[－75 G/A Polymorphism of Apolipoprotein A1 Gene Promoter Region in Normal Pregnant Women and Patients With Gestational Diabetes Mellitus]. / æ­£å¸¸å­•å¦‡åŠå¦Šå¨ ç³–å°¿ç— æ‚£è€ apoA1åŸºå› å¯åŠ¨å­åŒºï¼75 G/Aå¤šæ€æ€§çš„ç ”ç©¶.

Objective: To investigate the －75 G/A single-nucleotide polymorphism in the promoter region of apolipoprotein A1 gene (apoA1) and its association with gestational diabetes mellitus (GDM) in pregnant women and to provide references for the exploration in the molecular genetic basis of GDM. Methods: A total of 626 GDM patients and 1022 normal pregnant women, ie, the controls, were included in the study. The genotyping of apoA1 －75 G/A polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence immunoassay. The protein levels of apoA1 and apoB were measured by the turbidimetric immunoassay. Results: Allele frequencies of G and A were 0.718 and 0.282 in the GDM group and 0.713 and 0.287 in the control group, respectively. Distribution of the genotype frequencies was found to be in Hardy-Weinberg equilibrium in both the GDM and control groups. There was no significant difference in the frequencies of alleles G and A and the genotypes of apoA1 －75 G/A polymorphism between the GDM and the control group (P>0.05). In the GDM group, the carriers with the genotype AA were associated with significantly higher levels of TC, HDL-C, and apoA1 than those with genotypes GG and GA did (all P<0.05). After the GDM patients were divided into obese and non-obese subgroups, the genotype-related apoA1 variation was observed only in obese patients, while the genotype-related TC and HDL-C variations were evident in non-obese patients (P<0.05). In the control group, carriers of genotypes AA and GA had higher systolic blood pressure (SBP) and HDL-C than the carriers of genotype GG did (all P<0.05). Carriers of genotypes AA had significantly lower Glu levels than carriers of genotypes GG and GA did (P<0.05). The control subjects were further divided into subgroups according to their body mass index (BMI). Analysis of the subgroups showed that AA carriers were associated with higher SBP levels in the obese control women only, while lower Glu levels were evident in both obese and non-obese control women. Conclusion: These results suggest that －75 G/A polymorphism in the apoA1 gene is not associated with GDM. However, the genetic variation is closed associated with the plasma apoA1, HDL-C, and TC levels in GDM patients and plasma HDL-C, Glu, and SBP levels in the control subjects. The apoA1 variant-associated lipids and SBP variation is BMI dependent in both groups.

Lymphangiogenic responses of lymphatic endothelial cells to steady direct-current electric fields.

Lymphangiogenesis plays pivotal roles in diverse physiological and pathological conditions. Steady direct-current electric fields (DC EFs) induce vascular endothelial behaviors related to angiogenesis have been observed. This study investigated the effects of DC EFs on the lymphangiogenic response of lymphatic endothelial cells (LECs). We demonstrated that EFs stimulation induced directional migration, reorientation, and elongation of human LECs in culture. These lymphangiogenic responses required VEGF receptor 3 (VEGFR-3) activation and were mediated through the PI3K-Akt, Erk1/2, and p38 MAPK signaling pathways in relation to the reorganization of the actin cytoskeleton. Our results indicate that endogenous EFs may play a role in lymphangiogenesis in vivo, and VEGFR-3 signaling activation may be involved in the cellular function of LECs driven by EFs.

[Association Between Apolipoprotein C-3 Sstâ Polymorphism and Serum Lipids in Patients With Gestational Diabetes Mellitus].

