Paraoxonase-1 activity in patients with hyperemesis gravidarum

Abstract

There is increasing evidence that oxidative stress may play a role in the pathophysiology of hyperemesis gravidarum. Serum paraoxonase-1 (PON-1) is a high density lipoprotein (HDL)-associated enzyme that prevents oxidative modification of low density lipoprotein. The aim of the study was to measure the serum levels of PON-1 activity in women with hyperemesis gravidarum. Thirty-four women with hyperemesis gravidarum and 31 healthy pregnant women were enrolled in the study. Serum PON-1 activity was measured spectrophotometrically. Lipid hydroperoxide (LOOH) levels were measured by iodometric assay. PON-1 activity was significantly lower and LOOH levels were significantly higher in pregnant women with hyperemesis gravidarum than in healthy pregnant women (P < 0.0001, for all). There were significant correlations between PON-1 and LOOH, triglyceride, total cholesterol, HDL, low density lipoprotein (LDL) and high sensitive C-reactive protein (HSCRP; P < 0.0001, for all). By using multiple regression analysis LDL, HDL, HSCRP and LOOH were independent determinants of serum PON-1 activity in the study. Decreased PON-1 activity might be related to increased oxidative stress and inflammation in pregnant women with hyperemesis gravidarum. Subjects with hyperemesis gravidarum might be more prone to the development of atherogenesis due to low serum PON-1 activity.     

Raised serum human chorionic gonadotrophin concentrations in hyperemesis gravidarum.

Serum human chorionic gonadotrophin (HCG) concentrations were determined by radioimmunoassay with an antiserum specific to HCG beta-subunit in 42 patients with hyperemesis gravidarum and 115 women with normal pregnancies. Mean concentrations (+/- SE of mean) were higher in the women with hyperemesis gravidarum at 7-8 weeks (40.8 +/- 5.2 IU/ml v 22.1 +/- 1.4 IU/ml; P less than 0.001), 9-11 weeks (38.1 +/- 2.3 IU/ml v 27.1 +/- 2.1 IU/ml; P less than 0.0025), and 12-14 weeks of gestation (35.9 +/- 4.2 IU/ml v 25.1 +/- 1.7 IU/ml; P less than 0.005), but there was no difference between the two groups at 15-20 weeks of gestation. In the hyperemesis gravidarum group primigravid women had a higher (P less than 0.005) mean HCG concentration (41.8 +/- 4.0 IU/ml) than multigravid women (32.2 +/- 2.3 IU/ml). The results suggest a causal relation between a high serum HCG concentration and hyperemesis gravidarum.     

Paraoxonase-1 and ischemia-modified albumin in patients with end-stage renal disease

End-stage renal disease (ESRD) with and/or without treatment by hemodialysis (HD) is associated with accelerated atherosclerosis, leading to cardiovascular disease (CVD) including acute coronary syndromes. Therefore, the regulation of CVD is a crucial issue for ESRD patients. Given the recent reports that paraoxonase-1 (PON-1) and ischemia-modified albumin (IMA) could predict CVD-related mortality in ESRD, the two recent biomarkers may be useful for preventive strategies for CVD. This review paper presents current data on the relationships between PON-1, IMA, and ESRD. Many studies have shown that circulating PON-1 activity is lower in ESRD patients, and we have shown that its levels increase after HD. Although circulating IMA levels can increase before HD in ESRD patients, there remains to be little data. Our pilot study has shown a significant inverse correlation between PON-1 and IMA in ESRD patients. Although the pathogenic link between PON-1 and IMA remains speculative, considering both biomarkers may provide new insights into the prevention of CVD in ESRD patients.     

凝结芽孢杆菌活菌片对妊娠剧吐的疗效观察

目的 观察和评价凝结芽孢杆菌活菌片（商品名：爽舒宝）对妊娠剧吐患者的临床疗效。方法 将56例妊娠剧吐患者随机分为两组,每组28例。分别给予静脉补液治疗（对照组）及静脉补液联合凝结芽孢杆菌活菌片治疗（观察组）,评估两组患者治疗效果,统计患者尿酮体转阴率、主要症状消失率、呕吐症状彻底消失时间、整体治疗持续时间等指标。结果 观察组患者治疗总有效率（100.00%）高于对照组患者（85.71%）,观察组患者尿酮体转阴率（100.00%）高于对照组患者（64.29%）,观察组患者恶心、呕吐症状消失率（64.29%）高于对照组患者（35.71%）,观察组患者厌食症状消失率（75.00%）高于对照组患者（46.43%）,观察组患者整体治疗持续时间、呕吐症状消失时间均短于对照组,差异均有统计学意义（P＜0.05）。结论 凝结芽孢杆菌活菌片治疗妊娠剧吐效果显著,值得临床推广。     

Paraoxonase-1 and linoleic acid oxidation in familial hypercholesterolemia

Serum paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme that can inhibit low-density lipoprotein (LDL) oxidation in vitro. The role of PON1 in vivo still remains to be clarified. We investigated the effect of PON1 genotype (-107C > T and 192Q > R), concentration, paraoxonase activity, and arylesterase activity on the early phase of lipid peroxidation in plasma samples of 110 patients with heterozygous familial hypercholesterolemia. The degree of lipid oxidation was assessed by quantitation of oxidized-linoleic acid (the most abundant fatty acid present in LDL) using high performance liquid chromatography. We found a significant inverse correlation between paraoxonase activity and the oxidized-linoleic acid concentration (r = -0.22, P = 0.03), independent of baseline linoleic acid levels. These findings support an anti-oxidative role for PON1 in patients with FH, and thus may give insight into the functioning of PON1 in vivo.     

