The interval between the onset of increased blood pressure and proteinuria in preeclampsia and the contributing factors.

PURPOSE: New-onset proteinuria, as a pivotal sign of representative renal lesions in preeclampsia, is still the most common diagnostic tool for this condition and has been proven to be related to a significantly abnormal sFlt-1/VEGF ratio in circulation. At the same time, blood pressure control plays a vital role in the occurrence and evolution of proteinuria. Therefore, it is particularly helpful to investigate their interval, not only for performing urinalysis for protein more accurately but also for evaluating blood pressure as well as the aggravation of illness, as the related research is limited. METHODS: This retrospective study included 515 preeclampsia patients and 358 normotensive pregnant women who labored in the Second Hospital of Tianjin Medical University from January 2016 to January 2020. First, we described the onset circumstance of high blood pressure and proteinuria as well as the interval among the case group and the subgroups. Then, we determined whether there were significant differences in the basic information, laboratory test results, and newborns between the case and normal groups. Finally, multifactor ANOVA was used to determine the factors influencing the interval. RESULTS: 1. The two most common complications in preeclampsia were proteinuria (88.35%) and placental dysfunction (5.05%). Moreover, 72.04% of preeclampsia cases were diagnosed by abnormal blood pressure together with new-onset proteinuria. 2. The average interval between high blood pressure and proteinuria was 22 gestational days (from 0 to 106 days), and this interval was not significantly different between mild and severe PE (26 days vs. 21 days, P > 0.05) but significantly differed between early-onset and late-onset PE (9 days vs. 28 days, P < 0.05). 3. The number of prenatal visits, serum creatinine in the early trimester, gestational time and diastolic blood pressure value when increased blood pressure was initially detected may influence the interval between the onset of increased blood pressure and proteinuria. CONCLUSION: New-onset proteinuria was still the main parameter for identifying preeclampsia. The interval between increased blood pressure and proteinuria was probably related to the imbalance in the sFlt-1/VEGF ratio; therefore, we should pay attention to monitor proteinuria during the prenatal visits, especially for patients with a lower frequency of prenatal visits, higher serum creatinine in the early trimester, earlier onset and higher diastolic blood pressure at the initial onset of increased blood pressure.

Blood pressure patterns of hypertensive disorders of pregnancy in first and second trimester and contributing factors: a retrospective study.

We aimed to investigate the blood pressure (BP) patterns of hypertensive disorders of pregnancy (HDP) in the first and second trimesters and its contributing factors, which may help us understand its pathogenesis and identify this group of diseases in a timely manner. SPSS 21.0 was used to describe the BP patterns of 688 HDP as well as 2050 normotensive pregnancies respectively before 28 gestational weeks, and the repeated measurements and two-way ANOVA was used to decide the significant difference of blood pressure in the same period. The results revealed blood pressure in HDP underwent a mid-pregnancy drop as normal while the drop was unremarkable in advanced-age or obesity pregnancies. Besides, we found blood pressure was significantly higher in patients during first and second trimesters, not just after 20 weeks. In conclusion, our study indicated a significant elevation of blood pressure had appeared before 20 weeks in HDP pregnancies, we should pay more attention to monitoring blood pressure before 20 weeks, especially for advanced age and obese women.IMPACT STATEMENTWhat is already known on this subject? Gestational hypertension, preeclampsia as well as eclampsia were supposed to have the similar pathogenesis and their time of onset was strictly defined after 20 gestational weeks, while the reason for the time point was not clear. On the other hand, higher blood pressure in the first trimester was associated with increasing risk of developing HDP, while the blood pressure(BP) pattern of normal as well as HDP pregnancy was still controversial, especially for the existence of mid-trimester drop.What do the results of this study add? Firstly, we found blood pressure in HDP underwent a mid-pregnancy drop as normal while the BP drop was unremarkable in advanced-age or obesity pregnancies. Secondly, we noticed the blood pressure in HDP was significantly higher than the normal before 20 weeks, which had not been proved before.What are the implications of these findings for clinical practice and/or further research? On one hand, both the abnormal elevation of BP and the development of the placenta happened in the first trimester suggested toxic substances caused by the defective placenta played a vital role in the onset and aggravation of HDP, which guides us to pay more attention to monitor blood pressure before 20 weeks, especially for advanced age and obesity pregnancies. On the other hand, our results about BP patterns in HDP help us identify this group of diseases in time which can contribute to a better outcome.

Long non-coding RNA TUG1 regulates ovarian cancer proliferation and metastasis via affecting epithelial-mesenchymal transition.