Objective: To investigate the apolipoprotein C-3 (APOC3) gene Sst Ⅰ polymorphism and its relationship with changes in serum lipids in patients with gestational diabetes mellitus (GDM). Methods: A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of APOC3 Sst Ⅰ polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence. Apolipoproteins A 1 (apoA1) and B (apoB) levels were measured by turbidimetric immunoassay. Results: The allele frequencies of S1 and S2 of the APOC3 polymorphism at the SstⅠ locus were 0.704 and 0.296 in the GDM group and 0.721 and 0.279 in the control group, respectively. There was no significant difference in genotype frequency and allele frequency of APOC3 Sst Ⅰ polymorphism between the GDM and the control groups ( P>0.05). In the GDM group, those with S2S2 and S1S2 genotypes had higher plasma HDL-C levels and lower atherogenic index (AI) values than those with S1S1 genotype did, with the differences being statistically significant (all P<0.05). GDM patients were then divided into obesity and non-obesity subgroups. Further subgroup analysis showed that the association of APOC3 genotype with changes in HDL-C levels was observed only in obese GDM patients, while the association of APOC3 genotype with changes in AI values was observed in both obese and nonobese patients. In addition, in obese GDM patients, those with S2S2 genotype had significantly higher plasma TG levels than those with S1S1 and S1S2 genotypes did ( P<0.05 and P<0.01, respectively). In non-obese GDM patients, those with S2S2 genotype had significantly lower apoB/apoA1 ratio than S2S2 carriers did ( P<0.05). No genotype-related effect on lipid and apolipoprotein variations was evident in the normal controls. Conclusion: APOC3 Sst Ⅰ polymorphism in GDM patients is associated with HDL-C and TG levels as well as AI value and apoB/apoA1 ratio. The changes in lipid levels and apolipoprotein ratio showed BMI-dependent features. However, association between polymorphism at the locus and the development of GDM was not observed.

ATP-binding cassette transporter G1 (ABCG1) polymorphisms in pregnant women with gestational diabetes mellitus.

CONTEXT AND OBJECTIVES: Gestational diabetes mellitus (GDM) is the most common metabolic disorder in pregnancy, and it often leads to adverse pregnancy outcomes and seriously harms the health of mothers and infants. ATP-binding cassette transporter G1 (ABCG1) plays critical roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport. This study was designed to explore the relevance of the ABCG1 polymorphisms in the atherometabolic risk in GDM. STUDY DESIGN: The case-control population consists of 1504 subjects. The rs2234715 and rs57137919 single nucleotide polymorphisms (SNPs) were genotyped using PCR and DNA sequencing, and clinical and metabolic parameters were determined. RESULTS: The genotype distributions of the two SNPs showed no difference between the GDM patient and control groups. However, the rs57137919 polymorphism was associated with total cholesterol (TC), and diastolic blood pressure (DBP) levels in patients with GDM. Moreover, subgroup analysis showed that this polymorphism was associated with ApoA1 and DBP levels in overweight/obese patients with GDM, while it was associated with TC, and gestational weight gain (GWG) in non-obese patients with GDM. Meanwhile, the rs2234715 polymorphism was found to be associated with neonatal birth height in non-obese patients with GDM. CONCLUSIONS: The two polymorphisms in the ABCG1 have an influence on atherometabolic traits, GWG, and fetal growth in GDM, depending on the BMI of the patients.

[Cholesterol 7α-Hydroxylase Gene-204A/C Polymorphism in Normal and Gestational Diabetic Pregnancies].

Objective: To investigate the cholesterol 7α-hydroxylase gene ( CYP7A1)-204A/C single nucleotide polymorphism and its relationship with the blood lipid levels of pregnant women with gestational diabetes mellitus (GDM) and normal pregnant women. Methods: The genotype and allele frequencies of CYP7A1-204A/C gene polymorphism of 1037 normal pregnant women, the normal controls, and 627 pregnant women with GDM were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and blood glucose (Glu) were measured by enzymatic assay. Chemiluminescence determination of plasma insulin (Ins) was conducted. Apolipoproteins A1 (apoA1) and B (apoB) were measured by the turbidimetric immunoassay. Results: Allele frequencies of A and C at the CYP7A1-204A/C polymorphic locus were 0.586 and 0.414, respectively, in the GDM group and 0.557 and 0.443, respectively in the control group. The distribution of genotype frequencies in both groups showed conformity with the Hardy-Weinberg principle. There was no significant difference in allele and genotype frequencies between the GDM group and the control group. In the control group, carriers of the genotype AA were associated with significantly higher concentrations of apoA1 and lower levels of Ins and homeostatic model assessment of insulin resistance (HOMA-IR) compared with those with genotype CC (all P<0.05). In the non-obese subgroup of the control subjects, carriers of the genotype CC were associated with significantly higher plasma TG or apoA1 levels compared with those with genotype AA ( P<0.05). In the GDM group, carriers with genotype AA of CYP7A1-204A/C polymorphism had elevated levels of gestational weight gain (GWG) compared with those with genotype CC ( P<0.05). Conclusion: These results suggest that 204A/C polymorphism in the CYP7A1 gene is not associated with GDM, but may be closely associated with gestational weight gain in pregnant women with GDM. Variants in this locus are strongly associated with plasma apoA1, Ins, and HOMA-IR levels in the controls and elevated plasma TG levels in non-obese controls.

