Circ_0050444 represses esophageal squamous cell carcinoma progression through sponging miR-486-3p to upregulate C10orf91.

Esophageal squamous cell carcinoma (ESCC) ranks as the fourth leading cause of tumor-related deaths in China. Circ_0050444 has been revealed to be downregulated in ESCC tissues, however, its function and molecular mechanism underlying ESCC progression is unknown. Therefore, we attempted to clarify the functional role and molecular mechanism of circ_0050444 underlying ESCC progression. RT-qPCR and RNase R digestion assays were used to evaluate circ_0050444 expression and stability characteristics in ESCC cells. Gain-of-function assays were conducted to clarify circ_0050444 role in ESCC cell malignant behaviors. Bioinformatics and mechanism experiments were performed to assess the relationship between circ_0050444 or C10orf91 and miR-486-3p in ESCC cells. Rescue assays were conducted to evaluate the regulatory function of the circ_0050444-miR-486-3p-C10orf91 axis in ESCC cellular processes. Circ_0050444 expression was found to be downregulated both in ESCC patient tissues and cell lines. Functionally, circ_0050444 overexpression repressed ESCC cell proliferative, migratory, and invasive capabilities in cultured cells. Mechanistically, circ_0050444 was found to be competitively bound with miR-486-3p to upregulate C10orf91 in ESCC cells. Moreover, the impact of circ_0050444 elevation on ESCC cell proliferation, migration, and invasion was countervailed by C10orf91 silencing. Circ_0050444 presents downregulation and functions as a tumor suppressor in ESCC progression. Circ_0050444 suppresses ESCC proliferation, migration, and invasion through sponging miR-486-3p to upregulate C10orf91, providing a potential new direction for seeking therapeutic plans for ESCC.

Upregulation of SEMP1 Contributes to Improving the Biological Functions of Trophoblast via the PI3K/AKT Pathway in Preeclampsia.

Disturbance of extravillous trophoblast infiltration is associated with preeclampsia (PE), a severe condition of pregnancy characterized by hypertension and proteinuria. Senescence-associated epithelial membrane protein 1 (SEMP1), an integral membrane protein, is a vital component of tight junction strands in epithelial or endothelial cells, with no clear function reported in PE. Gene Expression Omnibus (GEO) datasets showed that SEMP1 expression was downregulated in the placental tissues of PE patients, which was confirmed by assessing SEMP1 levels in placental samples collected in our hospital. Furthermore, less SEMP1 was detected in cytokeratin 7 positive trophoblast cells in the spiral arteries of rat placentas post L-arginine methyl ester hydrochloride (L-NAME) treatment. Trophoblast cells acquired robust ability of proliferation, migration, and invasion when SEMP1 was overexpressed. Such capability was weakened in SEMP1-silenced cells. Trophoblast cells overexpressing SEMP1 secreted more vascular endothelial growth factor A (VEGFA), which facilitated the tube formation of human umbilical vein endothelial cells. Blockade of PI3K/AKT signaling transduction with LY294002 dampened the effects of SEMP1 on trophoblast cells. Collectively, we firstly indicated that SEMP1 inhibition is a potential driver for PE, which may be associated with the deactivation of the PI3K/AKT pathway.

Effects of group B streptococcus infection on vaginal micro-ecology and pregnancy outcomes of pregnant women in late pregnancy.

BACKGROUND: Invasive infection with group B streptococcus (GBS) can lead to intrauterine infection, and GBS can also spread via vertical transmission between mother and infant, resulting in adverse pregnancy outcomes. This study aimed to investigate the effects of GBS colonization in late gestation on vaginal micro-ecology, pregnancy outcomes and neonatal outcome. METHODS: One hundred and twenty pregnant women in the third trimester infected with GBS and 120 healthy counterparts who underwent a prenatal examination in the obstetrics department of the study hospital from June 2019 to December 2020 were selected for inclusion in the study. Vaginal micro-ecological index, mode of delivery, adverse pregnancy outcomes and neonatal Apgar score were compared between the two groups. RESULTS: The incidence rates of vaginal micro-ecological disorders, intrauterine infection and neonatal infection were significantly higher in the GBS group compared with the control group. The incidence rates of neonatal fetal distress and pathological jaundice were much higher in the GBS group compared with the control group. The neonatal Apgar score was markedly lower in the GBS group compared with the control group. CONCLUSIONS: GBS infection is correlated with the vaginal micro-environment. GBS colonization in late pregnancy has adverse effects on vaginal micro-ecology and pregnancy outcome.

