Mediation effect of maternal triglyceride and fasting glucose level on the relationship between maternal overweight/ obesity and fetal growth: a prospective cohort study.

BACKGROUND: Previous studies have suggested that maternal overweight/obesity is asscociated with macrosomia. The present study aimed to investigate the mediation effects of fasting plasma glucose (FPG) and maternal triglyceride (mTG) in the relationship between maternal overweight/obesity and large for gestational age (LGA) among non-diabetes pregnant women. METHODS: This prospective cohort study was conducted in Shenzhen from 2017 to 2021. A total of 19,104 singleton term non-diabetic pregnancies were enrolled form a birth cohort study. FPG and mTG were measured at 24-28 weeks. We analyzed the association of maternal prepregancy overweight/obesity with LGA and mediation effects of FPG and mTG. Multivariable logistic regression analysis and serial multiple mediation analysis were performed. The odds ratio (OR) and 95% confidence intervals (CIs) were calculated. RESULTS: Mothers who were overweight or obese had higher odds of giving birth to LGA after adjusting potential confounders (OR:1.88, 95%CI: 1.60-2.21; OR:2.72, 95%CI: 1.93-3.84, respectively). The serial multiple mediation analysis found prepregnancy overweight can not only have a direct positive effect on LGA (effect = 0.043, 95% CI: 0.028-0.058), but also have an indirect effect on the LGA through two paths: the independent mediating role of FPG (effect = 0.004, 95% CI: 0.002-0.005); the independent mediating role of mTG (effect = 0.003,95% CI: 0.002-0.005). The chain mediating role of FPG and mTG has no indirect effect. The estimated proportions mediated by FPG and mTG were 7.8% and 5.9%. Besides, the prepregnancy obesity also has a direct effect on LGA (effect = 0.076; 95%CI: 0.037-0.118) and an indirect effect on LGA through three paths: the independent mediating role of FPG (effect = 0.006; 95%CI: 0.004-0.009); the independent mediating role of mTG (effect = 0.006; 95%CI: 0.003-0.008), and the chain mediating role of FPG and mTG (effect = 0.001; 95%CI: 0.000-0.001). The estimated proportions were 6.7%, 6.7%, and 1.1%, respectively. CONCLUSION: This study found that in nondiabetic women, maternal overweight/obesity was associated with the occurence of LGA, and this positive association was partly mediated by FPG and mTG, suggesting that FPG and mTG in overweight/obese nondiabetic mothers deserve the attention of clinicians.

Reduced 2,4-dienoyl-CoA reductase 1 is served as an unfavorable biomarker and is related to immune infiltration in cervical cancer.

BACKGROUND: Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4-dienoyl-CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. METHODS: Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co-relationship among DECR1, immune markers, and typical molecules of apoptosis. RESULTS: DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. CONCLUSION: DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration.

Maternal BMI changes from the prepregnancy to postpartum period are associated with postpartum cardiometabolic risk factors: a longitudinal study.

PURPOSE: This study aimed at investigating the associations between the total body mass index (BMI) change at 3 or 4 years postpartum compared to the prepregnancy and cardiometabolic risk factors. METHODS: This longitudinal study included 1305 participants. Based on the total postpartum BMI changes, they were divided into < 0 units, 0-1.7 units, and > 1.7 units groups using the interquartile range. Multiple linear regression models were used to analyze the associations. RESULTS: Compared to the reference group, there was a progressive increase in the ßcoefficient (ßcoef) of homeostasis model assessment of insulin resistance (HOMA-IR) of cardiometabolic risk in the following groups: the '0-1.7 units' group with the 'overweight traj' [ßcoef 0.33; 95% confidence intervals (CI) 0.22, 0.44)] or the 'obesity traj' [0.66; (0.45, 0.88)] and the '> 1.7 units' group with the 'normal traj' [0.33; (0.22, 0.44)], the 'overweight traj' [0.54; (0.41, 0.67)] or the 'obesity traj' [0.97; (0.79, 1.15)]. The same increasing trend of ßcoef was also found in DBP, FPG, LDL, WHR, BF%. However, the '< 0 units' group with the 'low traj' [0.13; (0.06, 0.21)] and the '0-1.7 units' group with the 'low traj' [0.08; (0.03, 0.13)] had higher high-density lipoprotein cholesterol (HDL-C) level than the reference group. CONCLUSION: Women with a postpartum BMI gain > 1.7 units are positively associated with cardiometabolic risk factors, especially for those in the 'obesity traj' or 'traj D'. Conversely, women with a postpartum BMI loss > 0 units have negative association with cardiometabolic risk factors, especially for those in the 'low traj' or 'traj B'.