Migration of Human Renal Tubular Epithelial Cells in Response to Physiological Electric Signals.

Restoration of proximal tubular cell integrity and function after ischemic injury involves cell migration and proliferation. Endogenous fields are present during embryonic development and wound healing. Electric field (EF)-induced effects on cell migration have been observed in many cell types. This study investigated the effect of physiological direct current EF (dc EF) on the motility of renal epithelial cells. Human renal tubular epithelial (HK-2) and human-derived renal epithelial (HEK-293) cells were exposed to dc EF at physiological magnitude. Cell images were recorded and analyzed using an image analyzer. Cell lysates were used to detect protein expression by western blot. Scratch wounds were created in monolayers of HK-2 cells, and wound areas of cells were measured in response to EF exposure. Cells migrated significantly faster in the presence of an EF and toward the cathode. Application of an EF led to activation of the Erk1/2, p38 MAPK, and Akt signaling pathways. Pharmacological inhibition of Erk1/2, p38 MAPK, and Akt impaired EF-induced migratory responses, such as motility rate and directedness. In addition, exposure of the monolayers to EF enhanced EF-induced HK-2 wound healing. Our results suggest that EFs augment the rate of single renal epithelium migration and induce cell cathodal migration through activation of Erk1/2, p38 MAPK, and Akt signaling. Moreover, exposure of the renal epithelium to EF facilitated closure of in vitro small wounds by enhancing cell migration.

Maternal GALNT2 Variations Affect Blood Pressure, Atherogenic Index, and Fetal Growth, Depending on BMI in Gestational Diabetes Mellitus.

Background: GALNT2 is a GalNAc transferase that regulates serum lipid fractions, insulin signaling, and lipogenesis. Genetic variants are implicated in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of GALNT2 rs2144300 and rs4846914 single nucleotide polymorphisms (SNPs) with the risk of GDM and related traits. Methods: Two SNPs were genotyped, and clinical and metabolic parameters were determined in 461 GDM patients and 626 control subjects. Genetic associations with related traits were also analyzed. Results: The genotype distributions of the two SNPs in GDM patients were similar to those in normal controls. However, significant differences were noted across the three groups of genotypes with respect to the examined variables in subjects in a BMI-dependent manner. The rs4846914 and rs2144300 SNPs of GALNT2 were significantly associated with systolic blood pressure and/or diastolic blood pressure levels in nonobese GDM patients and atherogenic index (AI) in overweight/obese GDM patients. The rs4846914 SNP was also associated with fetal growth in overweight/obese GDM patients, and apo A1 and pregnancy weight gain in overweight/obese control women (all P<0.05). Conclusions: The two polymorphisms in the GALNT2 gene are associated with variations in blood pressure, atherogenic index, and fetal growth in GDM, depending on BMI, but not with GDM. Our findings highlight a link between related phenotypes in GDM mothers and their fetuses and the genetic components.

A Common R219K Variant of ATP-Binding Cassette Transporter A1 Gene Alters Atherometabolic Traits in Pregnant Women With Gestational Diabetes Mellitus.

Background: ATP-binding cassette transporter A1 (ABCA1) has important roles in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport, and is implicated in lipid-related disorders. Genetic variants are involved in the pathogenesis of gestational diabetes mellitus (GDM). The objective of this study was to investigate the association of rs2230806 (R219K), a single nucleotide polymorphism (SNP) in the lipid-related gene, with the risk of GDM and related traits. Methods: The SNP, rs2230806, was genotyped, and clinical and metabolic parameters were determined in 660 GDM patients and 1,097 control subjects. Genetic associations with related traits were also analyzed. Results: The genotype distributions were similar in GDM patients and normal controls. However, significant differences in the variables examined in the study subjects were noted across the three genotypes. The genotype at the rs2230806 polymorphism was significantly associated with HDL-cholesterol (HDL-C) levels and atherogenic index (AI) values in GDM patients and total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels in control subjects. Subgroup analysis showed that the polymorphism was associated with diastolic blood pressure, in addition to HDL-C levels and AI, in overweight/obese GDM patients, while it was associated with TC levels, AI, pre-pregnancy body mass index (BMI), and BMI at delivery in non-obese GDM patients. In addition, this polymorphism was associated with TC, LDL-C, and apoB levels in overweight/obese control subjects. Conclusions: The rs2230806 polymorphism in the ABCA1 gene was associated with variations in atherometabolic traits in GDM patients, with characteristics of BMI dependency, but not with GDM. Our findings highlight a link between related phenotypes in women with GDM and genetic factors.