miR-153 enhances the therapeutic effect of radiotherapy by targeting JAG1 in pancreatic cancer cells.

Pancreatic cancer is one of the deadliest diseases, due to the lack of early symptoms and resistance to current therapies, including radiotherapy. However, the mechanisms of radioresistance in pancreatic cancer remain unknown. The present study explored the role of microRNA-153 (miR-153) in radioresistance of pancreatic cancer. It was observed that miR-153 was downregulated in pancreatic cancer and positively correlated with patient survival time. Using stably-infected pancreatic cancer cells that overexpressed miR-153 or miR-153 inhibitor, it was found that miR-153 overexpression sensitized pancreatic cancer cells to radiotherapy by inducing increased cell death and decreased colony formation, while cells transfected with the miR-153 inhibitor promoted radioresistance. Further investigation demonstrated that miR-153 promoted radiosensitivity by directly targeting jagged canonical Notch ligand 1 (JAG1). The addition of recombinant JAG1 protein in the cell cultures reversed the therapeutic effect of miR-153. The present study revealed a novel mechanism of radioresistance in pancreatic cancer and indicated that miR-153 may serve as a potential therapeutic target for radioresistance.

Overexpression of tissue factor pathway inhibitor 2 attenuates trophoblast proliferation and invasion in preeclampsia.

Pre-eclampsia (PE) is a disorder of pregnancy characterized by proteinuria and high blood pressure, affecting 2-8% of pregnancies worldwide. Previous studies have shown that PE is closely associated with trophoblast cell dysfunction. Here, we investigated the role of tissue factor pathway inhibitor-2 (TFPI-2) in regulating the biological processes of trophoblast cells. The TFPI-2 levels in plasma samples and placental tissues were tested by ELISA, immunohistochemistry, qRT-PCR, and western blot. HTR8/Svneo cell line was used to simulate the primary trophoblast cells and H/R culture was applied to mimic the oxidative stress state of PE. MTT assay, Annexin V/propidium iodide (PI) apoptosis assay, and transwell assay were used to determine the cell proliferation, apoptosis, and invasion. The expression levels of matrix metalloproteinases (MMPs) were evaluated by western blot. The expression of TFPI-2 was remarkably up-regulated in both the serum and placenta of PE patients. Hypoxia/reoxygenation increased the expression of TFPI-2 in HTR-8/SVneo cell line. TFPI-2 promoted that cell proliferation and inhibited the cell apoptosis of HTR8/SVneo cells in H/R condition. In addition, downregulation of TFPI-2 increased the cell invasion and the expression of MMP2 and MMP9. This study reveals that TFPI-2 plays a crucial role in monitoring the biological function of trophoblast cells, which might provide theoretical basis and therapeutic targets for the treatment of PE.

miR-139-5p promotes the proliferation and invasion of trophoblast cells by targeting sFlt-1 in preeclampsia.