Elevated trophoblastic Siglec6 contributes to the impairment of vascular endothelial cell functions by downregulating Wnt6/ß-catenin signaling in preeclampsia.

Preeclampsia (PE), a systemic vascular disorder, is the leading cause of maternal and perinatal morbidity and mortality, and its pathogenesis has yet to be fully elucidated. Siglec6, a transmembrane protein, is highly expressed in human placental trophoblasts, and previous studies have shown that Siglec6 overexpression correlates with PE, but the role of Siglec6 during PE progression is unknown. Here, we demonstrated that the mRNA and protein expression levels of Siglec6 were upregulated in early-onset PE placentas compared with uncomplicated pregnancies, and Siglec6 was primarily located in syncytiotrophoblasts (STBs) and extravillous trophoblasts (EVTs). Moreover, our results showed that chemical reagent-induced HIF-1α accumulation promoted the mRNA and protein levels of Siglec6 in HTR8/SVneo and BeWo cells. Although Siglec6 overexpression did not affect HTR8/SVneo cell proliferation, migration, and invasion, the conditional medium derived from the Siglec6 overexpressed HTR8/SVneo cells (Siglec6-OE-CM) significantly impaired the proliferation, migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs). Subsequently, the transcriptome sequencing results revealed that Siglec6 overexpression led to the downregulation of Wnt6 in HTR8/SVneo cells, which was further confirmed by qPCR and ELISA. Recombinant human Wnt6 reversed Siglec6-OE-CM-mediated suppression of HUVEC functions by reactivating the Wnt/ß-catenin signaling pathway. Altogether, our study found that elevated trophoblastic Siglec6 contributed to the impairment of vascular endothelial cell functions by downregulating Wnt6/ß-catenin signaling.

Association of maternal obesity with preterm birth phenotype and mediation effects of gestational diabetes mellitus and preeclampsia: a prospective cohort study.

BACKGROUND: The association between maternal obesity and preterm birth remains controversial and inconclusive, and the effects of gestational diabetes mellitus (GDM) and preeclampsia (PE) on the relationship between obesity and preterm birth have not been studied. We aimed to clarify the relationship between prepregnancy body mass index (BMI) and the phenotypes of preterm birth and evaluate the mediation effects of GDM and PE on the relationship between prepregnancy BMI and preterm birth. METHODS: We conducted a prospective cohort study of 43,056 women with live singleton births from 2017 through 2019. According to the WHO International Classification, BMI was classified as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-25 kg/m2), overweight (BMI 25-30 kg/m2) and obese (BMI ≥30 kg/m2). Preterm birth was defined as gestational age less than 37 weeks (extremely, < 28 weeks; very, 28-31 weeks; and moderately, 32-36 weeks). The clinical phenotypes of preterm birth included spontaneous preterm birth (spontaneous preterm labor and premature rupture of the membranes) and medically indicated preterm birth. We further analyzed preterm births with GDM or PE. Multivariable logistic regression analysis and causal mediation analysis were performed. RESULTS: Risks of extremely, very, and moderately preterm birth increased with BMI, and the highest risk was observed for obese women with extremely preterm birth (OR 3.43, 95% CI 1.07-10.97). Maternal obesity was significantly associated with spontaneous preterm labor (OR 1.98; 95% CI 1.13-3.47), premature rupture of the membranes (OR 2.04; 95% CI 1.08-3.86) and medically indicated preterm birth (OR 2.05; 95% CI 1.25-3.37). GDM and PE mediated 13.41 and 36.66% of the effect of obesity on preterm birth, respectively. GDM mediated 32.80% of the effect of obesity on spontaneous preterm labor and PE mediated 64.31% of the effect of obesity on medically indicated preterm birth. CONCLUSIONS: Maternal prepregnancy obesity was associated with all phenotypes of preterm birth, and the highest risks were extremely preterm birth and medically indicated preterm birth. GDM and PE partially mediated the association between obesity and preterm birth.

Association between the cut-off value of the first trimester fasting plasma glucose level and gestational diabetes mellitus: a retrospective study from southern China.

