Circular RNA circ_0124644 exacerbates the ox-LDL-induced endothelial injury in human vascular endothelial cells through regulating PAPP-A by acting as a sponge of miR-149-5p.

The modulatory roles of numerous circular RNAs (circRNAs) have been exposited in atherosclerosis (AS). Our study paid attention to the function of circRNA_ 0124644 (circ_0124644) in AS development, as well as its functional mechanism. The AS cell model was established by the treatment of oxidized low-density lipoprotein (ox-LDL) to human vascular endothelial cells (HUVECs). Cell proliferation and cycle were severally measured by Cell Counting Kit-8 (CCK-8) and cell cycle detection kit. The examination of apoptosis rate was executed through flow cytometry. Western blot was exploited for detecting the associated proteins. The expression levels of circ_0124644 and microRNA-149-5p (miR-149-5p) and pregnancy-associated plasma protein-A (PAPP-A) were assayed using quantitative real-time polymerase chain reaction. The combination of targets was validated via the dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull-down assay. Clonal capacity was analyzed using colony formation assay. Ox-LDL restrained HUVECs proliferation and cycle, but facilitated apoptosis. Circ_0124644 expression was increased, while miR-149-5p was downregulated in ox-LDL-treated HUVECs. Besides, circ_0124644 served as a molecular sponge of miR-149-5p and intensified the ox-LDL-induced HUVECs injury by sponging miR-149-5p. PAPP-A was a target of miR-149-5p and miR-149-5p could mitigate the HUVECs injury caused by ox-LDL through inhibiting PAPP-A. Moreover, PAPP-A was positively regulated by circ_0124644 via the miR-149-5p. In this report, we concluded the promoted role of circ_0124644 in the ox-LDL-induced endothelial injury of HUVECs via the miR-149-5p/PAPP-A axis with an emphasis on its diagnostic and therapeutic values in AS.

Metallization and superconductivity in methane doped by beryllium at low pressure.

As one of the simplest hydrocarbons, methane (CH4) has great potential in the research of superconductors. However, the metallization of CH4 has been an issue for a long time. Here, we report the structure, metallization, and superconductivity of CH4 doped by Be at low pressures, based on first-principles calculations. The result shows that the thermodynamically stable BeCH4 with P1[combining macron] space-group can transform into a metal at ambient pressure. This ternary hydride BeCH4 exhibits a superconductivity of ∼6 K below 25.6 GPa. Interestingly, the superconducting critical temperature of BeCH4 can reach ∼30 K at 80 GPa in the form of an a-P1 space-group phase. The charge transfer from Be to CH4 molecules plays an important role in the superconductivity. Our results present a novel way to realize the metallization of methane at relative pressures and indicate that the doped methane is a potential candidate for seeking high temperature and low pressure superconductivity.

Identification of an eight-lncRNA prognostic model for breast cancer using WGCNA network analysis and a Cox­proportional hazards model based on L1-penalized estimation.

An ever­increasing number of long noncoding (lnc)RNAs has been identified in breast cancer. The present study aimed to establish an lncRNA signature for predicting survival in breast cancer. RNA expression profiling was performed using microarray gene expression data from the National Center for Biotechnology Information Gene Expression Omnibus, followed by the identification of breast cancer­related preserved modules using weighted gene co­expression network (WGCNA) network analysis. From the lncRNAs identified in these preserved modules, prognostic lncRNAs were selected using univariate Cox regression analysis in combination with the L1­penalized (LASSO) Cox­proportional Hazards (Cox­PH) model. A risk score based on these prognostic lncRNAs was calculated and used for risk stratification. Differentially expressed RNAs (DERs) in breast cancer were identified using MetaDE. Gene Set Enrichment Analysis pathway enrichment analysis was conducted for these prognostic lncRNAs and the DERs related to the lncRNAs in the preserved modules. A total of five preserved modules comprising 73 lncRNAs were mined. An eight­lncRNA signature (IGHA1, IGHGP, IGKV2­28, IGLL3P, IGLV3­10, AZGP1P1, LINC00472 and SLC16A6P1) was identified using the LASSO Cox­PH model. Risk score based on these eight lncRNAs could classify breast cancer patients into two groups with significantly different survival times. The eight­lncRNA signature was validated using three independent cohorts. These prognostic lncRNAs were significantly associated with the cell adhesion molecules pathway, JAK­signal transducer and activator of transcription 5A pathway, and erbb pathway and are potentially involved in regulating angiotensin II receptor type 1, neuropeptide Y receptor Y1, KISS1 receptor, and C­C motif chemokine ligand 5. The developed eight­lncRNA signature may have clinical implications for predicting prognosis in breast cancer. Overall, this study provided possible molecular targets for the development of novel therapies against breast cancer.