BACKGROUND: The biological functions of placental trophoblast cells have been reported to be critical in preeclampsia (PE) and its complications. Here, we aimed to investigate the role and underlying mechanism of soluble fms-like tyrsine kinase-1 (sFlt-1) and miR-139-5p in severe preeclampsia (sPE) by culturing the trophoblast cells from patients. METHODS: ELISA and qRT-PCR were used to measure the expression of sFlt-1 and miR-139-5p. The direct interaction between sFlt-1 and miR-139-5p was determined by luciferase reporter assay. Cell proliferation and invasion were evaluated by CCK-8 analysis and transwell assay. RESULTS: Our results showed that miR-139-5p was downregulated in sPE patients and was negatively correlated with the expression of sFlt-1. Further, sFlt-1 was a direct target of miR-139-5p, which monitored the expression of sFlt-1. Besides, miR-139-5p promoted the proliferation and invasion of trophoblast cells derived from sPE patients. Overexpression of sFlt-1 attenuated the effects of miR-139-5p on cell proliferation and invasion of trophoblast cells from sPE patients. CONCLUSION: Our research proposes a novel mechanism where the role of miR-139-5p is dependent on sFlt-1. Our data demonstrated that miR-139-5p promoted the proliferation and invasion of trophoblast cells by directly targeting sFlt-1 in PE.

Mangiferin ameliorates placental oxidative stress and activates PI3K/Akt/mTOR pathway in mouse model of preeclampsia.

Preeclampsia is an inflammatory disease which can induce oxidative stress in placenta. Oxidative stress in preeclampsia is regulated by the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. Mangiferin, an anti-oxidative molecule, is reported to ameliorate oxidative stress in the kidney and brain through activating the PI3K/Akt/mTOR pathway. We aimed to investigate the effects of mangiferin in a mouse model of preeclampsia, which was induced by phosphatidylserine/dioleoyl-phosphatidycholine (PS/PC) from day 5 to 17 of pregnancy. The female pregnant mice were divided into five groups according to drug treatment. Animals received mangiferin orally at doses of 10, 20, 40 mg/kg/day from day 0.5 to 17. In preeclampsia mouse model, elevated systolic blood pressure and proteinuria were ameliorated by mangiferin treatment. Mangiferin attenuated fms-like tyrosine kinase-1 and placental growth factor expression and oxidative stress in both blood and placenta of preeclampsia mice. The suppressed PI3K/Akt/mTOR pathway in placenta was activated by mangiferin treatment. This study demonstrates that mangiferin ameliorates placental oxidative stress and activates PI3K/Akt/mTOR pathway in a mouse model of preeclampsia.

The effect of folic acid throughout pregnancy among pregnant women at high risk of pre-eclampsia: A randomized clinical trial.

BACKGROUND: Pre-eclampsia is a serious hypertension disease that occurs during pregnancy. Folic acid (FA) supplementation has been reported to reduce pre-eclampsia risk in pregnant women. Here, we aimed to assess whether treatment of high doses of FA in pregnant women with high pre-eclampsia risk could prevent the onset of pre-eclampsia. METHODS: We conducted a randomized clinical trial in 1576 women who had pre-eclampsia or eclampsia in their last pregnancy and had a pregnancy plan. Subjects were randomized into two groups. The low dose (LD) group (n = 788) received 0.4 mg of FA daily from the first 3 months of pregnancy until the entire pregnancy, and the high dose (HD) group (n = 788) received 4 mg of FA per day. We followed up the subjects until production. RESULTS: The plasma homocysteine (homocysteine) and FA levels were significantly higher in the HD group that in the LD group. Severe gestational hypertension, early onset pre-eclampsia (<32 weeks' gestation), severe pre-eclampsia, and newborns' Apgar score <7 at 5 min were remarkably decreased in the HD group compared with the LD group. Further, the incidence of pre-eclampsia was reduced in the HD group with compliance >50%. CONCLUSION: This study has provided evidence that a high dosage of FA supplement from 3 months before pregnancy until the entire pregnancy reduces the recurrent pre-eclampsia.

Spontaneous rupture of unscarred uterus in the third trimester after in vitro fertilization-embryo transfer because of bilateral salpingectomy: A case report.

