Increased oxidative stress is associated with hyperandrogenemia in polycystic ovary syndrome evidenced by oxidized lipoproteins stimulating rat ovarian androgen synthesis in vitro.

PURPOSE: To determine the relationship between serum total testosterone (TT) levels and oxidative stress indices in patients with polycystic ovary syndrome (PCOS), and to investigate the effect of oxidative stress on androgen synthesis and its mechanism in rat ovarian theca-interstitial (T-I) cells. METHODS: Clinical, hormonal, metabolic, and oxidative stress parameters were analyzed in a cross-sectional case-control study including 626 patients with PCOS and 296 controls. The effects of oxidized low-density lipoprotein (ox-LDL) and oxidized high-density lipoprotein (ox-HDL) on cell proliferation, TT secretion, and expression of key enzymes involved in testosterone synthesis were evaluated in T-I cells. RESULTS: Serum TT levels were elevated with an increase in ox-LDL levels, whereas glutathione concentrations were lower in the high-TT subgroup than in the low-TT subgroup. The average ovarian volume and ox-LDL and malondialdehyde levels were significant predictors of TT levels in the multivariate regression models. In a rat ovarian T-I cell model, lipoprotein and oxidized lipoprotein treatments stimulated proliferation and promoted testosterone secretion. The mRNA and protein levels of 17α-hydroxylase were significantly higher in oxidized lipoprotein-treated cells than those in lipoprotein-treated cells. The mRNA levels of cholesterol side chain cleavage enzyme and steroidogenic acute regulatory protein were also significantly higher in ox-HDL-treated cells than in HDL-treated cells. CONCLUSIONS: Oxidative stress can promote androgen production by up-regulating the expression of testosterone synthesis-related enzymes in vitro and may be an essential factor in elevating serum TT levels in patients with PCOS.

[－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.

Heme oxygenase 2 genetic variants alter hormonal and metabolic traits in polycystic ovary syndrome.

Oxidative stress and metabolic disorders are involved in the pathogenesis of polycystic ovary syndrome (PCOS). Heme oxygenase 2 (HMOX2) plays a critical role in preserving heme metabolism as well as in modulating glycolipid metabolism, oxidative stress, and inflammation. This study examined the correlation between HMOX2 G554A (rs1051308) and A-42G (rs2270363) genetic variants with the risk of PCOS and assessed the effects of these genotypes on clinical, hormonal, metabolic, and oxidative stress indices using a case-control design that included 1014 patients with PCOS and 806 control participants. We found that the allelic and genotypic frequencies of the HMOX2 G554A and A-42G polymorphisms were comparable between the PCOS and control groups in Chinese women (P > 0.05). Nevertheless, it was discovered that patients with the AA or AG genotype of A-42G polymorphism had notably elevated levels of estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH ratio, high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (apo)B, and/or apoB/apoA1 ratio than those with the GG genotypes (P < 0.05). Patients with the GG or AG genotype of G554A polymorphism had elevated serum levels of LH, FSH, E2, LH/FSH ratio, TC, HDL-C, LDL-C, apoB, and/or apoB/apoA1 ratio and lower 2-h glucose concentration compared with those with the AA genotype (P < 0.05). Our findings indicate a potential association between the genetic variants and endocrine abnormalities in the reproductive system and metabolic irregularities in glycolipid levels in patients, thus suggesting their potential role in the pathogenesis of PCOS.

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.

Longitudinal changes of oxidative stress and PON1 lactonase activity and status in older pregnant women undergoing assisted reproductive technology: a prospective nested case-control study.