Ovarian cancer is the fifth leading cause of cancer-related death in women worldwide, and recent studies have highlighted the role of long non-coding RNAs (lncRNAs) in cancer development. However, the role of lncRNAs in ovarian cancer is largely unclear. In this study, we focused on the taurine up-regulated gene 1 (TUG1) and examined its molecular mechanism in ovarian cancer. Here, we reported that TUG1 was up-regulated in ovarian cancer tissues and ovarian cancer cells, and TUG1 expression was positively correlated with tumor grade and FIGO stage. In vitro functional assays (CCK-8 assay, colony formation assay, and cell invasion assay) revealed that knock-down of TUG1 by small RNA inference significantly inhibited cell proliferation, colony formation and cell invasion in ovarian cancer cells. Further experiment showed that knock-down of TUG1 induced cell apoptosis and altered the protein expression levels of apoptosis-related mediators in ovarian cancer cells. More importantly, knock-down of TUG1 also reversed epithelial-mesenchymal transition in ovarian cancer. In summary, our results suggest that knock-down of TUG1 may represent a novel therapeutic strategy for the treatment of ovarian cancer.

Association between rs1799724 of TNF- α gene and early onset preeclampsia in Chinese: A pilot study.

Objective: To investigate the association between polymorphisms of TNF- α (rs1799724, rs1800629), VEGF (rs3025039) and VEGFR1 (rs 722503) and early onset preeclampsia (EOPE) in Chinese. Methods: A total of 132 EOPE patients from January 2016 to December 2018 at the Second Hospital of Tianjin Medical University were selected as the EOPE group, and 156 normal pregnant patients as the Control group. In both groups, 5 ml of peripheral venous blood was obtained after admission. The characteristics of genotype and allele distribution at the four SNPs in the study subjects were examined by matrix-assisted laser desorption ionization time-of-flight mass spectrometric genotyping. Results: The genotype frequency distribution and allele frequency distribution of rs1799724 were significantly different between the EOPE group and the Control group (P = 0.002，P = 0.003). The T allele was statistically associated with the development of EOPE under a dominant genetic model (P = 0.001). The genotype and allele frequency distributions of rs1800629, rs3025039, and rs 722503 did not differ significantly between the EOPE group and the Control group (P > 0.05). There was no linkage disequilibrium among rs1799724, rs1800629 and rs3025039 loci, the corresponding haploid cannot be formed. Conclusions: The rs1799724 of TNF- α gene is a genetic susceptibility locus for EOPE and may be a potential predictors of preeclampsia.

Mitogenic and anti-apoptotic effects of insulin in endometrial cancer are phosphatidylinositol 3-kinase/Akt dependent.

OBJECTIVE: To determine serum insulin levels, expression and phosphorylation of InsR, IRS-1 and Akt in endometrial cancer (EC) tissues, and to explore the correlation between them. To investigate if insulin-induced mitogenic and anti-apoptotic effects are PI3K-dependent in EC cells. METHODS: Serum insulin levels were measured by radioimmunoassay. We performed RT-PCR and western blotting to evaluate the expression and activation of key proteins of PI3K/Akt pathway in 63 EC tissues. The proliferation and apoptosis rates were determined with MTT, BrdU and annexin V/PI assays. RESULTS: Serum insulin levels and InsR, IRS-1 and Akt expression and phosphorylation were significantly elevated in patients with EC compared to those without EC. Additionally, levels of p-InsR, p-IRS-1, and p-Akt were significantly higher in patients with high-grade, advanced stage, deep myometrial invasion, and lymph-node metastasis. The expression and activation of InsR, IRS-1, and p-Akt were positively related with the levels of serum insulin. The insulin-induced mitogenic and anti-apoptotic effects in EC cells were blocked when cells were pre-incubated with LY294002. Ishikawa 3-H-12 cells showed increased p-Akt levels after treatment with insulin at 10(-8)M for 15min. The insulin-induced Akt activation was inhibited by LY294002 in a dose-dependent manner. CONCLUSION: Insulin played an essential role in EC tumorigenesis. Activation of InsR, IRS-1, and Akt was associated with features of aggressive EC. Insulin was a mitogenic and anti-apoptotic agent for EC cells, and these effects were dependent on PI3K/Akt pathway. Decreasing insulin level and blocking the InsR-IRS-PI3K-Akt pathway could be viable preventive and therapeutic strategies for EC.

Development and validation of the prediction models for preeclampsia: a retrospective, single-center, case-control study.

