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。     

Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine

Rifamycins such as rifampicin, rifabutin, and rifapentine are used for the treatment of tuberculosis and induce various drug-metabolizing enzymes. Rifamycins have been reported to be mainly deacetylated by esterase(s) expressed in human liver microsomes (HLM) to 25-deacetylrifamycins, but the responsible enzyme remained to be determined. In this study, we found that recombinant human arylacetamide deacetylase (AADAC) could efficiently deacetylate rifamycins, whereas human carboxylesterases, which are enzymes responsible for the hydrolysis of many prodrugs, showed no activity. The involvement of AADAC in the deacetylation of rifamycins in HLM was verified by the similarities of the K_m and K_i values and the inhibitory characteristics between recombinant AADAC and HLM. Rifamycins exhibited potent cytotoxicity to HepG2 cells, but their 25-deacetylated metabolites did not. Luciferase assay using a reporter plasmid containing CYP3A4 direct repeat 3 and everted repeat 6 motifs revealed that 25-deacetylrifamycins have lesser potency to transactivate CYP3A4 compared with the parent drugs. Supporting these results, HepG2 cells infected with a recombinant adenovirus expressing human AADAC showed low cytotoxicity and induction potency of CYP3A4 by rifamycins. In addition, CYP3A4 induction in human hepatocytes by rifamycins was increased by transfecting siRNA for human AADAC. Thus, we found that human AADAC was the enzyme responsible for the deacetylation of rifamycins and would affect the induction rate of drug-metabolizing enzymes by rifamycins and their induced hepatotoxicity.     

Serum paraoxonase-1 activities and oxidative status in patients with plaque-type psoriasis with/without metabolic syndrome

Objective: Psoriasis is a chronic immune‐mediated inflammatory skin disease associated with metabolic syndrome, which is made up of a cluster of disorders, including obesity, diabetes mellitus, dyslipidemia, and cardiovascular disease. The aim of this study was to investigate serum paraoxonase‐1 activities and oxidative status parameters in patients with plaque‐type psoriasis with or without metabolic syndrome. Methods: In this study, patients with plaque‐type psoriasis with (n=25) or without (n=27) metabolic syndrome, according to the criteria of the International Diabetes Federation (IDF), were matched for age and sex to an equally sized control group (n=25). Results: In patients without metabolic syndrome, serum paraoxonase and arylesterase activities showed mean decreases of 29 and 6%, respectively, whereas in patients with metabolic syndrome, the mean decreases in the enzymes' activities were 35 and 11%, respectively, compared with those in the control group. Serum total antioxidant capacity and total oxidant status were not statistically significant in any of the three groups. Multiple linear regression analysis revealed that HDL cholesterol and log‐transformed triglyceride were independent variables for serum arylesterase activity and that fasting glucose and diastolic blood pressure were independent variables for serum paraoxonase activity. Conclusions: These results suggest that according to the criteria of the IDF, the significant decrease observed in serum paraoxonase activity was independent of the metabolic syndrome in patients with mild‐to‐moderate plaque‐type psoriasis, whereas the significant decrease in serum arylesterase activity was associated with the metabolic syndrome. J. Clin. Lab. Anal. 25:289–295, 2011. © 2011 Wiley‐Liss, Inc.     

Common Genetic Variants in the Myeloperoxidase and Paraoxonase Genes and the Related Cancer Risk: A Review

Modern approaches in health care are moving toward the model of “personalized medicine.” Today, current research in molecular biology and medicine is focused on developing genomic markers with predictive, therapeutic, and prognostic significance. One of the most widespread and significant genomic markers is the single nucleotide polymorphism (SNP), which represents a variation in DNA sequence when a single nucleotide differs between members of a biological species or paired chromosomes in an individual. Antioxidant defense enzymes break down dangerous reactive compounds, called reactive oxygen species, and prevent DNA strand from carcinogen-specific mutations. It is well known that inherited variations in genes that encode antioxidant defense enzymes may modulate individual susceptibility to cancer. In our previous study we have determined the predictive significance of several SNPs of superoxide dismutase (SOD) and glutathione peroxidase gene families in the context of cancer risk. The present review includes a summary and discussion of the current findings evaluating the role of SNPs of the myeloperoxidase (MPO) and paraoxanase (PON) genes in cancer occurrence and development. We suggest that rs2333227 (MPO_ -463G/A) and rs854560 polymorphisms have a great predictive significance; they could probably be utilized as cancer predictors in the future. Also, we recommend further in-depth research for rs11079344 (MPO), rs8178406 (MPO), rs2243828 (MPO), rs662 (PON1), rs705379 (PON1), and PON1_304A/G polymorphisms. These SNPs may become significant cancer-associated biomarkers.     

Leptin and paraoxonase activity in cord blood from obese mothers

Abstract

Objective: Obesity and/or psychopathological disorders of parents represent risk factors for childhood obesity. The aim of the study was to investigate the link between obesity in pregnancy and oxidative stress.

Methods: Venous blood was collected from 37 women at the eighth month of gestation (19 obese and 28 normal weight). Cord blood was obtained at birth from newborns of obese mothers and controls. Cord blood and maternal blood was used to separate plasma to be used for the evaluation of leptin, oxidized LDL and paraoxonase (PON1) activity.

Results: Higher levels of leptin were observed both in maternal blood and cord blood of children of obese women compared to normal-weight women. The data also showed lower levels of PON1 activity in plasma of obese women and in the cord blood of their children. Furthermore, a positive correlation was established between levels of PON1 activity in maternal blood and cord blood, suggesting a relationship between PON1 in maternal plasma and fetal cord blood.