Myeloperoxidase and CYBA genetic variants in polycystic ovary syndrome.

BACKGROUND: Oxidative stress plays a pivotal role in the pathogenesis of polycystic ovary syndrome (PCOS). Genetic variations in myeloperoxidase (MPO; G-463A) and NADPH oxidase p22phox subunit (CYBA; C242T) cause inter-individual variability in enzyme activities. Here, we investigated the associations between MPO activity and the MPO G-463A and CYBA C242T polymorphisms in Chinese women with PCOS. METHODS: This case-control study included 1003 patients with PCOS and 810 controls. The G-463A and C242T polymorphisms were detected by polymerase chain reaction and restriction analysis, and clinical, hormonal, metabolic and oxidative stress parameters and MPO activity were analysed. RESULTS: The frequencies of the GA + AA genotype and A allele frequency of the MPO G-463A polymorphism were significantly higher in the PCOS group than in the control group. Logistic regression analysis showed that the MPO-463A allele is a risk factor for PCOS (OR = 1.261, 95% CI: 1.042-1.526, P = .017). Patients with the AA genotype tended to have higher plasma MPO activity than those with the GG genotype. No statistical significance was found in the genotype and allele frequencies of the CYBA C242T polymorphism between the PCOS and control groups. However, we demonstrated that the coexistence of the MPO A allele (GA + AA genotypes) and the CYBA CC genotype was associated with an increased risk of PCOS when compared with the wild-type GG/CC genotypes (OR = 1.302, 95% CI: 1.030-1.646, P = .027). CONCLUSION: The MPO G-463A variant, but not CYBA C242T variant, is associated with a risk of PCOS in Chinese women.

Lactonase activity and status of paraoxonase 1 and oxidative stress in neonates of women with gestational diabetes mellitus.

BACKGROUND: The level and lactonase activity of paraoxonase 1 (PON1) and their association with PON1 genetic variants and oxidative stress are unclear in neonates of women with gestational diabetes mellitus (GDM). METHODS: This study included 362 neonates of women with GDM and 302 control neonates. The level, lactonase activity, normalized lactonase activity (NLA), and genetic polymorphisms of PON1, serum total oxidant status (TOS), total antioxidant capacity (TAC), and malondialdehyde (MDA) were analyzed. RESULTS: The neonates of the women with GDM had significantly higher levels, lactonase activity, and NLA of PON1, higher TOS, TAC, and MDA concentrations, and relatively higher oxidative stress index than those of the control neonates. The PON1 -108C → T variation decreased the lactonase activity, level, and NLA of PON1, while the PON1 192Q → R variation decreased the PON1 NLA in a genotype-dependent manner in the two groups. Multivariable regression analysis revealed the PON1 -108C/T or 192Q/R variation, apolipoprotein (apo)A1, or apoB as significant predictors of the level, lactonase activity, and NLA of PON1. CONCLUSIONS: The lactonase activity, level, and NLA of PON1 were increased in the neonates of women with GDM. The PON1 genetic variants, abnormalities in lipoproteins, and increased oxidative stress may be associated with these changes. IMPACT: This is the first study to report the elevated level, lactonase activity, and NLA of PON1 in the neonates of women with GDM. These neonates also exhibited increased oxidative stress and an adverse glycolipid metabolic profile. We further established that the -108C/T and/or 192Q/R genetic variants of the PON1 gene, abnormalities in lipoprotein metabolism, and/or increased oxidative stress had noticeable influences on the level and activities of PON1. Whether these changes potentially cause metabolic disorders later in life remains to be determined. Therefore, the neonates born to women with GDM require further clinical follow-ups.

