting of two 5-wk experimental periods [WM and control meat (CM)]. Significant PON1-L55M x PON1-Q192R interactions affected basal serum HDL-C (P = 0.019), LDL-C (P = 0.028) and TC (P = 0.022) and tended to affect arylesterase activity (P = 0.083). Basal arylesterase activity was positively correlated with basal HDL-C (r = 0.53; P < 0.05) and TC (r = 0.43; P < 0.05) and negatively correlated with LPO (r = -0.70; P < 0.01) and the ox-LDL:LDL ratio (r = -0.63; P < 0.01). WM decreased arylesterase activity in PON1-55M carriers (P = 0.012) but not in PON1-L55 individuals, and decreased LPO concentrations in PON1-192R carriers (P = 0.031) but not in PON1-Q192 subjects. To conclude, serum TC, HDL-C, and LDL-C concentrations and arylesterase activity depend on the interaction of PON1-L55M and PON1-Q192R polymorphisms. However, the PON1-Q192R polymorphism is more closely related to antioxidant status. Both polymorphisms modulate the effect of WM consumption on CVD biomarkers.     

Interethnic variability of plasma paraoxonase (PON1) activity towards organophosphates and PON1 polymorphisms among Asian populations--a short review

Organophosphate (OP) poisoning is a progressively worrying phenomenon as worldwide pesticide production and consumption has doubled. On average, WHO estimates that 3% of agricultural workers in developing Asian countries suffer an episode of pesticide poisoning every year. Furthermore, the threat of OP usage in terrorism is existent, as seen by the subway tragedy in Tokyo in 1995 where sarin was used. Despite these alarming facts, there is currently no global system to track poisonings related to pesticide use. Human serum paraoxonase (PON1) is the enzyme that hydrolyses OP compounds. Serum PON1 levels and activity vary widely among different ethnic populations. Two commonly studied polymorphisms of PON1 are PON1Q192R and PON1L55M. PON1R192 hydrolyses paraoxon faster than PON1Q192 but hydrolyses diazoxon, sarin and soman eight times slower, and vice versa. PON1M55 has lower plasma levels of PON1 than PON1L55. As the prevalence of the different alleles and genotypic distribution vary between the Asian populations we studied, we propose the necessity to study PON1 polymorphisms and its role in OP toxicity in Asian populations. This would help safeguard the proper care of agricultural workers who might be affected by OP poisoning, and alert relevant anti biological terrorism agencies on possible risks involved in the event of an OP attack and provide effective counter measures.     

The relationship of PON1 QR 192 and LM 55 polymorphisms with serum paraoxonase activities of Turkish diabetic patients

Paraoxonase (PON1) is a serum esterase responsible for the protection against xenobiotics toxicity such as paraoxon. Alterations in PON1 concentrations have been reported in a variety of diseases including diabetes mellitus (DM). It has been shown that the serum PON1 concentration and activity are decreased in patients with both type 1 and type 2 DM. This study aimed to investigate the lipid profiles and the relationship between PON1 activity and PON1, QR192 and LM55 polymorphisms in Turkish type 2 diabetic patients and non-diabetic control subjects. According to our results, RR variant had significantly higher PON activity than QQ and QR variants (p < 0.01) and LL variant had significantly higher PON activity than MM variant in both control and patient groups (p < 0.05). In conclusion, we found that PON1 192RR and 55LL genotypes are associated with higher PON activity than QQ and MM genotypes. This may be more protective to lipid peroxidation.     

Genotype and phenotype frequencies of paraoxonase 1 in fertile and infertile men

Abstract

Paraoxonase1 (PON1) is a glycoprotein associated with high density lipoprotein and has antioxidant activity. The impact of PON1 in various stages of spermatogenesis has also been suggested. This study was aimed to investigate frequencies of phenotypes and Q192R genotypes of PON1 in fertile and infertile males. Q192R variants of PON1 were determined in 150 fertile and 150 infertile men using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) technique. Plasma arylesterase and paraoxonase activities were detected by spectrophotometry and malondialdehyde (MDA) level was measured using thiobarbituric acid. Our results showed no significant difference in the distribution of PON1 genotypes and alleles between fertile and infertile groups. However morphology and motility of sperm were associated with various genotypes of PON1. The number of fertile males with the BB phenotype (high activity) was significantly higher than that of infertile males, whereas the number of individuals with the AB phenotype (moderate activity) was statistically higher in infertile men compared with the fertile group. Additionally, MDA and arylesterase activity levels were significantly higher in infertile subjects compared with fertile men. We speculate that the low activity of PON1 can be a risk factor for male infertility probably due to a decrease in antioxidant activity of PON1 and increase in lipid peroxidation.     

