Hypomethylation of PRDM1 is associated with recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) rates have continued to rise during the last few decades, yet the underlying mechanisms remain poorly understood. An emerging area of interest is the mediation of gene expression by DNA methylation during early pregnancy. Here, genome-wide DNA methylation from placental villi was profiled in both RPL patients and controls. Subsequently, differentially expressed genes were analysed for changes in gene expression. Many significant differentially methylated regions (DMRs) were identified near genes dysregulated in RPL including PRDM1. Differentially expressed genes were enriched in immune response pathways indicating that abnormal immune regulation contributes to RPL. Integrated analysis of DNA methylome and transcriptome demonstrated that the expression level of PRDM1 is fine-tuned by DNA methylation. Specifically, hypomethylation near the transcription start site of PRDM1 can recruit other transcription factors, like FOXA1 and GATA2, leading to up-regulation of gene expression and resulting in changes to trophoblast cell apoptosis and migration. These phenotypic differences may be involved in RPL. Overall, our study provides new insights into PRDM1-dependent regulatory effects during RPL and suggests both a mechanistic link between changes in PRDM1 expression, as well as a role for PRDM1 methylation as a potential biomarker for RPL diagnosis.

Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer-associated fibroblasts of TSCC.

Cancer-associated fibroblasts (CAFs) are "activated" fibroblasts in the tumor microenvironment (TME) and play a vital role in all steps of cancer development. Increasing evidence focusing on the function of CAFs suggests that CAFs are candidate therapeutic targets and that drugs targeting the modification of CAFs would suppress tumor progression and be beneficial to tumor treatment and prevention. In the present study, we found that curcumin reversed the phenotype of CAFs to that of peri-tumor fibroblast (PTF)-like cells by downregulating the expression of α-SMA (a special marker for CAFs) and inhibiting the secretion of pro-carcinogenic cytokines, including transforming growth factor-ß1 (TGF-ß1), matrix metalloproteinases 2 (MMP2), and stromal cell-derived factor-1 (SDF-1). We further demonstrated that the conditioned medium (CM) derived from CAFs promoted the proliferation of Cal27, and this effect was confirmed by the xenograft model. More importantly, we found that curcumin blocked the CAF-mediated enhancement of Cal27 proliferation in vitro and in vivo. In conclusion, our data suggest that curcumin reverses cell phenotype from CAF to PTF-like cells and suppresses the CAF-mediated proliferation and tumorigenicity of Cal27 by inhibiting TSCC CAFs.

Discovery of a novel, liver-targeted thyroid hormone receptor-ß agonist, CS271011, in the treatment of lipid metabolism disorders.

Introduction: Thyroid hormone receptor ß (THR-ß) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-ß agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. Methods: We conducted luciferase reporter gene assays to assess the activation of THR-ß and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. Results: Compared with MGL-3196, CS271011 showed higher THR-ß activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. Conclusions: CS271011 is a potent and liver-targeted THR-ß agonist for treating lipid metabolism disorders.

Cancer associated fibroblasts are distinguishable from peri-tumor fibroblasts by biological characteristics in TSCC.

The aim of the present study was to investigate the differential biological characteristics between cancer-associated fibroblasts (CAFs) and peri-tumor fibroblasts (PTFs) in tongue squamous cell carcinoma (TSCC). The primary CAFs and PTFs from TSCC were obtained and purified. Cell morphology was observed, and the expression of α-smooth muscle actin (α-SMA), vimentin and cytokeratin 19 (CK19) was detected by immunohistochemistry (IHC). The percentage of α-SMA positive cells in CAFs and PTFs was calculated separately, and α-SMA expression was further confirmed by western blot analysis. Cell viability and the expression of matrix metalloproteinase 2 (MMP2), stromal cell derived factor1 (SDF-1) and transforming growth factor ß1 (TGFß1) in the purified fibroblasts was detected separately. CAFs and PTFs were attained and purified. Compared with PTFs, CAFs were long-fusiform shaped cells with reduced cytoplasm and variable size. CAFs crowded together in a disorderly manner when the cell density was increased, but this phenomenon did not occur with PTFs. IHC results verified that there was no significant difference between CAFs and PTFs in the percentage of cells staining positive for CK19 and vimentin (P>0.05); the percentage of positive staining cells for α-SMA in CAFs was significantly higher compared with that in PTFs (P<0.001) Western blot analysis showed that α-SMA expression in CAFs was 4.3-fold higher compared with that in PTFs (P<0.001). A Cell Counting Kit-8 assay indicated that the viability of CAFs increased significantly compared with that in the PTFs (P<0.05). Reverse transcription-quantitative polymerase chain reaction and ELISA analysis showed that the expression of MMP2, SDF-1 and TGF ß1 in CAFs was higher compared with that in PTFs (P<0.05). CAFs are distinguishable from PTFs with respect to their morphology, cellular phenotype, cell viability and pro-carcinogenic cytokine expression.