GALNT2 Gene Variant rs4846914 Is Associated with Insulin and Insulin Resistance Depending on BMI in PCOS Patients: a Case-Control Study.

GALNT2 is a GalNAc transferase that regulates insulin signaling, lipogenesis, and serum lipid fractions. The objective of this study was to investigate the association of GALNT2 rs2144300 and rs4846914 single nucleotide polymorphisms (SNPs) with the risk of polycystic ovary syndrome (PCOS) and related traits. The two SNPs were genotyped in 616 PCOS patients and 482 control subjects. Genetic associations with related traits were also analyzed. The genotype distributions of the two SNPs in PCOS patients were similar to those of normal controls. However, significant differences were noted across the three groups of genotypes with respect to the examined variables. In the PCOS group, subjects with genotype AA at the rs4846914 SNP exhibited an increased fasting serum insulin and homeostasis model insulin resistance (HOMA-IR) index compared with that of corresponding GG or GA genotype carriers (all P < 0.05). When PCOS patients were further separated into obese and non-obese subgroups, the genotype-related effects on insulin and HOMA-IR were more obvious, and variations in BMI and FSH levels were exclusively observed in obese PCOS subjects (all P < 0.05). In addition, fasting plasma glucose levels were affected by the genotypes of the rs2144300 SNP in normal control women (P < 0.05). rs4846914 and rs2144300 polymorphisms in the GALNT2 gene are associated with insulin and HOMA-IR, BMI, and FSH levels in obese PCOS patients and glucose levels in normal control women, respectively, but not with PCOS. GALNT2 rs4846914 AA carrier status may be associated with insulin resistance and related traits in obese patients.

In vitro study of the effects of DC electric fields on cell activities and gene expression in human choriocarcinoma cells.

Physiological electric fields (EFs), as one of the environmental cues influencing both normal and tumor cells, have profound effects on tumor cell malignancy potential. The cellular responses to EFs by choriocarcinoma cells and their underlying mechanisms are unknown. In this study, the migration/motility, cell cycle progression and proliferation of choriocarcinoma cells in electric field culture showed that choriocarcinoma cells migrated cathodally in an applied EF, and EF stimulation influenced cell cycle progression through G2/M arrest and therefore induced a reduction in cellular proliferation. The transcriptome of choriocarcinoma cells subjected to EF stimulation (150 mV/mm) was analyzed using RNA sequencing (RNA-Seq), and the results were verified by reverse transcription quantitative polymerase chain reaction. A Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that ErbB and HIF-1 signaling pathways that are involved in cell migration/motility, cell cycle progression and proliferation were significantly altered in cells treated with an EF of 150 mV/mm compared with control cells, and in addition, the downstream pathways of these signaling pathways such as AKT and P42/P44 MAPK (ERK1/2) showed primary activation by Western blotting. This study's results suggest that an applied EF is an effective cue in regulating cellular phenotypes of choriocarcinoma cells and that transcriptional analysis contributes to the understanding of the mechanism of EF-guided cell functions.

[Analysis of rs4420638A/G and -317H1/H2 polymorphisms of APOC1 gene among Chinese patients with pre-eclampsia].

OBJECTIVE: To assess the association of apolipoprotein (apo) C1 (APOC1) gene rs4420638A/G and -317H1/H2 polymorphisms with the risk of pre-eclampsia (PE) and the influence of their genotypes on the clinical and metabolic indexes among Chinese women. METHODS: In total 289 PE patients and 824 women with uncomplicated pregnancies were included. The rs4420638A/G genotype was determined by a Taqman real-time PCR allelic discrimination assay. The -317H1/H2 genotype was measured through PCR and restriction fragment length polymorphism analysis. Serum lipid and apo levels were measured by an enzymatic kit and a PEG-enhanced immunoturbidimetric assay. RESULTS: Allelic and genotypic frequencies of the APOC1 gene rs4420638A/G and -317H1/H2 were not significantly different between the two groups (all P> 0.05). However, patients carrying the G allele of the rs4420638A/G locus had higher serum levels of triglyceride, non-HDL-C and apoB, and a higher apoB/apoA1 ratio compared with those with an AA genotype (all P< 0.05). Patients carrying the H2 allele of the -317H1/H2 polymorphism had smaller delivery gestational weeks compared with those with the H1H1 genotype (P< 0.05). CONCLUSION: Polymorphisms of the APOC1 gene rs4420638 and -317H1/H2 sites may be associated with abnormal lipoprotein metabolism among Chinese patients with PE, though no association was found between variants of the APOC1 gene and the risk of PE among them.