A prospective cohort study investigating associations between hyperemesis gravidarum and cognitive, behavioural and emotional well-being in pregnancy

Objectives

To investigate the association between hyperemesis gravidarum and altered cognitive, behavioural and emotional well-being in pregnancy.

Methods

The study cohort consisted of 3423 nulliparous women recruited in the Screening for Pregnancy Endpoints (SCOPE) study performed in Auckland, New Zealand; Adelaide, Australia; Cork, Ireland; Manchester and London, United Kingdom between November 2004 and August 2008. Women were interviewed at 15±1 weeks'' gestation and at 20±1weeks'' gestation. Women with a diagnosis of hyperemesis gravidarum (HG) were compared with women who did not have a diagnosis of HG. Main outcome measures included the Short form State- Trait Anxiety Inventory (STAI) score (range 6–24), Perceived Stress Scale score (PSS, range 0–30), Edinburgh Postnatal Depression Scale (EPDS) score (range 0–30 or categories a–c) and behavioural responses to pregnancy score (limiting/resting [range 0–20] and all-or-nothing [range 0–28]).

Results

During the study period 164 women suffered from HG prior to their 15 week interview. Women with HG had significantly higher mean STAI, PSS, EPDS and limiting response to pregnancy scores compared to women without HG. These differences were observed at both 15±1 and 20±1 weeks'' of gestation. The magnitude of these differences was greater in women with severe HG compared to all women with HG. Women with severe HG had an increased risk of having a spontaneous preterm birth compared with women without HG (adjusted OR 2.6 [95% C.I. 1.2, 5.7]).

Conclusion

This is the first large prospective study on women with HG. Women with HG, particularly severe HG, are at increased risk of cognitive, behavioural and emotional dysfunction in pregnancy. Women with severe HG had a higher rate of spontaneous preterm birth compared to women without HG. Further research is required to determine whether the provision of emotional support for women with HG is beneficial.     

Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells

The upregulation of endothelial cell MCP-1 production by ox-LDL is a major initiating event in atherogenesis. HDL and PON1 retard the oxidation of LDL and therefore may retard endothelial cell MCP-1 production. The endothelial cell line EAhy926 was incubated with ox-LDL in the presence and absence of HDL and PON1 and the production of MCP-1 was measured by ELISA. Human HDL and PON1 significantly inhibited the in vitro oxidation of LDL and completely prevented the ox-LDL induced increase in MCP-1 production by endothelial cells. Ostrich HDL that does not contain PON1 was unable to prevent LDL-oxidation or the production of MCP-1 by endothelial cells. PON1 attenuates the ox-LDL induced MCP-1 production by endothelial cells. This is one, early, mechanism by which PON1 may be anti-atherogenic.     

Paraoxonase-1介导硫化氢的抗甲醛神经毒性作用

我们以往的研究工作证实了硫化氢(hydrogen sulfide,H2S)对甲醛神经毒性和氧化应激具有拮抗作用.Paraoxonase-1(PON-1)是机体重要的内源性抗氧化剂.本研究的目的是探讨PON-1是否可介导H2S的抗甲醛神经毒性作用.采用甲醛损伤PC12细胞为甲醛神经毒性的细胞模型.硫氢化钠(NaHS,一种H2S的供体)不仅可以上调PC12细胞PON-1的活力,还可恢复甲醛对PC12细胞PON-1表达与活力的抑制作用.2-hydroxyquinoline(2-HQ)是一种选择性PON-1抑制剂,它可显著降低H2S对甲醛细胞毒性、凋亡和活性氧(reactive oxygen species,ROS)累积的抑制作用.而且,2-HQ可阻止H2S逆转甲醛激活PC12细胞caspase-3和下调PC12细胞bcl-2表达.结果提示H2S依赖PON-1去保护PC12细胞对抗甲醛的神经毒性.我们的这一发现表明PON-1有希望成为防治甲醛神经损伤的新靶点.     

Paraoxonase-1 is a major determinant of clopidogrel efficacy

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.     

Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I

Paraoxonase-1 (PON1) and HDL are tightly associated in plasma, and this is generally assumed to reflect the need for the enzyme to associate with a hydrophobic complex. The association has been examined in coronary cases and age-matched controls. Highly significant (P < 0.0001), positive associations were observed between PON1 activities and concentrations and HDL-cholesterol and apolipoprotein A-I (apoA-I) concentrations in cases and controls. Corrected slopes were significantly different in cases (cases vs. controls: arylesterase, r = 0.19 vs. 0.38, P < 0.02 for apoA-I and r = 0.15 vs. 0.34, P < 0.02 for HDL-cholesterol) such that if PON1 should influence serum HDL, it would be less effective in coronary cases. When examined as a function of the PON1 gene promoter polymorphism C-107 T, highly significant differences (P < 0.001) in HDL-cholesterol and apoA-I were observed between genotypes for controls, with high expresser alleles having the highest HDL concentrations. This relationship was lost in cases with coronary disease. The coding region polymorphisms Q192R and L55M of the PON1 gene showed no association with HDL. The promoter polymorphism was an independent determinant of HDL concentrations in multivariate analyses. These data are consistent with an impact of PON1 on plasma concentrations of HDL, with detrimental modifications to the relationship in coronary cases.