PURPOSE: Our previous studies have suggested that the first trimester fasting plasma glucose (FPG) level is associated with gestational diabetes mellitus (GDM) and is a predictor of GDM. The aim of the present study was to provide valuable insights into the accuracy of the first trimester FPG level in the screening and diagnosis of GDM in southern China. METHODS: This retrospective study included pregnant women who had their first trimester FPG level recorded at 9-13+6 weeks and underwent screening for GDM using the 2-h 75 g oral glucose tolerance test (OGTT) between the 24th and 28th gestational weeks. Differences between the GDM and non-GDM groups were assessed by Student's t test and the chi-squared test according to the nature of the variables. A restricted cubic spine was used to explore the relationship between the first trimester FPG level and the odds ratio (OR) of GDM in pregnant women. Cut-off values of first trimester FPG were determined using receiver operating characteristic (ROC) curves and the area under the curve (AUC), and 95% confidence intervals (CIs), the positive predictive value (PPV) and the negative predictive value (NPV) were calculated. RESULTS: The medical records of 28,030 pregnant women were analysed, and 4,669 (16.66%) of them were diagnosed with GDM. The average first trimester FPG level was 4.62 ± 0.37 mmol/L. The OR of GDM increased with increasing first trimester FPG levels and with a value of first trimester FPG of approximately 4.6 mmol/L, which was equal to 1 (Chi-Square = 665.79, P < 0.001), and then started to increase rapidly afterwards. The ROC curve for fasting plasma glucose in the first trimester (4.735 mmol/L) for predicting gestational diabetes mellitus in pregnant women was 0.608 (95% CI: 0.598-0.617), with a sensitivity of 0.490 and a specificity of 0.676. CONCLUSION: Based on the research, we recommend that all pregnant women undergo FPG testing in the first trimester, particularly at the first antenatal visit. Furthermore, we suggest that the risks of GDM should be given increased attention and management as soon as the first trimester FPG value is more than 4.7 mmol/L. First trimester FPG levels should be considered a screening marker when diagnosing GDM in pregnant women but this needs to be confirmed by more prospective studies. These factors may have a significant impact on the clinical treatment of pregnant women.

Targeting of Annexin A1 in Tumor-associated Macrophages as a therapeutic strategy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common aggressive, malignant tumor with limited treatment options. Currently, immunotherapies have low success rates in the treatment of HCC. Annexin A1 (ANXA1) is a protein related to inflammation, immunity and tumorigenesis. However, the role of ANXA1 in liver tumorigenesis remains unknown. Therefore, we sought to explore the feasibility of ANXA1 as a therapeutic target for HCC. Here, we analyzed ANXA1 expression and localization by HCC microarray and immunofluorescence experiments. Using an in vitro culture system, monocytic cell lines and primary macrophages were employed to investigate the biological functions of cocultured HCC cells and cocultured T cells. In vivo, Ac2-26, human recombinant ANXA1 (hrANXA1), and cell depletion (macrophages or CD8 + T cells) experiments were further conducted to investigate the role of ANXA1 in the tumor microenvironment (TME). We found that ANXA1 was overexpressed in mesenchymal cells, especially macrophages, in human liver cancer. Moreover, the expression of ANXA1 in mesenchymal cells was positively correlated with programmed death-ligand 1 expression. Knockdown of ANXA1 expression inhibited HCC cell proliferation and migration by increasing the M1/M2 macrophage ratio and promoting T-cell activation. hrANXA1 promoted malignant growth and metastasis in mice by increasing the infiltration and M2 polarization of tumor-associated macrophages (TAMs), generating an immunosuppressive TME and suppressing the antitumor CD8 + T-cell response. Together, our findings reveal that ANXA1 may be an independent prognostic factor for HCC and demonstrate the clinical translational significance of ANXA1 for tumor immunotherapy in HCC.

Third-Trimester Maternal Serum Chemerin and Hypertension After Preeclampsia: A Prospective Cohort Study.

Background Limited data are available for postpartum hypertension prediction after preeclampsia. Methods and Results We examined the association between maternal serum chemerin levels in patients with preeclampsia and blood pressure (BP) levels after delivery in a prospective birth cohort of 15 041 singleton pregnant women. A total of 310 cases among 322 patients with preeclampsia (follow-up rate, 96.3%) were followed up during a mean 2.8 years after delivery. Compared with matched uncomplicated controls (n=310), serum chemerin measured at ≈35 gestational weeks was significantly increased in preeclampsia (171.8±49.2 versus 140.2±53.5 ng/mL; P<0.01) and positively correlated with the occurrence of postpartum hypertension, defined as either BP ≥130/80 mm Hg (per 1-SD increase: odds ratio [OR], 4.01 [95% CI, 2.77-5.81]) or as BP ≥140/90 mm Hg (per 1-SD increase: OR, 1.70 [95% CI, 1.28-2.25]) in patients with preeclampsia. The addition of chemerin levels improved the predictive performance of the clinical variable-derived prediction models for postpartum hypertension (for BP ≥130/80 mm Hg: area under the curve, 0.903 [95% CI, 0.869-0.937], Δ area under the curve, 0.070, P<0.001; for BP ≥140/90 mm Hg: area under the curve, 0.852 [95% CI, 0.803-0.902], Δ area under the curve, 0.030, P=0.002). The decision curve analysis revealed a net benefit of the chemerin-based prediction model for postpartum BP ≥130/80 mm Hg. Conclusions This study provides the first evidence supporting the independent predictive role of third-trimester maternal chemerin levels for postpartum hypertension after preeclampsia. Future study is warranted for external validation of this finding.

