Function of Long Noncoding RNAs in Glioma Progression and Treatment Based on the Wnt/ß-Catenin and PI3K/AKT Signaling Pathways.

Gliomas are a deadly primary malignant tumor of the central nervous system, with glioblastoma (GBM) representing the most aggressive type. The clinical prognosis of GBM patients remains bleak despite the availability of multiple options for therapy, which has needed us to explore new therapeutic methods to face the rapid progression, short survival, and therapy resistance of glioblastomas. As the Human Genome Project advances, long noncoding RNAs (lncRNAs) have attracted the attention of researchers and clinicians in cancer research. Numerous studies have found aberrant expression of signaling pathways in glioma cells. For example, lncRNAs not only play an integral role in the drug resistance process by regulating the Wnt/ß-catenin or PI3K/Akt signaling but are also involved in a variety of malignant biological behaviors such as glioma proliferation, migration, invasion, and tumor apoptosis. Therefore, the present review systematically assesses the existing research evidence on the malignant progression and drug resistance of glioma, focusing on the critical role and potential function of lncRNAs in the Wnt/ß-catenin and PI3K/Akt classical pathways to promote and encourage further research in this field.

circTOP2A functions as a ceRNA to promote glioma progression by upregulating RPN2.

Competing endogenous RNA (ceRNA)-mediated signaling pathway dysregulation provides great insight into comprehensively understanding the molecular mechanism and combined targeted therapy for glioblastoma. circRNA is characterized by high stability, tissue/developmental stage-specific expression and abundance in brain and plays significant roles in the initiation and progression of cancer. Our previous published data have demonstrated that RPN2 was significantly upregulated in glioma and promoted tumor progression via the activation of the Wnt/ß-catenin pathway. Furthermore, we proved that miR-422a regulated the Wnt/ß-catenin signaling pathway by directly targeting RPN2. In this study, based on the glioblastoma microarray profiles, we identified the upstream circTOP2A, which completely bound to miR-422a and was co-expressed with the RPN2. circTOP2A was significantly overexpressed in glioma and conferred a poor prognosis. circTOP2A could regulate RPN2 expression by sponging miR-422a, verified by western blot, dual-luciferase reporter gene assay, and RNA pull-down assay. Functional assays including CCK8, transwell and FITC-annexin V were performed to explore the RPN2-mediated role of the circTOP2A effect on the glioma malignant phenotype. Additionally, TOP/FOP and immunofluorescence analysis were used to confirm that sh-circTOP2A could suppress the Wnt/ß-catenin pathway partly through RPN2. Finally, a tumor xenograft model was applied to validate the biological function of circTOP2A in vivo. Taken together, our findings reveal the critical role of circTOP2A in promoting glioma proliferation and invasion via a ceRNA mechanism and provide an exploitable biomarker and therapeutic target for glioma patients.

Safety investigation of Pulsatilla chinensis saponins from chronic metabonomic study of serum biomedical changes in oral treated rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla chinensis (Bunge) Regel is a valuable traditional Chinese medicine (TCM) which is widely used for the treatment of schistosomiasis, inflammatory, bacterial infections. In recent years, P chinensis has been reported to exhibit antitumor activities. However, the mechanisms underlying its toxic effects remain largely unresolved. This paper is designed to investigate the damage of long-term oral P. chinensis saponins (PRS) and to explore its potential damage mechanisms by serum metabonomics approach. MATERIALS AND METHODS: The serum samples from control and PRS treated rats were analyzed by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) in positive ionization mode and negative ionization mode. Liver function index of ALT, AST and ALP, blood biochemistry and biomarkers were examined to identify specific changes of injury. Acquired data were subjected to principal component analysis (PCA) for differentiating the control and PRS treated groups. Then, serum metabolic profiling was analyzed and pathway analysis performed on the biomarkers reversed after PRS treated and further integration of metabolic networks. RESULTS: The results suggested that serum liver function indexes of ALT had significantly changed and stage increased. AST, ALP detection content show volatility changes. Changes in the 15 biomarkers found in the serum, such as acetaminophen glucuronide, 9 E, 11 E-linoleic acid, chenodeoxycholic acid, monoacylglycerides, sphingomyelin (SM), 7-ketodeoxycholic acid and 12-keto-deoxycholic acid, which were closely related to changes in liver injury. It could be seen clearly that with the change of the dosing time, the biomarkers in the serum have undergone obvious, regular and progressive changes through the score plot and corresponding loading plot. The underlying regulations of PRS-perturbed metabolic pathways were discussed according to the identified metabolites. CONCLUSION: The present study proves the potential of UPLC-QTOF-MS based metabonomics in mapping metabolic response. Long-term oral administration of P. chinensis saponins can cause chronic liver injury, and its safety needs further attention. It is of great significance in safeguarding human health to explore the damage mechanism of Pulsatilla chinensis saponins on liver by serum metabolomics.

Fetal Growth Patterns in Pregnancies With First-Trimester Bleeding.

OBJECTIVE: To assess the relationship between first-trimester vaginal bleeding and fetal growth patterns. METHODS: We conducted a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, a prospective cohort study of low-risk, nonobese women with healthy lifestyles. Duration of bleeding was self-reported at enrollment (10 0/7 to 13 6/7 weeks of gestation) and categorized as 0, 1, or more than 1 day. Longitudinal measures of fetal biometrics were obtained in up to six study visits, and estimated fetal weight was computed. Growth trajectories were created for biometrics and estimated fetal weight. When global tests among groups was significant (P<.05), week-specific global and pairwise differences were tested. Birth weight and risk of a small-for-gestational-age (SGA) neonate were secondary outcomes. All analyses were adjusted for maternal age, weight, height, parity, and racial-ethnic group and neonatal sex in a sensitivity analysis. RESULTS: In 2,307 eligible women, 410 (17.8%) reported first-trimester bleeding, of whom 176 bled for 1 day and 234 bled for more than 1 day. Women with more than 1 day of bleeding demonstrated decreased fetal abdominal circumference from 34 to 39 weeks of gestation compared with women without bleeding. For women with more than 1 day of bleeding, compared with women without bleeding, estimated fetal weight was 68-107 g smaller from 35 to 39 weeks of gestation. Mean birth weight at term was 88 g smaller, confirming differences in calculated fetal weight, and SGA neonates were delivered to 148 (8.5%), 9 (5.7%), and 33 (15.7%) women in the no bleeding, 1 day, and more than 1 day of bleeding groups, respectively. CONCLUSION: More than 1 day of first-trimester vaginal bleeding was associated with smaller estimated fetal weight late in pregnancy driven by smaller abdominal circumference. The magnitude of decrease in birth weight was small, albeit comparable with observed decreases associated with maternal smoking. It remains unknown whether early pregnancy bleeding is associated with short-term or long-term morbidity and whether additional intervention would be of benefit. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.