BACKGROUND: Childbearing in women with advanced maternal age (AMA) has increased the need for artificial reproductive technology (ART). ART and oxidative stress are associated with many pregnancy complications. Paraoxonase (PON) 1 is one of the key components responsible for antioxidative activity in high-density lipoprotein (HDL). This study aimed to investigate the longitudinal changes of oxidative stress and PON1 lactonase activity and status in older women undergoing ART. METHODS: This prospective nested case-control study included 129 control and 64 ART women. Blood samples were obtained respectively at different stages of pregnancy. PON1 level and lactonase activity were assessed using 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) and 5-thiobutyl butyrolactone (TBBL) as a substrate, respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase to DEPCyMCase activity. Serum total oxidant status (TOS), total antioxidant capacity (TAC), malondialdehyde (MDA), homocysteine (HCY), PON1 C-108T and Q192R genetic polymorphisms, and metabolic parameters were analyzed. RESULTS: Lactonase activity and level of PON1 gradually decreased with pregnancy progression, while glycolipid metabolism parameters and TAC levels increased with pregnancy progression or significantly raised during the 2nd and 3rd trimesters, and NLA of PON1, TOS, OSI, MDA, and HCY significantly increased before delivery in the ART and control groups. Compared with the control women, the ART women had substantially higher or relatively high lactonase activity and NLA of PON1 and TAC during pregnancy; higher triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, atherogenic index, apolipoprotein (apo) B, and apoB/apoA1 ratio in the 1st trimester; and higher fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, and TG levels before delivery. No significant differences were found in the frequencies of PON1 C-108T and Q192R genotypes and alleles between the ART and control groups. CONCLUSIONS: Women with AMA undergoing ART had higher TAC, PON1 lactonase activity, and PON1 NLA than control women, suggesting increased compensatory antioxidant capacity in ART women, thus showing higher sensitivity to oxidative stress-related injury and diseases.

CYP2E1 C-1054T and 96-bp I/D genetic variations and risk of gestational diabetes mellitus in chinese women: a case-control study.

BACKGROUND: Cytochrome P450 2E1 (CYP2E1) plays a key role in the metabolism of xenobiotic and endogenous low-molecular-weight compounds. This study aimed to determine if the genetic variations of 96-bp insertion/deletion (I/D) and C-1054T (rs2031920) in CYP2E1 were associated with the risk of gestational diabetes mellitus (GDM). METHODS: CYP2E1 polymorphisms were genotyped in a case-control study of 1,134 women with uncomplicated pregnancies and 723 women with GDM. The effects of genotype on the clinical, metabolic, and oxidative stress indices were assessed. RESULTS: The CYP2E1 C-1054T variant was associated with an increased risk of GDM based on the genotype, recessive, dominant, and allele genetic models (P < 0.05). The TT + CT genotype remained a significant predictive factor for GDM risk after correcting for maternal age and pre-pregnancy body mass index (OR = 1.277, 95% CI: 1.042-1.563, P = 0.018). Moreover, fasting insulin concentrations and homeostatic model assessment of insulin resistance were significantly higher in GDM patients carrying the T allele than in those with the CC genotype (P < 0.05). Furthermore, the combined genotype II + ID/TT + CT of the 96-bp I/D and C-1054T polymorphisms further increased the risk of GDM when the combined genotype DD/CC was set as the reference category (OR = 1.676, 95% CI: 1.182-2.376, P = 0.004). CONCLUSIONS: The T allele of the C-1054T polymorphism and its combination with the I allele of the 96-bp I/D variation in CYP2E1 are associated with an increased risk of GDM in the Chinese population. The - 1054T allele may be associated with more serious insulin resistance in patients.

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.

Association between genetic polymorphisms of leptin receptor and preeclampsia in Chinese women.

OBJECTIVE: Leptin signaling plays an important role in regulating metabolism and reproduction. In the present study, we investigated the relationship between polymorphisms of leptin receptor (LEPR) gene A223G and A668G and preeclampsia (PE) and evaluated influences of genotypes on clinical, metabolic, and oxidative stress indices in Chinese women. METHODS: This is a case-control study including 322 patients with PE and 1295 healthy pregnant women. The two polymorphisms were genotyped by polymerase chain reaction-restriction fragments length polymorphism method. Clinical and biochemical parameters were analyzed. RESULTS: The frequencies of the AA + AG genotypes (28.6% vs. 36.1%) and A allele (14.9% vs. 19.8%) of LEPR A223G polymorphism, and those of the AA + AG genotypes (17.7% vs. 24.6%) and A allele (9.0% vs. 12.9%) of LEPR A668G polymorphism were significantly lower in the PE group than those in the control group. The 223A and 668A alleles were protective factors against PE in the regression model, which included age and delivery body mass index as covariates (OR = 0.684, 95% CI: 0.506-0.926, p = .014; OR = 0.650, 95% CI: 0.456-0.927, p = .017, respectively). When the 668GG/223GG combined genotype served as the reference category, the 668A/223A combined allele had further enhanced the protective effect on PE (OR = 0.558, 95% CI: 0.374-0.833, p = .004). Patients possessing the LEPR 223A allele had higher total antioxidant capacity and lower oxidative stress index (p < .05), while those with the LEPR 668A allele had higher high-density lipoprotein cholesterol levels (p = .045) compared with those carrying the corresponding GG genotype. CONCLUSIONS: The 223A and 668A alleles of LEPR polymorphisms are genetic protective factors for PE in Chinese women. The two alleles may exert a beneficial effect on oxidative stress and lipid metabolism in 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.

