Placental glycosylation senses the anti-angiogenic milieu induced by human sFLT1 during pregnancy.

Abnormal placental angiogenesis during gestation resulting from high levels of anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin, has been implicated in the progression of preeclampsia (PE). This heterogeneous syndrome (defined by hypertension with or without proteinuria after 20 weeks of pregnancy) remains a major global health burden with long-term consequences for both mothers and child. Previously, we showed that in vivo systemic human (hsFLT1) overexpression led to reduced placental efficiency and PE-like syndrome in mice. Galectins (gal-1, -3 and -9) are critical determinants of vascular adaptation to pregnancy and dysregulation of the galectin-glycan circuits is associated with the development of this life-threatening disease. In this study, we assessed the galectin-glycan networks at the maternal-fetal interface associated with the hsFLT1-induced PE in mice. We observed an increase on the maternal gal-1 expression in the decidua and junctional zone layers of the placenta derived from hs FLT1high pregnancies. In contrast, placental gal-3 and gal-9 expression were not sensitive to the hsFLT1 overexpression. In addition, O- and N-linked glycan expression, poly-LacNAc sequences and terminal sialylation were down-regulated in hsFLT1 high placentas. Thus, the gal-1-glycan axis appear to play an important role counteracting the anti-angiogenic status caused by sFLT1, becoming critical for vascular adaptation at the maternal-fetal interface.

Mental health and lower urinary tract symptoms: Results from the NHANES and Mendelian randomization study.

BACKGROUND: The clinical observations suggest a correlation between lower urinary tract symptoms (LUTSs) and mental health problems. Nonetheless, establishing a direct causal relationship between them remains challenging. METHODS: We initially conducted a cross-sectional study using 2005-2018 the National Health and Nutrition Examination Survey (NHANES) data. Multivariable-adjusted logistic regression was the primary statistical approach. Additionally, we employed Mendelian randomization (MR) to reducing confounding and reverse causation. Genetic instruments were obtained from publicly available genome-wide association study (GWAS) databases. Inverse Variance Weighted was the primary statistical method. RESULTS: The cross-sectional study involved 29,439 participants. Individuals with mental health problems had a higher risk of urinary incontinence (OR:4.38; 95%CI:3.32-5.76; P < 0.01) and overactive bladder (OR:2.31; 95%CI:2.02-2.63; P < 0.01). MR analysis then indicated a potential causal relationship between mental health problems and LUTSs. Depression symptoms was linked with urinary tract infection (UTI) (OR:1.005; 95%CI:1.003-1.008; PFDR < 0.01). Anxiety symptoms was related to the occurrence of UTI (OR:1.024; 95%CI:1.011-1.037; PFDR < 0.01) and bladder calcified/ contracted/ overactive (OR:1.017; 95%CI:1.007-1.027; PFDR < 0.01). The personality trait of neuroticism was related to the occurrence of cystitis (OR:1.072; 95%CI:1.022-1.125; PFDR = 0.02), extravasation of urine and difficulties with micturition (OR:1.001; 95%CI:1.001-1.002; PFDR < 0.01), and urinary frequency and incontinence (OR: 1.001; 95%CI:1.000-1.001; PFDR < 0.01). CONCLUSIONS: Our study provides various evidence for the correlation between mental health and LUTSs, emphasizing the significance of adopting a holistic approach to LUTSs management that incorporates both physical and psychological factors.

Dexamethasone may inhibit placental growth by blocking glucocorticoid receptors via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin and reactive oxygen species/AMP-activated protein kinase signalling pathways in human placental JEG-3 cells.

This study explored the molecular mechanism underlying the effects of dexamethasone (DEX, 1 µM) on glucose transporters (GLUT) in JEG-3 human placental choriocarcinoma cells. JEG-3 cells were treated with DEX, an expression plasmid encoding human glucocorticoid receptor α (GRα), pcDNA3.1-GRα, GRα short interference (si) RNA, LY294002, xanthine oxidase (XO)/hypoxanthine (HX), rapamycin, insulin-like growth factor (IGF) 1, N-acetylcysteine (NAC) or phosphatidic acid (PA), and cell proliferation, apoptosis, mitochondrial membrane potential (MMP), human chorionic gonadotrophin (hCG) content, human placental lactogen (hPL) content, glucose uptake, reactive oxygen species levels and signalling pathway modulation were evaluated. Treatment of JEG-3 cells with DEX (1 µM), GRα siRNA, LY294002 (50 µM), XO/HX (7.2 µM/36 nM) or rapamycin (80 nM) inhibited cell proliferation, induced apoptosis, significantly decreased MMP and hCG and hPL content and increased ROS levels. In addition, glucose uptake was decreased through downregulation of the mRNA and protein expression of GRα, GLUT1 and GLUT3. Treatment of JEG-3 cells with GRα siRNA, LY294002, XO/HX or rapamycin inhibited phosphorylation of phosphatidylinositol 3-kinase (PI3K), Akt, glycogen synthase kinase 3 and mammalian target of rapamycin (mTOR) and induced the phosphorylation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex 2. The effects of GRα overexpression and IGF1 (100 nM), NAC (5 nM) or PA (100 µM) treatment on JEG-3 cells contrasted with those of DEX treatment. DEX blocked glucose uptake by downregulating GRα expression, which reduced GLUT1 and GLUT3 mRNA and protein expression, which, in turn, may have inhibited the PI3K/AKT/mTOR pathway and activated the ROS/AMPK pathway.