Background: Preeclampsia (PE) is a major cause of adverse maternal and infant outcomes. Accurate screening of PE is currently the focus of clinical attention. This study aimed to develop a model for predicting PE. Methods: A retrospective case-control study was conducted with 916 pregnant women who received care at the Second Hospital of Tianjin Medical University (October 2018 to July 2020). Women were randomly divided into the training (n=680) and testing (n=236) sets based on a ratio of 3:1. Demographic and clinical data of women were collected. In training set, logistic regression (LR), classification tree (CT) model, and random forest (RF) algorithm were used to develop prediction models for PE. Using the testing set was to validate these prediction models. The predictive performance of three models were assessed by the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Of the total 916 women, 237 had PE. The family history of hypertension, pre-pregnancy body mass index (pBMI), blood pressure (BP) ≥130/80 mmHg in early pregnancy, age, chronic hypertension, and duration of hypertension were the predictors of PE. The AUCs for the LR, CT, and RF models were 0.778, 0.850, and 0.871, respectively (all P<0.05 for all pair-wise comparisons). The RF had the best predictive efficiency with sensitivity, specificity, PPV, and NPV of 79.6%, 94.7%, 79.6%, and 94.7%, respectively. Conclusions: The RF model could be a practical screening approach for predicting PE, which is helpful for clinicians to identify high-risk individuals and prevent the occurrence of adverse pregnancy outcomes.

[Expression and activation of insulin receptor substrate-1 in endometrial carcinoma].

OBJECTIVE: To investigate the mRNA, protein expression and tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in endometrial carcinoma. METHODS: Sixty-three endometrial carcinoma (EC) patients, 21 endometrial atypical hyperplasia (AHE) patients and 22 normal control (NE) entered this study. Their clinical information were collected. Fasting serum C-peptide concentration was measured. Expression of IRS-1 in endometrium was examined by RT-PCR and western blot. Immunoprecipitation was used to measure the tyrosine phosphorylation of IRS-1. RESULTS: C-peptide concentration in EC group was higher than that in NE group [(3.2 +/- 1.1) vs (2.5 +/- 0.7) microg/L, P=0.007]. There were no significant differences in IRS-1 mRNA and protein expression among the three groups. Tyrosine phosphorylation of IRS-1 in EC group [(62 +/- 36) %] was higher than that in AHE and NE groups [(53 +/-34)% and (35 +/- 33)%; P=0.048, 0.002]. IRS-1 activation in AHE group was also higher than normal control (P=0.045). IRS-1 activation in endometrioid carcinoma [(69 +/- 33) %] was higher than that in other histological types [(34 +/- 31)%; t=2.300, P=0.025]. IRS-1 tyrosine phosphorylation was significantly higher in patients with advanced stage, high grade, deep myometrial invasion and pelvic lymph node metastasis. IRS-1 activation in endometrium was positively correlated with fasting serum C-peptide concentration (r=0.491, P=0.001). CONCLUSIONS: There is excessive activation of IRS-1 in endometrial carcinoma and atypical hyperplasia. Activation of IRS-1 in endometrial carcinoma is related with poor clinical-pathologic features and may be a prognostic predictor for this tumor. Over-activation of IRS-1 may be an intermediate event linking the hyperinsulinemia and endometrial carcinoma.

[Effects of insulin on proliferation and apoptosis of endometrial carcinoma cell].

OBJECTIVE: To study the expression of insulin receptor (INSR) in endometrial cell line Ishikawa3-H-12, and the effects of insulin on proliferation, cell cycle distribution and apoptosis of Ishikawa3-H-12 cells. METHODS: Immunocytochemistry and RT-PCR methods were used to investigate the expression of INSR in Ishikawa3-H-12 cells. The effects of insulin at different concentrations and different time on proliferation, apoptosis and cell cycle distribution of endometrial carcinoma cells were observed by methyl thiazolyl tetrazolium (MTT) assay and fluorescence-activated cell sorting technique. RESULTS: (1) We demonstrated the expression of INSR in Ishikawa3-H-12 cell line. (2) Incubation with insulin stimulated a dose- and time-dependent proliferation response in Ishikawa3-H-12 cells with the peak response occurring at 48 hours with 1 x 10(-4) mol/L insulin incubation [proliferative rate: (340.2 +/- 15.9)%, vs control (100%), P < 0.05]. (3) The percentage of Ishikawa3-H-12 cells at G(0)/G(1) phase decreased and percentage at S phase increased significantly with insulin treatment in a dose- and time-dependent manner with the peak response occurring at 72 hours with 1 x 10(-4) mol/L insulin incubation [G(0)/G(1) phase (27.7 +/- 2.5)%, S phase (55.2 +/- 1.4)%, vs control: (67.6 +/- 1.5)% and (15.7 +/- 1.0)%, P < 0.05], whereas that of G(2)/M phase did not show significant alteration. (4) The apoptosis rate of Ishikawa3-H-12 cells was decreased gradually with increasing concentration of insulin, while the alteration was time-independent. The peak response occurred with 1 x 10(-4) mol/L insulin incubation [apoptosis rate: (1.76 +/- 0.16)%, (1.70 +/- 0.15)%, (1.56 +/- 0.20)%, (1.31 +/- 0.24)% when incubated at 24, 48, 72 and 96 hours respectively, vs control, P < 0.05]. CONCLUSION: Insulin can promote the proliferation and inhibit the apoptosis of endometrial carcinoma cells.