Direct Current Electric Field Stimulates Nitric Oxide Production and Promotes NO-Dependent Angiogenesis: Involvement of the PI3K/Akt Signaling Pathway.

Electric fields (EFs) promote angiogenesis in vitro and in vivo. These results indicate the feasibility of the application of EFs to modulate angiogenesis. Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is an important regulator of angiogenesis. However, the role of direct current EFs in eNOS activity and expression in association with angiogenesis of endothelial cells has not been investigated. In the present study, we stimulated human umbilical vein endothelial cells (HUVECs) with EFs and evaluated the activity and expression of eNOS. EFs induced significant phosphorylation of eNOS, upregulation of the expression of eNOS protein, and an increase in NO production from HUVECs. L-NAME, a specific inhibitor of eNOS, abolished EF-induced HUVEC angiogenesis. EFs stimulated Akt activation. Inhibition of PI3K activity inhibited EF-mediated Akt and eNOS activation and inhibited NO production in the endothelial cells. Moreover, EFs stimulated HUVEC proliferation and enhanced the S phase cell population of the cell cycle. We conclude that EFs stimulate eNOS activation and NO production via a PI3K/Akt-dependent pathway. Thus, activation of eNOS appears to be one of the key signaling pathways necessary for EF-mediated angiogenesis. These novel findings suggest that NO signaling may have an important role in EF-mediated endothelial cell function.

Association of the G994T and R92H genotypes of platelet-activating factor acetylhydrolase with risk of preeclampsia in Chinese women.

OBJECTIVE: To investigate the relationship between platelet-activating factor acetylhydrolase (PAF-AH) gene (PLA2G7) G994T (V279F, rs76863441) and R92H (rs1805017) polymorphisms and risk of preeclampsia (PE) in Chinese women. STUDY DESIGN: This is a case-control study of 273 patients with PE and 530 healthy pregnant women. MAIN OUTCOME MEASURES: PLA2G7 genotypes were determined by polymerase chain reaction amplification and restriction analysis. Plasma PAF-AH, apolipoprotein (apo) B-containing lipoprotein-associated PAF-AH (apoB-PAF-AH), total high-density lipoprotein (HDL)-associated PAF-AH (H-PAF-AH), apoE-containing HDL-associated PAF-AH (apoE-H-PAF-AH) activities, and clinical, metabolic, and oxidative stress parameters were also analyzed. RESULTS: The frequencies of the GT + TT genotype (14.7 versus 9.2%, P = 0.019) and T allele (7.5% versus 4.6%) of PLA2G7 G994T polymorphism were significantly higher in patients with PE than in the control subjects. The GT + TT genotypes remained a significant predictor for PE in a regression model including age, body mass index (BMI), plasma PAF-AH, H-PAF-AH, apoE-H-PAF-AH and apoB-PAF-AH activities as covariates (odds ratio (OR) = 4.926, 95% confidence interval (CI): 1.707-14.219, P = 0.003). The ratio of apoB-PAF-AH to H-PAF-AH activities was significantly higher, while serum triglyceride levels were lower in patients with the GT genotype compared with patients with the GG genotype (P < 0.05). No significant differences were observed in the frequencies of the R92H genotype and allele between the PE and control groups. CONCLUSIONS: The PLA2G7 G994T, but not R92H, genetic polymorphism is associated with the risk of PE in Chinese women.

Lactonase Activity, Status, and Genetic Variations of Paraoxonase 1 in Women with Gestational Diabetes Mellitus.