Relation between methylmercury exposure and plasma paraoxonase activity in inuit adults from Nunavik

Background: Methylmercury (MeHg) exposure has been linked to an increased risk of coronary heart disease (CHD). Paraoxonase 1 (PON1), an enzyme located in the high-density–lipoprotein (HDL) fraction of blood lipids, may protect against CHD by metabolizing toxic oxidized lipids associated with low-density liproprotein and HDL. MeHg has been shown to inhibit PON1 activity in vitro, but this effect has not been studied in human populations.Objectives: This study was conducted to determine whether blood mercury levels are linked to decreased plasma PON1 activities in Inuit people who are highly exposed to MeHg through their seafood-based diet.Methods: We measured plasma PON1 activity using a fluorogenic substrate and blood concentrations of mercury and selenium by inductively coupled plasma mass spectrometry in 896 Inuit adults. Sociodemographic, anthropometric, clinical, dietary, and lifestyle variables as well as PON1 gene variants (rs705379, rs662, rs854560) were considered as possible confounders or modifiers of the mercury–PON1 relation in multivariate analyses.Results: In a multiple regression model adjusted for age, HDL cholesterol levels, omega-3 fatty acid content of erythrocyte membranes, and PON1 variants, blood mercury concentrations were inversely associated with PON1 activities [β-coefficient = –0.063; 95% confidence interval (CI), –0.091 to –0.035; p < 0.001], whereas blood selenium concentrations were positively associated with PON1 activities (β-coefficient = 0.067; 95% CI, 0.045–0.088; p < 0.001). We found no interaction between blood mercury levels and PON1 genotypes.Conclusions: Our results suggest that MeHg exposure exerts an inhibitory effect on PON1 activity, which seems to be offset by selenium intake.     

Lead exposure is associated with decreased serum paraoxonase 1 (PON1) activity and genotypes

Lead exposure causes cardiac and vascular damage in experimental animals. However, there is considerable debate regarding the causal relationship between lead exposure and cardiovascular dysfunction in humans. Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, is capable of hydrolyzing oxidized lipids and thus protects against atherosclerosis. Previous studies have shown that lead and several other metal ions are able to inhibit PON1 activity in vitro. To investigate whether lead exposure has influence on serum PON1 activity, we conducted a cross-sectional study of workers from a lead battery manufactory and lead recycling plant. Blood samples were analyzed for whole-blood lead levels, serum PON1 activity, and three common PON1 polymorphisms (Q192R, L55M, -108C/T). The mean blood lead level (+/-SD) of this cohort was 27.1+/-15 microg/dL. Multiple linear regression analysis showed that blood lead levels were significantly associated with decreased serum PON1 activity (p<0.001) in lead workers. This negative correlation was more evident for workers who carry the R192 allele, which has been suggested to be a risk factor for coronary heart disease. Taken together, our results suggest that the decrease in serum PON1 activity due to lead exposure may render individuals more susceptible to atherosclerosis, particularly subjects who are homozygous for the R192 allele.     

对氧磷酶基因多态性及其临床意义的研究进展

对氧磷酶（ＰＯＮ） 由３５５ 个氨基酸组成, 有两个位点具有多态性, ＰＯＮ 表型多态性是由其基因多态性引起的, 人类ＰＯＮ 基因位于７ｑ２１－２２, 在两个单一位点出现多态性。ＰＯＮ 多态性对有机磷酸酯等类化合物中毒保护及心血管疾病等具有实际意义。     

Methodological constraints in interpreting serum paraoxonase-1 activity measurements: an example from a study in HIV-infected patients

Background  

Paraoxonase-1 (PON1) is an antioxidant enzyme that attenuates the production of the monocyte chemoattractant protein-1 (MCP-1) in vitro. Although oxidation and inflammation are closely related processes, the association between PON1 and MCP-1 has not been completely characterised due, probably, to that the current use of synthetic substrates for PON1 measurement limits the interpretation of the data. In the present study, we explored the relationships between the circulating levels of PON1 and MCP-1 in human immunodeficiency virus-infected patients in relation to the multifunctional capabilities of PON1.     

Increased influence of genetic variation on PON1 activity in neonates

PON1 (paraoxonase-1) detoxifies organophosphates by cleavage of active oxons before they have a chance to inhibit cholinesterases. The corresponding gene PON1 has common polymorphisms in both the promoter (-909, -162, -108) and the coding region (L55M, Q192R). The five PON1 genotypes were determined for maternal blood (n= 402) and cord blood (n= 229) as part of a study of the effects of organophosphate pesticide exposure on infant growth and neurodevelopment. PON1 enzymatic activities were determined for a majority of subjects. The population contained Caucasians, Caribbean Hispanics, and African Americans. PON1 activity was strongly dependent upon the promoter alleles in both maternal and cord blood. For example, PON1 activities for position -108CC, CT, and TT mothers were 146, 128, and 109 arylesterase U/mL (analysis of variance, p< 0.0001), whereas the same PON1 activities for the respective cord bloods were 49.0, 32.4, and 23.2 U/mL (p < 0.0001). Compared with adults, neonates had lower PON1 activity, implying reduced capacity to detoxify organophosphates. In addition there was a larger difference in activity between genotype groups in neonates than in adults. Because the five polymorphisms in PON1 occur in a short stretch of DNA, they were tested for linkage disequilibrium (LD). Significant LD was found among all three promoter polymorphisms as well as between promoter polymorphisms and L55M, with the strongest LD for Caucasians and the weakest for African Americans. The Caribbean Hispanics fall between these two groups. Surprisingly, significant LD also was observed between the promoter polymorphisms and C311S in PON2. LD between the promoter polymorphisms and Q192R was not significant.