Knockdown of DNMT1 Induces SLCO3A1 to Promote Follicular Growth by Enhancing the Proliferation of Granulosa Cells in Mammals.

In female mammals, the proliferation and apoptosis of granulosa cells (GCs) have been shown to determine the fate of follicles. DNA methyltransferases (DNMTs) and SLCO3A1 have been reported to be involved in the survival of GCs and follicular growth. However, the molecular mechanisms enabling DNMTs to regulate the expression of SLCO3A1 to participate in follicular growth are unclear. In this study, we found that the knockdown of DNMT1 enhanced the mRNA and protein levels of SLCO3A1 by regulating the chromatin accessibility probably. Moreover, SLCO3A1 upregulated the mRNA and protein levels of MCL1, PCNA, and STAR to promote the proliferation of GCs and facilitated cell cycle progression by increasing the mRNA and protein levels of CCNE1, CDK2, and CCND1, but it decreased apoptosis by downregulating the mRNA and protein levels of CASP3 and CASP8. Moreover, SLCO3A1 promoted the growth of porcine follicles and development of mice follicles. In conclusion, the knockdown of DNMT1 upregulated the mRNA and protein levels of SLCO3A1, thereby promoting the proliferation of GCs to facilitate the growth and development of ovarian follicles, and these results provide new insights into investigations of female reproductive diseases.

Comprehensive analysis of prognostic gene signatures based on immune infiltration of ovarian cancer.

BACKGROUND: Ovarian cancer (OV) is one of the most common malignant tumors of gynecology oncology. The lack of effective early diagnosis methods and treatment strategies result in a low five-year survival rate. Also, immunotherapy plays an important auxiliary role in the treatment of advanced OV patient, so it is of great significance to find out effective immune-related tumor markers for the diagnosis and treatment of OV. METHODS: Based on the consensus clustering analysis of single-sample gene set enrichment analysis (ssGSEA) score transformed via The Cancer Genome Atlas (TCGA) mRNA profile, we obtained two groups with high and low levels of immune infiltration. Multiple machine learning methods were conducted to explore prognostic genes associated with immune infiltration. Simultaneously, the correlation between the expression of mark genes and immune cells components was explored. RESULTS: A prognostic classifier including 5 genes (CXCL11, S1PR4, TNFRSF17, FPR1 and DHRS95) was established and its robust efficacy for predicting overall survival was validated via 1129 OV samples. Some significant variations of copy number on gene loci were found between two risk groups and it showed that patients with fine chemosensitivity has lower risk score than patient with poor chemosensitivity (P = 0.013). The high and low-risk groups showed significantly different distribution (P < 0.001) of five immune cells (Monocytes, Macrophages M1, Macrophages M2, T cells CD4 menory and T cells CD8). CONCLUSION: The present study identified five prognostic genes associated with immune infiltration of OV, which may provide some potential clinical implications for OV treatment.

Topical versus systemic tranexamic acid after total knee and hip arthroplasty: A meta-analysis of randomized controlled trials.

BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug widely used to reduce blood loss during joint replacements, including total knee arthroplasty (TKA) and total hip arthroplasty (THA). However, there is no final consensus regarding the composition of an optimal administration of TXA regime between topical and systemic (intravenous). The purpose of our study was to compare the efficacy of topical and intravenous (IV) regimen of TXA during TKA and THA. METHODS: Five relevant electronic online databases, PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science and Chinese Biomedical Database were systematically searched in November 2015. Randomized controlled trials (RCTs) that compared topical with intravenous TXA in patients with TKA or THA were included. The search terms included "topical," "intravenous," "tranexamic acid," "knee arthroplasty" and "hip arthroplasty." Two reviewers independently extracted data and assessed the risk of bias and study quality. Data were analyzed with Review Manager 5.3 software. Grades of Recommendation Assessment, Development and Evaluation (GRADE) were used to assess the quality of evidence. RESULTS: Sixteen RCTs with 1250 patients undergoing TKA and 4 RCTs involving 550 patients undergoing THA were included. There were no significant differences in total blood loss (mean difference [MD]TKA = -28.72 mL, 95% confidence interval [CI] -195.97 to 138.54 mL, P = 0.74; MDTHA = 14.03 mL, 95% CI -35.53 to 63.59 mL; P = 0.78), total drain out (MDTKA = -3.09 mL, 95% CI -39.05 to 32.88 mL; P = 0.87; MDTHA -31.00 mL, 95% CI -66.56 to 4.66 mL; P = 0.09), and transfusion rates (ORTKA = 0.90, 95% CI 0.58-1.40, P = 0.64; ORTHA = 1.19, 95% CI 0.67-2.09; P = 0.63) between topical and intravenous (IV) TXA. CONCLUSIONS: The current evidence suggested that topical TXA was equally effective and safe compared with intravenous TXA in reducing blood loss and transfusion rate following TKA or THA. We recommended that either topically or systemically could be used in TKA and THA to decrease perioperative blood loss.