Myeloperoxidase G-463A and CYBA C242T genetic variants in gestational diabetes mellitus.

Oxidative stress plays an important role in the pathophysiology of gestational diabetes mellitus (GDM). We investigated the relationship between NADPH oxidase p22phox subunit (CYBA) C242T (rs4673) and myeloperoxidase (MPO) G-463A (rs2333227) genetic variants and GDM in 719 patients with GDM and 1205 control women. Clinical, metabolic, and oxidative stress parameters were analyzed. We found that frequencies of the A allele (15.6% vs 12.3%) and GA + AA genotype (28.5% vs 23.2%) of the MPO G-463A variation were significantly higher in patients with GDM than in the control women (OR = 1.318, 95% CI: 1.068-1.625, P = 0.010 for the dominant model; OR = 1.999, 95% CI: 1.040-3.843, P = 0.034 for the recessive model; OR = 1.320, 95% CI: 1.095-1.591, P = 0.004 for the allele model). Genotype GA + AA remained a significant predictor of GDM in a logistic regression model including age and BMI at delivery (OR = 1.282, 95% CI: 1.037‒1.583, P = 0.021). Furthermore, the ‒463A allele was associated with higher TG and the 242T allele was related to higher pre-pregnancy BMI and oxidative stress index in all subjects (P < 0.05). The 242T allele was also associated with higher homeostatic model assessment of insulin resistance but lower serum total antioxidant capacity in patients with GDM (P < 0.05). We conclude that the MPO G-463A, but not the CYBA C242T, genetic variation is associated with an increased risk of GDM in Chinese women. These two genetic polymorphisms may be linked to obesity, dyslipidemia, insulin resistance, and oxidative stress.

Association of CYBA C242T and superoxide dismutase 2 A16V genetic variants with preeclampsia.

OBJECTIVE: To investigate the relationship between NADPH oxidase p22phox subunit (CYBA; C242T) and superoxide dismutase 2 (SOD2; A16V) polymorphisms and the risk of preeclampsia (PE) in Chinese women. METHODS: This case-control study included 325 patients with PE and 1294 controls. The genotypes were determined by polymerase chain reaction-restriction fragments length polymorphism method. Clinical, metabolic, and oxidative stress parameters were analyzed. RESULTS: Participants with T allele of the CYBA C242T polymorphism had a decreased risk of PE (OR = 0.62, 95% CI: 0.42-0.92, P = 0.016) and those with the A allele of the SOD2 A16V polymorphism had increased risk of PE (OR = 1.44, 95% CI: 1.09-1.89, P = 0.010). The coexistence of the SOD2 AA + AV genotypes and the CYBA CC genotype further increased the risk of PE (OR = 2.32, 95% CI: 1.31-4.10, P = 0.003) when the CT + TT/VV combined genotype was the reference category. CONCLUSION: The T allele of the CYBA C242T polymorphism is related to a decreased risk of PE, while the A allele of the SOD2 A16V polymorphism and its combination with the CYBA CC genotype are associated with an increased risk of PE in Chinese women.

Association of Polymorphisms of Glutamate Cysteine Ligase Genes GCLC C-129 T and GCLM C-588 T with Risk of Polycystic Ovary Syndrome in Chinese Women.

Polycystic ovary syndrome (PCOS) is generally considered a multifactorial disease caused by interactions between multiple susceptible genes and environmental factors. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme in glutathione biosynthesis. This study examined the relationship between single nucleotide polymorphisms (SNPs) in the GCL catalytic subunit (GCLC C-129 T) and the modifier subunit (GCLM C-588 T) and PCOS. The two SNPs were genotyped in 1017 PCOS patients and 793 control women. Clinical, metabolic, hormonal, and oxidative stress parameters were also assessed. The frequencies of the CT + TT genotypes (21.6% vs. 27.7%) and T allele (11.5% vs. 14.7%) of SNP GCLC C-129 T were significantly lower in hyperandrogenism (HA)-PCOS patients than in control women. Logistic regression analysis revealed that the relative hazard of HA-PCOS was lower in individuals with the -129 T allele (CT + TT genotypes) than in those with the CC genotype (OR = 0.723, 95% CI: 0.571-0.915, P = 0.007). When using the GCLC-CC/GCLM-CC combined genotype as the reference category, the GCLC-CT + TT/GCLM-CC combined genotype was a protective factor for PCOS with HA (OR = 0.743, 95% CI: 0.566-0.976, P = 0.033). HA-PCOS patients with the -129 T allele had lower waist circumference, waist-to-hip ratio, and body mass index (BMI) and lower fasting insulin concentration and homeostatic model assessment of insulin resistance after correcting for age and BMI (P < 0.05). The T allele of SNP GCLC C-129 T and its combination with the CC genotype of SNP GCLM C-588 T are associated with decreased risk of HA-PCOS in Chinese women.