RATIONALE: Rupture of an unscarred uterus after in vitro fertilization-embryo transfer (IVF-ET) in a primiparous woman is rare. Assisted reproductive technology (ART)-induced rupture of an unscarred uterus is usually attributable to increased dizygotic twinning rates. Salpingectomy can result in cornual scarring and increase the risk of uterine rupture as well as the mortality rate in a subsequent ectopic pregnancy. Here, we present the first reported case of a spontaneous, third-trimester, uterine rupture in a primiparous woman after IVF-ET due to a history of bilateral salpingectomy because of bilateral oviduct and ovarian cysts; the patient did not have an ectopic pregnancy or any cornual or other uterine scarring during this pregnancy after IVF-ET. PATIENT CONCERNS: A 24-year-old woman with a history of IVF-ET and bilateral salpingectomy was admitted to our hospital with unexplained acute upper abdominal pain during the third trimester. DIAGNOSIS: The fetal heart rate was abnormal. Abdominal ultrasonography was negative. Computed tomography revealed a small amount of abdominal and pericardial effusion. Laboratory tests revealed increased white blood cells. A diagnosis of pregnancy complicated by acute abdomen was considered. Emergent exploratory laparotomy revealed a uterine rupture at the right fundus adjacent to the right cornual area. INTERVENTIONS: The patient was successfully managed with simultaneous exploratory laparotomy and lower-segment cesarean section. The rupture site was repaired. OUTCOMES: Two live infants were uneventfully delivered. Follow-up assessments of the mother and the female baby on the 42nd postpartum day yielded normal results. The male infant was diagnosed with left hydronephrosis and required an operation. LESSONS: We conclude that the ART-associated increase in dizygotic twinning rates may be a neglected risk factor for spontaneous rupture of the unscarred uterus, especially in patients who have undergone salpingectomy. Uterine rupture should be considered in a patient with multiple pregnancy following IVF-ET who presents with acute abdominal pain and abnormal fetal heart rate. Timely exploratory laparotomy is the key to a good prognosis.

Vitexin ameliorates preeclampsia phenotypes by inhibiting TFPI-2 and HIF-1α/VEGF in a l-NAME induced rat model.

Preeclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality with few safe, effective, and minimally invasive therapeutics. Inflammation, oxidative stress, and angiogenic imbalance have been reported to contribute to PE pathogenesis. Vitexin (VI) possesses various pharmacological activities including the potent regulation of the above biological processes in different conditions. This study aims to investigate whether VI has therapeutic potential to PE and the underlying mechanisms. Sprague-Dawley pregnant rats pretreated with or without VI were fed with l-NAME-containing water to induce experimental PE. Results showed that VI decreased high systolic blood pressure and urinary protein in PE rats time- and dose-dependently. Meanwhile, VI of higher dosage (45, 60 mg/kg) corrected abnormal pregnancy outcomes, including low pup weight and low pups/placenta ratio. In addition, VI of high dosage (60 mg/kg) decreased sFlt-1, increased PlGF and alleviated oxidative stress both in blood and placental samples compared with nontreated PE group. Furthermore, VI alleviated placental TFPI-2, HIF 1α, and VEGF in PE rats. In short, the present study suggests that the inhibition of placental TFPI-2 and HIF-1α/VEGF might be one of the potential mechanisms underlying the protective effects of VI to experimental PE induced by l-NAME.

The Association of HOTAIR with the Diagnosis and Prognosis of Gastric Cancer and Its Effect on the Proliferation of Gastric Cancer Cells.