Focusing on the role of secretin/adhesion (Class B) G protein-coupled receptors in placental development and preeclampsia.

Preeclampsia, a clinical syndrome mainly characterized by hypertension and proteinuria, with a worldwide incidence of 3-8% and high maternal mortality, is a risk factor highly associated with maternal and offspring cardiovascular disease. However, the etiology and pathogenesis of preeclampsia are complicated and have not been fully elucidated. Obesity, immunological diseases and endocrine metabolic diseases are high-risk factors for the development of preeclampsia. Effective methods to treat preeclampsia are lacking, and termination of pregnancy remains the only curative treatment for preeclampsia. The pathogenesis of preeclampsia include poor placentation, uteroplacental malperfusion, oxidative stress, endoplasmic reticulum stress, dysregulated immune tolerance, vascular inflammation and endothelial cell dysfunction. The notion that placenta is the core factor in the pathogenesis of preeclampsia is still prevailing. G protein-coupled receptors, the largest family of membrane proteins in eukaryotes and the largest drug target family to date, exhibit diversity in structure and function. Among them, the secretin/adhesion (Class B) G protein-coupled receptors are essential drug targets for human diseases, such as endocrine diseases and cardiometabolic diseases. Given the great value of the secretin/adhesion (Class B) G protein-coupled receptors in the regulation of cardiovascular system function and the drug target exploration, we summarize the role of these receptors in placental development and preeclampsia, and outlined the relevant pathological mechanisms, thereby providing potential drug targets for preeclampsia treatment.

Excessive gestational weight gain in early pregnancy and insufficient gestational weight gain in middle pregnancy increased risk of gestational diabetes mellitus.

BACKGROUND: Gestational weight gain (GWG) is associated with the risk of gestational diabetes mellitus (GDM). However, the effect of weight gain in different trimesters on the risk of GDM is unclear. This study aimed to evaluate the effect of GWG on GDM during different trimesters. METHODS: A birth cohort study was conducted from 2017 to 2020 in Shenzhen, China. In total, 51,205 participants were included comprising two models (early pregnancy model and middle pregnancy model). Gestational weight (kg) was measured at each prenatal clinical visit using a standardized weight scale. Logistic regression analysis was used to assess the risk of GDM. Interaction analysis and mediation effect analysis were performed in the middle pregnancy model. RESULTS: In the early pregnancy model, the risk of GDM was 0.858 times lower (95% confidence interval [CI]: 0.786, 0.937) with insufficient GWG (iGWG) and 1.201 times higher (95% CI: 1.097, 1.316) with excessive GWG after adjustment. In the middle pregnancy model, the risk of GDM associated with iGWG increased 1.595 times (95% CI: 1.418, 1.794) after adjustment; for excessive GWG, no significant difference was found ( P  = 0.223). Interaction analysis showed no interaction between GWG in early pregnancy (GWG-E) and GWG in middle pregnancy (GWG-M) ( F  = 1.268; P  = 0.280). The mediation effect analysis indicated that GWG-M plays a partial mediating role, with an effect proportion of 14.9%. CONCLUSIONS: eGWG-E and iGWG-M are associated with an increased risk of GDM. Strict control of weight gain in early pregnancy is needed, and sufficient nutrition should be provided in middle pregnancy.

Fasting plasma glucose in the first trimester is related to gestational diabetes mellitus and adverse pregnancy outcomes.