STORE-gastrointestinal functions and gastrointestinal hormones in patients with liver failure.

This study aims to investigate the gastrointestinal functions of patients with liver failure (LF) based on gastrointestinal dysfunction (GD) scores and serum gastrointestinal hormone levels.The GD in LF patients was scored using the gastrointestinal dysfunction scoring criteria. Serum gastrin (GAS), cholecystokinin (CCK), and motilin (MTL) levels were determined in LF patients. In addition, liver function and prothrombin activity were detected, and ultrasonography was performed.The GD score was significantly higher in the LF groups than in the control group. Compared with the control group, serum GAS, CCK, and MTL levels significantly increased in the LF groups, and was positively correlated with the severity of LF. Furthermore, in the LF groups, GD was positively correlated with the severity of LF. However, the GD score and serum GAS, CCK, and MTL levels in the acute LF group were not statistically different, when compared with those in the subacute LF group, acute-on-chronic LF group and chronic LF group.LF plays a key role in the development of GD, and may be the main cause of obvious gastrointestinal symptoms, such as abdominal distension, nausea, vomiting and anorexia, in LF patients. The severity of GD is not associated with LF type, but is positively correlated with the severity of LF, suggesting that GD in LF patients may have complicated mechanisms.

A correlation between gastrointestinal dysfunction and cirrhosis severity.

This study aims to investigate the relationship between gastrointestinal dysfunction (GD) and cirrhosis severity in cirrhotic patients, to provide evidences for the prevention and treatment of GD in cirrhotic patients.A total of 95 cirrhotic inpatients and outpatients, who were treated in the Department of Gastroenterology of Xinqu Hospital of the First Affiliated Hospital of Henan University of Science and Technology, were enrolled in the present study, and assigned as the experimental group (cirrhosis group). According to Child-Pugh classification, these patients were divided into 3 groups: group A (n = 45), group B (n = 23), and group C (n = 27). Forty healthy adults who received health check-ups during the same period served as the control group. The gastrointestinal (GI) symptoms of cirrhotic patients were scored, and the fasting serum gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) levels were measured in all subjects.The potential correlations of GI symptom scores of patients in these cirrhosis groups with GI hormone levels and cirrhosis severity were analyzed. In cirrhotic patients, the GI symptom scores significantly increased. Furthermore, the symptom scores gradually increased along with the aggravation of liver damage. Moreover, serum GAS and VIP levels were significantly higher in the cirrhosis groups than in the control group, whereas MTL levels were significantly lower. These changes were significantly correlated with cirrhosis severity. The linear correlation analysis revealed that the GI symptom score was positively correlated with GAS and VIP levels, and negatively correlated with MTL level. In addition, the linear correlation analysis revealed that GI symptom score and GAS and VIP levels were positively correlated with cirrhosis severity, whereas MTL level was negatively correlated with cirrhosis severity.Cirrhotic patients have more obvious GI symptoms and higher GI hormone levels, which are closely correlated with the progression of liver cirrhosis and the degree of liver function damage.

Down-regulated let-7b-5p represses glycolysis metabolism by targeting AURKB in asthenozoospermia.

Glycolysis, through anaerobic respiration, can supply energy for human sperm motility. MicroRNAs (miRNAs) could participate in the glycolytic pathway through regulating target genes. To investigate the potential role of glycolysis-related miRNAs in asthenozoospermia, TaqMan Low Density Array (TLDA) was used to screen potentially functional miRNAs, and seven glycolysis-related miRNAs were isolated to be related to asthenozoospermia. After qRT-PCR validation, only one seminal plasma miRNA, let-7b-5p, was found significantly decreased in severe asthenozoospermia cases compared with healthy controls. To further understand whether let-7b-5p is involved in asthenozoospermia by regulating the glycolytic pathway, we carried out gain-and-loss function study of let-7b-5p in GC-2 cells and detected the glycolytic activities. Our results showed that knocking down let-7b-5p could inhibit glycolytic activities. Besides, we also found overexpressed Aurkb (a target gene of let-7b-5p) could recapitulate the effects of knocking down let-7b-5p. Our findings indicated that low expression of let-7b-5p could repress glycolysis in asthenozoospermia by targeting AURKB.