Background: Long noncoding RNAs (lncRNAs) are a group of noncoding RNA with the length of more than 200nt. They have been identified as important diagnostic and prognostic molecules for many cancers and play an important role in the development of cancers. However, their clinical value and roles in gastric cancer (GC) remain unclear. Methods: The expression levels of HOTAIR in 54 GC tissues and their matched adjacent nontumor tissues from GC patients and 24 normal mucosa or those with minimal gastritis as healthy controls were determined by qRT-PCR. The expression levels of HOTAIR in human GC cell lines and a normal gastric epithelium cell line were also assessed by qRT-PCR. The potential relationships between its level in GC tissues and the clinicopathological features were analyzed. Furthermore, a receiver operating characteristic (ROC) curve was constructed. Additionally, the correlation between this lncRNA and overall survival (OS) was analyzed. SiRNA transfection was used to silence the expression of HOTAIR in GC cells. And cell proliferation and cell cycle assays were employed to determine the effect of HOTAIR on GC cell growth. Western blot was performed for the detection of the P53, P21, and Bcl2 proteins. Results: The expression levels of HOTAIR were significantly upregulated in GC tissues and cell lines. Increased HOTAIR was associated with tumor differentiation, lymph node and distant metastasis, and clinical stage. Furthermore, the area under the ROC curve (AUC) was up to 0.8416 (95 % CI=0.7661 to 0.9170, P<0.0001). The sensitivity and specificity were 66.67 and 87.04%, respectively. The correlation between HOTAIR expression and overall survival (OS) was statistically significant. The hazard ratio was 2.681, and 95% CI of ratio was 1.370 to 5.248. In addition, knockdown of HOTAIR can inhibit GC cell growth and affect cell cycle distribution. And knockdown of HOTAIR could enhance the protein levels of P21 and P53. Conclusion: The present study demonstrated that HOTAIR was highly expressed in GC tissues and may serve as a potential diagnostic and prognostic biomarker for GC. And HOTAIR promoted GC cell proliferation.

CircTRNC18 inhibits trophoblast cell migration and epithelial-mesenchymal transition by regulating miR-762/Grhl2 pathway in pre-eclampsia.

Dysfunctions of epithelial-mesenchymal transition (EMT)-regulated cell migration and invasion have been involved in the pathogenesis of pre-eclampsia (PE). However, the role of circRNAs in EMT of PE has not been widely investigated. In this study, we identified that circTNRC18 was upregulated in PE placentas compared with normal pregnancy placentas. Moreover, circTNRC18 negatively regulated trophoblast cell migration and EMT. Overexpression of circTNRC18 reduced while depletion of circTNRC18 enhanced trophoblast cell migration and EMT. Mechanistically, circTNRC18 sponged miR-762 contributed to inhibit miR-762 activity and elevated EMT-related transcriptional factor Grhl2 protein level. miR-762 expression was lower in PE placentas and played a promoting role in trophoblast cell migration and EMT. In contrast, Grhl2 was highly expressed in PE placentas. Furthermore, we confirmed that upregulation of Grhl2 by circ-TNRC18-induced inhibition of miR-762 led to trophoblast cell migration and EMT. In conclusions, circTNRC18/miR-762/Grhl2 axis plays a key role in trophoblast cell migration and EMT. circTNRC18/miR-762/Grhl2 axis may be a potential therapeutic target in PE.

RASGRF1 Hypermethylation, a Putative Biomarker of Colorectal Cancer.

OBJECTIVE: RASGRF1 is a guanine nucleotide exchange factor, which promotes the release of GDP from inactive Ras and stabilizes the apoprotein. In this study, the methylation status of RASGRF1 promoter and its correlation with clinicopathological parameters were evaluated in colorectal cancer (CRC). METHODS: Methylation-specific PCR and bisulfate-sequencing PCR were carried out to investigate the promoter methylation status of the RASGRF1 gene in tumor tissues and adjacent non-tumor tissues of 68 CRC patients. The effect of RASGRF1 promoter hypermethylation on its mRNA and protein expression was evaluated by quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry. RESULTS: RASGRF1 was methylated in 58.6% tumor tissues and negatively correlated with its mRNA or protein expression. There was a statistical relationship between the degree of differentiation, lymph node metastasis and clinical stage and RASGRF1 hypermethylation. Furthermore, RASGRF1 mRNA and protein levels in tumor tissues were both significantly decreased compared with that in adjacent non-tumor tissues. In addition, the correlations between RASGRF1 hypermethylation, mRNA or protein expression, and overall survival were statistically significant. CONCLUSIONS: Collectively, our data suggest that RASGRF1 hypermethylation is involved in an epigenetic field defect in CRC and that it might be a potential risk factor for CRC.