Conclusions: Essential obesity in pregnancy is associated with hyperleptinemia. PON1 exerts an antioxidant role; therefore, our results demonstrated that obesity exposes to an increased susceptibility to oxidative damage in both mothers and newborns.     

Knockdown of paraoxonase 1 expression influences the ageing of human dermal microvascular endothelial cells

Skin is one of the most commonly studied tissues for microcirculation research owing to its close correlation of cutaneous vascular function, ageing and age‐related cardiovascular events. To elucidate proteins that determine this correlation between endothelial cell function and ageing in the vascular environment of the skin, we performed a proteomic analysis of plasma samples from six donors in their 20s (young) and six donors in their 60s (old). Among identified proteins, paraoxonase 1 (PON1) was selected in this study. To elucidate the role of PON1 on skin ageing and determine how it controls cellular senescence, the characteristics of PON1 in human dermal microvascular endothelial cells (HDMECs) were determined. When the expression of endogenous PON1 was knocked‐down by small interfering RNA (siRNA) targeting PON1, HDMECs showed characteristic features of cellular senescence such as increases in senescence‐associated β‐galactosidase stained cells and enlarged and flattened cell morphology. At 48 h post‐transfection, the protein expression of p16 in PON1 siRNA‐treated HDMECs was higher than that in scrambled siRNA‐treated HDMECs. In addition, the expressions of moesin and rho GTP dissociation inhibitor, additional age‐related candidate biomarkers, were decreased by PON1 knock‐down in HDMECs. In conclusion, these results suggest that PON1 functions as an ageing‐related protein and plays an important role in the cellular senescence of HDMECs.     

对氧磷酶1基因多态性与2型糖尿病视网膜病变的相关性研究

目的探讨对氧磷酶1(PON1)192和55位点的基因多态性与2型糖尿病视网膜病变(DR)关系。方法采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)法检测184例不同程度视网膜病变的2型糖尿病(T2DM)患者和136例健康对照者(NGT)PON1 Q192R和L55M的多态性。结果 PON1Q192R基因在DR组QQ基因型及Q等位基因频率高于NDR组,差异有统计学意义(P<0.05)。但NGT与T2DM比较以及非增殖期糖尿病视网膜病变(NPDR)与增殖期糖尿病视网膜病变(PDR)比较,差异无统计学意义。PON1L55M基因在各组间的分布差异无统计学意义。结论PON1Q192R基因多态性可能与DR的发生有关,但与DR的严重程度无关,Q等位基因是DR的独立危险因素,PON1L55M基因多态性与DR无显著相关性。     

血浆对氧磷酯酶1活性在溃疡性结肠炎中的变化及临床意义

目的探讨对氧磷酯酶1（PON1）活性在溃疡性结肠炎（UC）中的变化及临床意义。方法分别测定44例活动期UC患者、23例缓解期UC患者及32例健康对照者的血浆PON1、C-反应蛋白（CRP）及丙二醛（MDA）含量,分析其相关性。结果活动期及缓解期UC组血浆CRP、MDA含量显著高于对照组（P〈0.05）,血浆PON1活性显著低于对照组（P〈0.05）。活动期患者组血浆CRP、MDA含量显著高于缓解期患者组（P〈0.05）,血浆PON1活性显著低于缓解期患者组（P〈0.05）。UC患者组对氧磷酯酶1活性与MDA及CRP水平呈负相关（r=-0.358,P〈0.01,r=-0.422,P〈0.01）。结论UC患者PON1活性显著降低,增加的氧自由基（OFR）导致致氧化环境可能使血浆PON1活性显著降低。     

Naphthoquinones,benzoquinones, and anthraquinones: Molecular docking,ADME and inhibition studies on human serum paraoxonase-1 associated with cardiovascular diseases

Paraoxonase-1 (PON1) has essential roles such as protecting low-density lipoprotein against detoxification and oxidation of highly toxic compounds. Quinones are a class of compounds and a type of plant-derived secondary metabolites. Here, PON1 was purified using very simple methods and evaluation of the interactions between the enzyme and some quinones. It was found that these quinones displayed effective inhibitor properties for PON1 with the IC₅₀ values in the range of 3.27–82.90 μM and the K _i values in the range of 2.50 ± 0.65 to 30.90 ± 7.20 μM. These quinones displayed distinct inhibition mechanisms. It was determined that except for 5-hydroxy-2-methyl-1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone all quinones exhibit competitive inhibition effects. Also, molecular docking and in silico ADME studies were performed. Usage of drugs including quinone derivatives in structure with biological activity would be hazardous in some cases.     

对氧磷酯酶 2 S311C基因多态性与2型糖尿病的关系

目的探讨对氧磷酯酶 2(PON2)Ser311Cys(S311C) 基因多态性与中国2型糖尿病(T2DM)的相关性. 方法 运用荧光偏振-模板依赖的染料掺入反应法(TDI-FP)技术检测PON2 S311C基因多态性在T2DM患者和健康对照者中的等位基因和基因型频率. 结果 17例T2DM患者,SS基因型5例,SC基因型6例,CC基因型6例;16例正常对照,SS基因型11例,SC基因型3例,CC基因型2例. T2DM组PON2基因C311等位基因分布显著高于正常对照组(P<0.01), C311等位基因与T2DM发生相关联(OR=4.018, 95%CI 1.371-11.774). 结论 应用荧光偏振-模板依赖的染料掺入反应法(TDI-FP)能准确敏感地检测PON2 S311C基因多态性,PON2 C311等位基因可能是T2DM易感遗传标志.