Diosgenin ameliorates gestational diabetes through inhibition of sterol regulatory element-binding protein-1.

Gestational diabetes (GD) is a pathological condition, affecting 2-5% of pregnant women. Diosgenin (DSG) possesses a variety of biological activities. The present study was designed to examine the effect of DSG on GD and to investigate the possible mechanism in C57BL/KsJ-Lepdb/+ (db/+) mice. We found that DSG could remarkably ameliorated GD in pregnant db/+ mice, as reflected by the improvement of glucose and insulin intolerance, and the decrease of fasting blood glucose and insulin level and the increase of hepatic glycogen content. The results showed that DSG could inhibit oxidative stress in pregnant db/+ mice, as evidenced by decrease of thiobarbituric acid reactive substances (TBARS) content, increase of glutathione (GSH) level and superoxide dismutase (SOD) and catalase (CAT) activities. DSG could also attenuate the abnormal changes of lipid profiles, including TC, TG and LDL, in pregnant db/+ mice. The increase of the expression of sterol regulatory element-binding transcription factor-1 (SREBP-1) and its target genes, including fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and acetyl coenzyme A carboxylase (ACC), was inhibited by DSG in pregnant db/+ mice. Moreover, overexpression of SREBP-1 by LV-SREBP-1 injection could markedly inhibit the protective effect of DSG against disorder of glucose and lipid metabolism and oxidative stress in GD mice. The data demonstrated that SREBP-1 may be of major target of DSG that mediated its anti-diabetic activities in GD. The data provide novel insights into the biological activities of DSG and pave way for the investigation of the anti-diabetic activities against GD.

[Study on the gestational diabetes mellitus and histocompatibility human leukocyte antigen DRB allele polymorphism].

OBJECTIVE: To investigate the allelic frequency of histocompatibility leukocyte antigen (HLA)-DRB of gestational diabetes mellitus (GDM) women, in order to find out the susceptible or protective gene associated with GDM and the relationship between HLA-DRB genes and the clinical characteristic. METHODS: Thirty GDM women served as study group, 40 normal pregnant women were selected as control group. The distribution of HLA-DRB alleles frequency of 30 GDM and 40 normalpregnant women was examed by polymerase chain reaction sequence specific primer (PCR-SSP). RESULTS: There was significantly increased gene frequency of HLA-DR6 (13) in GDM women compared with normal pregnancy (12% Vs 2%, P < 0.05, RR = 5.8). The frequency of HLA-DR3 and HLA-DR9 gene in GDM women were increased, but the statistical difference was not significant (8% Vs 4%, 23% Vs 16%, P > 0.05). A much lower frequency of HLA-DR2 (15), HLA-DR51 were observed in GDM women than in normal pregnancy (10% Vs 24%, P < 0.05; 10% Vs 38%, P < 0.05). There were relationship between HLA-DR3 gene or HLA-DR6 (13)/DR9 heterozygote and severe type of GDM, relative risk (RR) were 27.1 and 8.5 respectively; HLA-DR6 (13)/DR9 heterozygote or HLA-DR3 gene were also correlated with abnormal plasma glucose levels. CONCLUSIONS: Alleles HLA-DR6 (13) were significantly implicated in their susceptibility to GDM. Conversely, HLA-DR2 (15), HLA-DR51 alleles might confer protection against GDM. HLA-DR3 gene and HLA-DR6 (13)/DR9 heterozygote were associated with severity and prognosis of GDM. It may be a marker of grade and prognosis of GDM and may direct the treatment.

Insulin promotes proliferation, survival, and invasion in endometrial carcinoma by activating the MEK/ERK pathway.

The involvement of insulin in endometrial carcinoma (EC) was investigated using radioimmunoassay, Western blot, immunoprecipitation, MTT, and Annexin V-FITC/PI assays in tissue samples and cultured cells. Serum levels of insulin, p-p52Shc, p-p46Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1 were elevated in patients with EC. Expression of key proteins in the MEK/ERK pathway, including p-p52Shc, Shc·Grb2 complexes, p-MEK, p-ERK, and cyclin D1, was significantly higher in patients with advanced FIGO stage, high grade, and lymph-node metastasis and correlated positively with serum insulin concentration. Insulin promotes Ishikawa 3-H-12 cell proliferation, survival, and invasion, and these effects induced by insulin were significantly blocked by MEK inhibitor PD98059. Insulin thus promotes EC cell proliferation, survival, and invasion via the MEK/ERK pathway.