Resveratrol, a natural antioxidant, protects monosodium iodoacetate-induced osteoarthritic pain in rats.

BACKGROUND: Osteoarthritis (OA) is a chronic progressive joint disease characterized by advanced joint pain, subchondral bone sclerosis and articular cartilage degeneration. Resveratrol has been shown to have anti-inflammatory, cardioprotective and antioxidant properties and to inhibit platelet aggregation and coagulation. However, the effects of resveratrol on OA have not been examined. In this study, we investigate the protective effects of resveratrol on monosodium iodoacetate (MIA)-induced OA through inhibition of cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) signaling pathway in a rat model. METHODS: A single intra-articular injection of MIA was injected into rats for the induction of OA. The mechanical, heat and cold hyperalgesia were measured at days 0, 7 and 14. The serum and synovial fluid levels of IL-1ß, IL-10 and TNF-α and osteocalcin were measured by enzyme-linked immunosorbent assay. The mRNA and protein expressions of IL-1ß, IL-10, TNF-α, Il-6, MMP-13 and COX-2 and iNOS were determined by RT-PCR and western blot, respectively. Osteoarthritic lesion in the knee joint was evaluated by histological analysis. RESULTS: MIA-injected rats treated with resveratrol at a dose of either 5 or 10mg/kg body weight were significantly reduced hyperalgesia of mechanical, heat and cold and increased the vertical and horizontal movements. Subsequently, MIA-injected rats increased serum and synovial fluid levels of IL-1ß, IL-10, IL-6, TNF-α, MMP-13 and osteoclastic activity marker, osteocalcin and its articular cartilage mRNA and protein expressions. Further, MIA-injected rats increased COX-2 and iNOS mRNA and protein expressions were decreased by resveratrol. The protective effect of resveratrol was comparable to a reference drug, etoricoxib. The cartilage damage induced by MIA were attenuated by resveratrol. CONCLUSIONS: Taken together, resveratrol has the potential to improve MIA-induced cartilage damage by inhibiting the levels and expressions of inflammatory mediators suggesting that resveratrol may be a potential therapeutic agent for OA.

Molecular mechanisms of osteoarthritis using gene microarrays.

This study aimed to investigate the molecular mechanisms of osteoarthritis (OA) by microarray analysis. Three gene expression datasets GSE1919, 19664 and 55235 were downloaded from the Gene Expression Omnibus, and data of OA samples and healthy controls were used. After data preprocessing, differential expression analysis between the OA group and controls was performed using LIMMA (Linear Models for Microarray Data) package and genes with |log2FC (fold change)|>1 and P<0.05 were screened as DEGs (differentially expressed genes). The screened DEGs were then subject to functional annotation and pathway enrichment analysis using DAVID (Database for Annotation Visualization and Integrated Discovery). Next, gene-set enrichment analysis was performed using Enrichment map Cytoscape plug-in, followed by detecting sub-networks using clusterONE. Finally, risk subpathways were screened using iSubpathwayMiner package. A total of 141 DEGs were screened, including 52 up-regulated ones and 89 down-regulated ones. These DEGs were enriched in 48 GO terms that were mainly related to locomotory behavior, taxis, adhesion, and 11 pathways that were related to cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesion, as well as several signaling pathways. The enrichment map enriched gene-sets mainly related to cell death and apoptosis, and extracellular components. The risk pathways up-regulated DEGs were exclusively related to arachidonic acid metabolism and glycosphingolipid biosynthesis, and the top two risk pathways were tyrosine metabolism for the down-regulated ones. From this study we conclude that genes involved in cell death and apoptosis, as well as cell-extracellular matrix interaction, may be essential for OA pathogenesis by altering multiple signaling pathways.

Testing pattern synchronization in coupled systems through different entropy-based measures.

Pattern synchronization (PS) can capture one aspect of the dynamic interactions between bivariate physiological systems. It can be tested by several entropy-based measures, e.g., cross sample entropy (X-SampEn), cross fuzzy entropy (X-FuzzyEn), multivariate multiscale entropy (MMSE), etc. A comprehensive comparison on their distinguishability is currently missing. Besides, they are highly dependent on several pre-defined parameters, the threshold value r in particular. Thus, their consistency also needs further elucidation. Based on the well-accepted assumption that a tight coupling necessarily leads to a high PS, we performed a couple of evaluations over several simulated coupled models in this study. All measures were compared to each other with respect to their consistency and distinguishability, which were quantified by two pre-defined criteria-degree of crossing (DoC) and degree of monotonicity (DoM). Results indicated that X-SampEn and X-FuzzyEn could only work well over coupled stochastic systems with meticulously selected r. It is thus not recommended to apply them to the intrinsic complex physiological systems. However, MMSE was suitable for both, indicating by relatively higher DoC and DoM values. Final analysis on the cardiorespiratory coupling validated our results.