Differential effects of p38 and Erk1/2 on the chondrogenic and osteogenic differentiation of dental pulp stem cells.

The extracellular signal-regulated protein kinase 1/2 (Erk1/2) and p38 mitogen­activated protein­kinase pathways serve important roles in the regulation of osteogenic and chondrogenic differentiation in mesenchymal stem cells (MSCs). However, the exact mechanism remains unclear, and the effect is controversial. In the present study, the effects of Erk1/2 and p38 on the osteogenic and chondrogenic differentiation of dental pulp stem cells (DPSCs) were compared in vitro. The results indicated that inhibition of Erk1/2 is able to enhance the osteogenic differentiation of DPSCs and inhibit chondrogenic differentiation, whereas inhibition of p38 demonstrated the opposite effect. When compared with previous studies, the present study further confirmed that Erk1/2 and p38 serve important, but complicated, roles in regulating the differentiation of MSCs. Different chemical and physical stimuli, cell types, culture methods, times of inhibitor administration and the dosage of the inhibitor may influence the effect of Erk1/2 and p38 on the differentiation of MSCs. The present study aims to better understand the mechanisms that control the differentiation of MSCs and may be helpful in creating more effective tissue regeneration.

Suicidal ideation among Chinese cancer inpatients of general hospitals: prevalence and correlates.

Cancer patients are at high risk for suicide, particularly when they are informed about the cancer diagnosis or hospitalized for cancer treatment. Therefore, oncology healthcare settings such as large general hospitals in China, may represent an ideal setting to identify and treat suicidality in cancer patients. However, the clinical epidemiology of suicidality of Chinese cancer patients remains largely unknown. This study examined the prevalence and correlates of suicidal ideation among Chinese cancer inpatients of large general hospitals. A total of 517 cancer inpatients were consecutively recruited from two tertiary general hospitals of a metropolitan city in northern China, and administered with standardized questionnaires to collect data on sociodemographics, mental health, and cancer-related clinical characteristics. Suicidal ideation and mental health were measured with a single self-report question "In the past month, did you think about ending your life?" and Hospital Anxiety and Depression Scale, respectively. The one-month prevalence of suicidal ideation was 15.3% in Chinese cancer inpatients. In multivariable Logistic regression, depression, anxiety, moderate-to-severe pain, metastatic cancer, poor performance status, surgery, and palliative care were significantly associated with suicidal ideation. Cancer inpatients of large Chinese general hospitals have high prevalence of suicidal ideation and therefore potentially at high risk for suicide. Suicide prevention efforts for cancer inpatients should include periodic evaluation of suicidality, effective pain management, psychooncological supports, and, when necessary, psychiatric treatment and crisis intervention.

Selenium and Preeclampsia: a Systematic Review and Meta-analysis.

Conflicting results exist between selenium concentration and preeclampsia. The role of selenium in the development of preeclampsia is unclear. We conducted a meta-analysis to compare the blood selenium level in patients with preeclampsia and healthy pregnant women, and to determine the effectiveness of selenium supplementation in preventing preeclampsia. We searched PubMed, ScienceDirect, the Cochrane Library, and relevant references for English language literature up to November 25, 2014. Mean difference from observational studies and relative risk from randomized controlled trials were meta-analyzed by a random-effect model. Thirteen observational studies with 1515 participants and 3 randomized controlled trials with 439 participants were included in the meta-analysis. Using a random-effect model, a statistically significant difference in blood selenium concentration of -6.47 µg/l (95 % confidence interval (CI) -11.24 to -1.7, p = 0.008) was seen after comparing the mean difference of observational studies. In randomized controlled trials, using a random-effect model, the relative risk for preeclampsia was 0.28 (0.09 to 0.84) for selenium supplementation (p = 0.02). Evidence from observational studies indicates an inverse association of blood selenium level and the risk of preeclampsia. Supplementation with selenium significantly reduces the incidence of preeclampsia. However, more prospective clinical trials are required to assess the association between selenium supplementation and preeclampsia and to determine the dose, beginning time, and duration of selenium supplementation.