The therapeutic effects and underlying mechanisms of the intrauterine perfusion of granulocyte colony-stimulating factor on a thin-endometrium rat model.

AIMS: This study aims to investigate the effects of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on a thin-endometrium rat model. MAIN METHODS: Twenty rats in two groups of 10 were used. Group I was perfused with normal saline (NS) in the right uterine horn and 95% ethanol in the left one. Group II was bilaterally perfused with 95% ethanol into the uterine horns. After three estrous cycles, Group II was perfused with NS in the right uterine horn and G-CSF (30 µg/kg) in the left one. Hematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to detect changes in endometrial thickness and expression of cytokeratin 19 (CK19) and vimentin (Vim). The relative expression levels of vascular endothelial growth factor (Vegf) and leukemia inhibitory factor (Lif) were also tested via reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and Western-blot analyses. KEY FINDINGS: G-CSF treatment significantly increased the thickness of the endometrium in the 95% ethanol-induced thin-endometrium rat model. The expression levels of endometrial glandular epithelial cell marker for CK19 and stromal cell marker Vim were augmented in the G-CSF-treated group compared with the control group. Moreover, G-CSF treatment stimulated the expression of VEGF and LIF in the 95% ethanol-induced thin-endometrium rat model. SIGNIFICANCE: G-CSF intrauterine perfusion improved endometrial receptivity in the thin-endometrium rat model by stimulating endometrial proliferation and angiogenesis.

Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6.

The molecular mechanisms of normal cervical squamous epithelium advancing to cervical intraepithelial neoplasia (CIN) and eventually to cervical squamous cell carcinoma (CSCC) are largely unknown. This study explored abnormal expression of Yin Yang 1 (YY1) in cervical cancer and its correlation with the expression of E-cadherin and human papillomavirus (HPV) 16 E6. YY1, E-cadherin and HPV16 E6 expression were detected by immunohistochemistry in 90 cervical tissue specimens collected from 30 patients with hysteromyoma, 15 patients with CIN I, 15 patients with CIN II-III, and 30 patients with CSCC. The H-score method was employed to measure the expression of YY1, E-cadherin and HPV16 E6. Increased expression of YY1 and HPV16 E6, and the decreased expression levels of E-cadherin were strongly associated with malignant transformation of the cervical epithelium and the histological progression of CSCC. The expression of YY1 in cervical tissues was inversely correlated with E-cadherin expression, and positively correlated with HPV16 E6 expression. Expression of YY1 in CSCC tissues was not significantly correlated with tumor differentiation, but was significantly correlated with an advanced clinical stage of CSCC. These results suggest that up-regulation of YY1 is closely associated with the progression of CSCC, and YY1 may play an important role in the pathogenesis of cervical cancer by modulating the expression of E-cadherin and HPV16 E6.

Downregulation of tyrosine threonine kinase inhibits tumor growth via G2/M arrest in human endometrioid endometrial adenocarcinoma.

Endometrial cancer is the most common gynecologic malignancy, about 80% of which is endometrial endometrioid carcinoma. Dysregulation of spindle assembly checkpoint plays a vital role in endometrial endometrioid carcinoma tumorigenesis and progression. The purpose of this study was to explore how tyrosine threonine kinase, a spindle assembly checkpoint-related protein, promotes the endometrial endometrioid carcinoma progression. We found that both messenger RNA and protein levels of tyrosine threonine kinase in endometrial endometrioid carcinoma tissues are higher than those in normal endometrial tissues, and its expression is associated with tumor stages. Genetic depletion of tyrosine threonine kinase by RNA interference in two endometrial endometrioid carcinoma cell lines significantly inhibits cell proliferation and induces apoptosis. Mechanistically, depletion of tyrosine threonine kinase induces G2/M cell cycle arrest and triggers caspase-dependent cell apoptosis. Collectively, tyrosine threonine kinase is significantly upregulated in endometrial endometrioid carcinoma, and downregulation of tyrosine threonine kinase can suppress endometrial endometrioid carcinoma cell proliferation and promote apoptosis via G2/M cell cycle arrest. Our study demonstrates that tyrosine threonine kinase can be a potential therapeutic target for endometrial endometrioid carcinoma treatment.

Two adjustment strategies for imputation across genotyping arrays.

Genotype imputation is a powerful approach in genome-wide association studies (GWAS) because it can provide higher resolution for associated regions and facilitate meta-analysis. However, bias can exist if different genotyping arrays are used and are unbalanced for case versus control subjects. The intersection imputation strategy [imputation based on single nucleotide polymorphisms (SNPs) available on all arrays] is a valid strategy that eliminates the bias caused by unbalanced genotyping, but achieved at the expense of reduced statistical power. In order to improve power in this situation, we introduce two new strategies: the replacement strategy based on the imputation quality score (IQS) ≥0.9 and the correction strategy. The IQS is a score that we have previously introduced based on Cohen's kappa of rater agreement. The replacement strategy with IQS ≥0.9 is a hybrid approach that utilizes measured genotypes for SNPs available on one or more of all arrays whenever the SNP has a high imputation quality (defined by IQS ≥0.9). The correction strategy combines measured genotypes as well as imputed and corrected genotype dosages for SNPs available on one or more of all arrays. The correction strategy yields a valid statistical test, while the replacement strategy with IQS ≥0.9 eliminates most spurious associations. Both strategies maintain statistical power.