PURPOSE: To investigate and identify first-trimester fasting plasma glucose (FPG) is related to gestational diabetes mellitus (GDM) and other adverse pregnancy outcomes in Shenzhen population. METHODS: We used data of 48,444 pregnant women that had been retrospectively collected between 2017 and 2019. Logistic regression analysis was used to evaluated the associations between first-trimester FPG and GDM and adverse pregnancy outcomes, and used to construct a nomogram model for predicting the risk of GDM. The performance of the nomogram was evaluated by using ROC and calibration curves. Decision curve analysis (DCA) was used to determine the clinical usefulness of the first-trimester FPG by quantifying the net benefits at different threshold probabilities. RESULTS: The mean first-trimester FPG was 4.62 ± 0.42 mmol/L. A total of 6998 (14.4%) pregnancies developed GDM.489(1.01%) pregnancies developed polyhydramnios, the prevalence rates of gestational hypertensive disorder (GHD), cesarean section, primary cesarean section, preterm delivery before 37 weeks (PD) and dystocia was 1130 (2.33%), 20,426 (42.16%), 7237 (14.94%), 2386 (4.93%), and 1865 (3.85%), respectively. 4233 (8.74%) of the newborns were LGA, and the number of macrosomia was 2272 (4.69%), LBW was 1701 (3.51%) and 5084 (10.49%) newborns had admission to the ICU, which all showed significances between GDM and non-GDM groups (all P < 0.05). The univariate analysis showed that first-trimester FPG was strongly associated with risks of outcomes including GDM, cesarean section, macrosomia, GHD, primary cesarean section, and LGA (all OR > 1, all P < 0.05), furthermore, the risks of GDM, primary cesarean section, and LGA was increasing with first-trimester FPG as early as it was at 4.19-4.63 mmol/L. The multivariable analysis showed that the risks of GDM (ORs for FPG 4.19-4.63, 4.63-5.11 and 5.11-7.0 mmol/L were 1.137, 1.592, and 4.031, respectively, all P < 0.05) increased as early as first-trimester FPG was at 4.19-4.63 mmol/L, and first-trimester FPG which was also associated with the risks of cesarean section, macrosomia and LGA (OR for FPG 5.11-7.0 mmol/L of cesarean section: 1.128; OR for FPG 5.11-7.0 mmol/L of macrosomia: 1.561; OR for FPG 4.63-5.11 and 5.11-7.0 mmol/L of LGA: 1.149 and 1.426, respectively, all P < 0.05) and with its increasing, the risks of LGA increased. Furthermore, the nomogram had a C-indices 0.771(95% CI: 0.763~0.779) and 0.770(95% CI:0.758~0.781) in training and testing validation respectively, which showed an acceptable consistency between the observed, validation and nomogram-predicted probabilities, the DAC curve analysis indicated that the nomogram had important clinical application value for GDM risk prediction. CONCLUSIONS: FPG in the first trimester was an independent risk factor for GDM which can be used as a screening test for identifying pregnancies at risk of GDM and adverse pregnancy outcomes.

OLA1 is a potential prognostic molecular biomarker for endometrial cancer and promotes tumor progression.

Obg-like ATPase 1 (OLA1) is upregulated in the tumor tissues in different types of cancer. However, the function of OLA1 and its molecular mechanisms in endometrial cancer (EC) remain unknown. The present study aimed to elucidate OLA1 expression level and its biological function in endometrial cancer. The differential expression of OLA1 between EC tissues and non-cancerous tissues was analyzed using The Cancer Genome Atlas database and clinical samples. The association between clinicopathological characteristics and OLA1 expression was analyzed using bioinformatics analysis. Cell proliferation, migration and invasion were analyzed by short interfering RNA-mediated knockdown experiments, Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine incorporation, wound healing, Transwell and Boyden assays. The potential signaling pathways associated with OLA1 in endometrial cancer were evaluated by Gene Set Enrichment Analysis. The expression levels of OLA1 in EC tissues were upregulated compared with that in non-cancerous tissues (P<0.001). Furthermore, patients with worse survival were found to have higher OLA1 expression, and increased OLA1 expression in endometrial cancer associated with clinical stage (P<0.01), histological type (P<0.01), histological grade (P<0.01), menstrual status (P<0.01), cancer status (P<0.05) and distant metastasis (P<0.05). In RL95-2 and HEC-1B cell lines, decreased levels of OLA1 inhibited proliferation, invasion and migration, and the TGF-ß signaling pathway, ubiquitin-mediated proteolysis and Wnt signaling pathway may be involved in these mechanisms. The present study revealed that OLA1 could be a potential prognostic indicator and therapeutic target in endometrial cancer, and that the TGF-ß signaling, Wnt signaling and ubiquitin-mediated proteolysis pathways may be regulated by OLA1.