BACKGROUND: Paraoxonase 1 (PON1) is a calcium-dependent multifunctional enzyme that binds to high-density lipoproteins. The physiological function of PON1 is related to its lactonase activity. However, this activity has not been analyzed in women with gestational diabetes mellitus (GDM). The present study investigated the lactonase activities and status of PON1 and their association with PON1 genetic variants and oxidative stress indices in Chinese women with GDM. METHODS: This is a case-control study of 347 women with GDM and 288 women with uncomplicated pregnancies. PON1 levels and lactonase activities were analyzed using 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) and 5-thiobutyl butyrolactone (TBBL), respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase to DEPCyMCase activity. Serum malondialdehyde (MDA), total oxidant status (TOS), total antioxidant capacity (TAC) levels, and PON1 genetic variants and oxidative stress indices in Chinese women with GDM. RESULTS: PON1 lactonase activity and levels of TOS, TAC, and MDA were higher in the GDM women compared with the control women. The PON1 -108C→T genetic variation decreased the levels and lactonase activities of PON1 in a genotype-dependent manner in the patient and control groups. GDM patients with the PON1 -108TT genotype displayed lower NLA than those with the -108CC or -108CT genotype. GDM patients with the RR genotype of PON1 192Q/R polymorphism had significantly lower PON1 lactonase activities and NLA and tended to have decreased PON1 levels compared with those with the QQ or QR genotype. Multivariable regression analysis revealed that the PON1 -108C/T or 192Q/R variations, apolipoprotein (apo) A1, apoB, TAC, MDA, or age was significant predictors of the levels, lactonase activities, or NLA of PON1. CONCLUSIONS: The lactonase activities of PON1 are increased in women with GDM. PON1 genetic variants, increased oxidative stress, and abnormalities in lipoproteins may be associated with these changes.PON1 genetic variants and oxidative stress indices in Chinese women with GDM.

Association of GPx1 P198L and CAT C-262T Genetic Variations With Polycystic Ovary Syndrome in Chinese Women.

Background: Oxidative stress plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Glutathione peroxidase 1 (GPx1) and catalase (CAT) are the major intracellular antioxidant enzymes that can detoxify hydrogen peroxide into water, preventing cellular injury from reactive oxygen species. The aim of the present study was to investigate the association of GPx1 P198L (Pro198Leu, C559T, rs1050450) and CAT C-262T (rs1001179) genetic polymorphisms with the risk of PCOS and evaluate the effects of the genotypes on clinical, hormonal, metabolic and oxidative stress parameters in Chinese women. Methods: This is a case-control study of 654 patients with PCOS and 535 controls. The GPx1 P198L, CAT C-262T, and superoxide dismutase 2 (SOD2) A16V genotypes were determined by polymerase chain reaction amplification and restriction analysis. Clinical, hormonal, metabolic and oxidative stress parameters were also analyzed. Results: The frequencies of the PL + LL genotype (14.1 vs. 8.4%) and L allele (7.3 vs. 4.4%) of GPx1 P198L polymorphism were significantly higher in patients with PCOS than in control subjects. Genotype (PL + LL) remained a significant predictor for PCOS in prognostic models including age, body mass index (BMI), insulin resistance index, total cholesterol, triglycerides, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol as covariates (OR = 2.105, 95%CI: 1.330-3.331, P = 0.001). Patients carrying the L allele had relatively high average ovarian volume, waist circumference, and malondialdehyde levels (P < 0.07) compared with patients with the PP genotype. We also demonstrated that the subjects with both GPx1 L and SOD2 A alleles further increase the risk of PCOS compared with the individuals carrying the PP/VV genotype after adjusting for age and BMI (OR = 5.774, 95%CI: 2.243-14.863, P < 0.001). However, no significant differences were observed in the frequencies of the CAT C-262T genotypes and alleles between PCOS and control groups. Conclusions: The GPx1 P198L, but not CAT C-262T, genetic polymorphism is associated with the risk of PCOS in Chinese women.

Effect of a Small Physiological Electric Field on Angiogenic Activity in First-Trimester Extravillous Trophoblast Cells.