Ginkgolide B Mediated Alleviation of Inflammatory Cascades and Altered Lipid Metabolism in HUVECs via Targeting PCSK-9 Expression and Functionality.

The potential of oxidized-LDL (Ox-LDL) to elicit inflammatory responses in macrophages leading to the atherosclerosis (AS) progression is well known. Since proprotein convertase subtilisin/Kexin-9 (PCSK-9), the posttranslational regulator of LDL-receptor, is associated with elevated LDL in the circulation, the present report was aimed to uncover the ameliorative effects of Ginkgolide B, a terpenic lactone from Ginkgo biloba, against Ox-LDL-induced alterations in cholesterol metabolism in HUVECs. Consequently, our results demonstrated that incubation with Ox-LDL significantly upregulated the PCSK-9 expression in HUVECs, which was significantly downregulated, both at mRNA and protein level, after Ginkgolide B treatment via subsequent suppression of sterol element binding protein (SREBP-2) expression. Moreover, Ginkgolide B-mediated inhibition of PCSK-9 activity was also validated by in silico methods which revealed that it interferes the PSCK-9 interaction with LDL-receptor (LDL-R). Interestingly, Ox-LDL-induced LDL-R expression was further enhanced by Ginkgolide B treatment in HUVECs. Moreover, Ginkgolide B treatment lead to downregulation of lectin-like Ox-LDL receptor (LOX-1) and NADPH oxidase (NOX-4) expression which was upregulated in Ox-LDL-treated HUVECs, along with the attenuation of mitochondrial ROS generation. Furthermore, Ginkgolide B significantly inhibited the augmented expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in Ox-LDL-activated HUVECs. Ginkgolide B also significantly ameliorated the inflammatory response in Ox-LDL-activated HUVECs by suppressing the expression of IL-1α, IL-1ß, IL-6, CXCL-1, CXCL-2, and monocyte chemotactic protein (MCP-1), at mRNA and protein level. Our in vitro and in silico study established that Ginkgolide B alleviated the Ox-LDL-induced inflammatory cascades and altered lipid metabolism in HUVECs by suppressing the PCSK-9 and, thus, could be established as a treasured alternative therapeutic candidate in the atherosclerosis management.

Various roles of astrocytes during recovery from repeated exposure to different doses of lipopolysaccharide.

Previous studies have demonstrated that the outcomes associated with neuroinflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) at different dosages vary and either resolve or result in sepsis. The mechanisms underlying differential recoveries from varying doses of LPS are unclear. Additionally, changes in recovery involving chronic or continuous systemic inflammatory responses remain unclear. The present experiments were designed to evaluate the effects of systemic inflammation induced by repeated intraperitoneal injection of LPS at different doses on cognitive impairment. These experiments were also designed to investigate the roles of microglia and astrocytes in systemic inflammation and confirm the mechanisms that influence these processes. Kunming mice were given intraperitoneal injections of LPS at either 5mg/kg or 10mg/kg or saline for 7 consecutive days. Following the 7-day course of injections, a number of mice were kept undisturbed in their home cage for 30 days (30-day recovery), and other mice were similarly kept for 90 days (90-day recovery). The results revealed that the cognitive and physiological changes induced by 5mg/kg LPS included weight loss, impairments in spatial learning and memory, phenotypic changes in glia cells, and altered levels of pro-inflammatory cytokines; all of which were reversible. A potential recovery mechanism involves a neuroprotective function of activated astrocytes that secreted glial-derived neurotrophic factor (GDNF) following 30-day recovery. The changes induced by 10mg/kg LPS included weight loss, phenotypic changes in glia cells, and altered levels of pro-inflammatory cytokines were also reversible; however, a longer recovery was required (90 days). Although 10mg/kg LPS-induced neuroinflammation was reversible, the associated impairments in spatial learning and memory were permanent. A potential mechanism underlying permanent damage associated with 10mg/kg LPS involves the role of the activated astrocytes changing from neuroprotection to destruction, which is mediated by increased pro-inflammatory cytokines in more serious neuroinflammation.