[Clinical Study of the Impact of ACE I/D Gene Variation on the Clinical Parameters of Patients with Polycystic Ovary Syndrome].

OBJECTIVE: To investigate the relationship between angiotensin Ⅰ-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the genetic risks for polycystic ovary syndrome (PCOS) and to evaluate the impact of ACE I/D genotypes on clinical, hormonal, metabolic and oxidative stress parameters in patients with PCOS. METHODS: This was a retrospective case-control study involving a total of 1 020 PCOS patients and 825 female controls who visited the outpatient clinic of the Department of Reproductive Endocrinology, West China Second Hospital of Sichuan University between 2006 and 2019. The ages of the subjects ranged between 17 and 44. The ACE I/D genotypes were determined by polymerase chain reaction (PCR) and gel electrophoresis. 667 PCOS patients and 527 controls were selected for an analysis of their genotypes and the hormonal, metabolic and oxidative stress parameters. RESULTS: The genotype distributions of the ACE I/D single nucleotide polymorphism was in Hardy-Weinberg equilibrium in both the PCOS group and the control group (all P>0.05), which was representative of the population. There were no statistically significant differences in genotype and allele frequencies between the PCOS and the control groups ( P>0.05). After adjusting for both age and body mass index (BMI), there was no statistically significant difference in clinical characteristics among all genotypes in either the PCOS group or the control group. In the PCOS group, compared with the II genotype subgroup, the ID genotype subgroup had lower luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, while the DD genotype subgroup had higher homeostatic model assessment of insulin resistance (HOMA-IR) and malondialdehyde (MDA) levels. Compared with the ID genotype subgroup, the DD genotype subgroup had lower serum sex hormone binding globulin (SHBG) level, but higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels ( P<0.05). In the control group, II genotype subgroup had a higher level of total oxidant status (TOS) than that of the DD genotype subgroup. CONCLUSION: ACE I/D genetic polymorphism is not associated with risks for PCOS. The I/D variation of ACE gene may be related to insulin resistance, dyslipidaemia, hyperandrogenemia and oxidative stress in PCOS patients.

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.

Oxidative stress promotes hyperandrogenism by reducing sex hormone-binding globulin in polycystic ovary syndrome.

OBJECTIVE: To determine the relationships between circulating sex hormone-binding globulin (SHBG) and oxidized low-density lipoprotein (ox-LDL), total oxidant status, total antioxidant capacity, oxidative stress index, malondialdehyde, and the high-density lipoprotein (HDL) inflammatory index in patients with polycystic ovary syndrome (PCOS) and to investigate the effect of oxidative stress on the expression of SHBG and its mechanism in HepG2 cells. DESIGN: Cross-sectional study. SETTING: University hospital. PATIENT(S): A total of 533 women with PCOS and 292 control women were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Circulating SHBG, hormones, and metabolic and oxidative stress indices were determined in all subjects. The effects of ox-LDL and ox-HDL on the mRNA and protein expression of SHBG and related transcription factors were observed in HepG2 cells. RESULT(S): The HDL inflammatory index, total oxidant status, oxidative stress index, and malondialdehyde levels were significantly higher in the three PCOS subgroups with different SHBG levels than in the controls. The ox-LDL and total antioxidant capacity were higher in the PCOS subgroups with SHBG levels <75th percentile compared with the controls or the PCOS subgroup with SHBG levels ≥75th percentile. In HepG2 cells, the SHBG concentration in the culture supernatant, the mRNA levels of SHBG and hepatocyte nuclear factor-4α (HNF-4α), and the protein levels of HNF-4α were significantly lower in ox-LDL- and ox-HDL-treated cells than in the control cells and lipoprotein-treated cells. CONCLUSION(S): Oxidative stress inhibits the expression and secretion of SHBG by downregulating HNF-4α in vitro and may be an important factor promoting the occurrence of hyperandrogenemia in PCOS.

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.