Electrical stimulation induces significant angiogenesis in vivo. We have shown that electrical stimulation of trophoblast cells has important functions in aspects of angiogenesis. In this study, we investigated the effects of a direct current electrical field on trophoblast angiogenic tube formation. A 6-hour exposure to electric fields ranging from 50 to 150 mV/mm dose dependently increased tube growth and network formation. Additionally, the effect was time dependent, with increased tube formation occurring between 4 and 8 hours, indicating stimulation of trophoblast cell angiogenesis. Electrical fields of small physiological magnitude stimulated vascular endothelial growth factor expression by trophoblast cells in the culture. Electric field treatment also resulted in activation of Akt, while the activity of extracellular-regulated kinase 1/2, p38, and c-Jun NH2-terminal kinase was not significantly changed. Pretreatment with the vascular endothelial growth factor receptor (VEGFR)-2 inhibitor, SU1498, resulted in potent inhibition of tube growth, and the Akt inhibitor, MK-2206 2HCl, significantly reduced electric field-stimulated tubulogenesis. These data suggest the importance of the VEGFR-2 signaling pathway during electric field-induced trophoblastic angiogenesis. This novel evidence indicates that endogenous electrical fields may promote angiogenesis of trophoblast cells by stimulating the VEGFR signaling pathway.

Physiological electric field works via the VEGF receptor to stimulate neovessel formation of vascular endothelial cells in a 3D environment.

Electrical stimulation induces significant neovessel formation in vivo We have shown that electrical stimulation of endothelial cells functions as an important contributor to angiogenesis in monolayer culture. Because angiogenesis occurs in a three-dimensional (3D) environment, in this study we investigated the effects of a direct current (DC) electrical field (EF) on endothelial neovessel formation in 3D culture. There was a significant increase in tube formation when endothelial cells were stimulated with EF for 4 h. The lengths of the tube-like structures were augmented further by the continued EF exposure. The lengths of the tubes also increased dose-dependently in the EF-treated cultures in the field strengths of 50 mV/mm∼200 mV/mm for 6 h. Electrical fields of small physiological magnitude enhanced VEGF expression by endothelial cells in 3D culture. EF treatment also resulted in activation of VEGFR2, Akt, extracellular regulated kinase 1,2 (Erk1/2), as well as the c-Jun NH2-terminal kinase (JNK). The tyrosine kinase inhibitor SU1498 that blocks VEGFR2 activity exhibited a potent inhibition of tube growth, and the Akt inhibitor MK-2206 2HCl, the Erk1/2 inhibitor U0126 and the JNK inhibitor SB203580 significantly reduced EF-stimulated tubulogenesis. These results suggest the importance of the VEGFR2 signaling pathway during EF-induced angiogenesis. The results of this study provide novel evidence that endogenous EFs may promote blood vessel formation of endothelial cells by activating the VEGF receptor signaling pathway.

[Relationship between GSTM1 and GSTT1 gene polymorphisms and plasma lipid and apolipoprotein levels in Chinese normalipidemic and endogenous hypertriglyceridemic subjects].

OBJECTIVE: To investigate effects of GSTM1 and GSTT1 gene polymorphisms on serum lipid and apopoprotein levels in healthy normolipidemic and endogenous hypertriglyceridemic subjects. METHODS: Two hundred and thirty-seven healthy normolipidemic and 102 endogenous hypertriglyceridemic subjects from a population of Chinese Han nationality in Chengdu area were studied using the multiplex polymerase chain reaction (PCR). Serum lipids were measured by enzymatic kits and apolipoproteins AⅠ, AⅡ, B100, CⅡ, CⅢ and E were measured by the RID kits. RESULTS: The non-null and null genotype frequencies for GSTM1 site were 39.2% and 60.8% in the control group, respectively, and 47.6% and 52.4% in the HTG group, respectively. The non-null and null genotype frequencies for GSTT1 site were 51.5% and 48.5% in the control group, respectively, and 57.3% and 42.7% in the HTG group, respectively. The GSTM1 and GSTT1 genotype frequencies in HTG subjects were not different from those in the controls, respectively (P>0.05). However, in control group subjects with both null genotypes (GSTT1- and GSTM1-) showed the lowest plasma HDL-C levels (1.29±0.30 mmol/L), whereas those with each of the other three genotype combinations showed relatively higher HDL-C levels. There was significant difference of HDL-C levels between subjects with GSTT1-/GSTM1-and those with GSTT1+/GSTM1-(P<0.05). Similar result was not observed in HTG group. No significant changes of lipid and lipoprotein levels were observed in either GSTM1 or GSTT1 polymorphism alone in control or HTG group. CONCLUSION: The present study provides an evidence that the presence of double deletion genotypes is associated with low HDL-cholesterol levels in normal Chinese subjects. However, these polymorphisms are not associated with lipid levels in endogenous hypertriglyceridemia in Chinese population of Chengdu area.