Influence of cilostazol on thromboangiitis obliterans in rats and the mechanism involved

Purpose: To study the effect of Cilostazol on rat thromboangiitis obliterans (TAO), and the mechanism of action involved. Methods: Rats (N = 45) were injected with sodium laurate to establish the model of TAO, and then divided into Sham group (n = 15), TAO group (n = 15) and TAO + cilostazol group (n = 15). After administration of cilostazol, TAO lesions in the rats were graded, and the femoral arteries were stained by hematoxylin-eosin (H&E) to determine the degree of vascular lesions. The status of vascular endothelial cells was determined using transmission electron microscopy. Furthermore, the expression and transcription levels of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) proteins were evaluated by Western blotting and real-time polymerase chain reaction (RT-PCR) respectively. Results: In contrast to Sham group, TAO group exhibited symptoms such as changes in skin temperature and color, and limb swelling and thanatosis, while in the TAO + cilostazol group, the damage was reversed, vascular and vascular endothelial cell lesions were significantly ameliorated (p < 0.05), and the transcription and translation levels of HIF-1α and VEGF significantly suppressed (p < 0.05). Conclusion: Cilostazol alleviates sodium laurate-induced TAO lesions in rats via HIF-1α/VEGF pathway. This study may provide new insights for the treatment of TAO. Keywords: Cilostazol; Hypoxia-inducible factor/vascular endothelial growth factor pathway; Thromboangiitis obliterans; Limb swelling; Thanatosi

Calycosin regulates glucocorticoid-induced apoptosis via Nrf2/ARE signaling in MC3T3-E1 cells

Purpose: To determine the anti-osteoporotic effect of calycosin (CA) and investigate the mechanism involved.Methods: To establish a cell model of osteoporosis, MC3T3-E1 cells were treated with dexamethasone (DEX). Subsequently, the levels of accumulated reactive oxygen species (ROS) and subsequent apoptotic cell death (using flow cytometry) were determined. Relevant mRNA and protein expression levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblot respectively.Results: CA reduced the apoptosis and accumulation of ROS in DEX-treated cells. DEX induced the expression of caspase-3/-8/-9 in the cleavage of poly ADP-ribose polymerase (PARP), whereas CA treatment decreased expression levels of caspase-3/-8/-9 and PARP. In addition, DEX treatment significantly suppressed the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as its downstream targets, viz, heme oxygenase-1 and quinone oxidoreductase-1. Interestingly, CA treatment reversed this suppressive effect. It was also found that Nrf2 small interfering RNA effectively inhibited the protective effects of CA against DEX-induced ROS overproduction as well as apoptosis.Conclusion: CA attenuates the cytotoxicity of DEX via inhibition of the generation of ROS and promotion of Nrf2 expression. These findings offer novel insights into a molecular approach to the treatment of glucocorticoid-induced osteoporosis via the application of natural compounds.Keywords: Calycosin, Osteoporosis, Nrf2, Antioxidant response elements, Apoptosi

Cross-cell DNA methylation annotation and analysis for pan-cancer study

Pan-cancer study can uncover cell- and tissue-specific genomic loci and regions with underlying biological functions, as one of fundamental procedures toward precision medicine. We utilized the online curated resource of DNA methylation annotation knowledgebase, to implement the cross-cell interrogation of pan-cancer study of breast cancer. The study revealed genome-wide differentially-methylated loci and regions by the reduced representation bisulfite sequencing profiling. The knowledgebase contains three level of curated information across multiple cancer and normal cells from the ENCODE Consortium. The reference base covers all identified differentially-methylation CpG sites and regions of interest, further annotated gene information, together with tumor suppressor gene and methylation level. Lastly, it includes the inferred functional association network and related Gene Ontology analysis results based on all the tumor suppressor genes identified from the differentially-methylated regions of interest. Our knowledgebase and analysis results provide a thorough reference source for biomedical researchers and clinicians. The cross-cell analysis results are deposited at: http://github.com/gladex/DMAK.

Research on Concrete Durability Improving for Existing Island-Building and Its Application

China’s coastal cities contain a large number of islands with abundant human activities, in which buildings are in a typical marine corrosion environment and the corrosion of reinforced concrete structures is very prominent. This paper makes research work on two aspects: (1) the durability assessment and durability improvement after a thorough investigation of the architecture of Xiangtan County, Ningbo city, on an island and (2) the application research of the bidirectional electromigration rehabilitation (BIEM) technology to enhance the durability of existing island building life. This paper designs a set of BIEM equipment based on solar power supply and develops a BIEM control system with an automatic control system based on 3G networks, which realized the functions of indoor BIEM parameter setting, data receiving and wire breaking, and so on. The research results show that the complete set of BIEM techniques proposed in this paper can effectively remove the chloride ion in the concrete and transfer the rust inhibitor to the surface of steel bar. The research results have important effects on the durability and safety of island buildings

Discovery of Selective Inhibitors Against EBNA1 via High Throughput In Silico Virtual Screening

Background: Epstein-Barr Virus (EBV) latent infection is associated with several human malignancies and is a causal agent of lymphoproliferative diseases during immunosuppression. While inhibitors of herpesvirus DNA polymerases, like gancyclovir, reduce EBV lytic cycle infection, these treatments have limited efficacy for treating latent infection. EBNA1 is an EBVencoded DNA-binding protein required for viral genome maintenance during latent infection. Methodology: Here, we report the identification of a new class of small molecules that inhibit EBNA1 DNA binding activity. These compounds were identified by virtual screening of 90,000 low molecular mass compounds using computational docking programs with the solved crystal structure of EBNA1. Four structurally related compounds were found to inhibit EBNA1-DNA binding in biochemical assays with purified EBNA1 protein. Compounds had a range of 20–100 mM inhibition of EBNA1 in fluorescence polarization assays and were further validated for inhibition using electrophoresis mobility shift assays. These compounds exhibited no significant inhibition of an unrelated DNA binding protein. Three of these compounds inhibited EBNA1 transcription activation function in cell-based assays and reduced EBV genome copy number when incubated with a Burkitt lymphoma cell line. Conclusions: These experiments provide a proof-of-principle that virtual screening can be used to identify specific inhibitor

PDTD: a web-accessible protein database for drug target identification

<p>Abstract</p> <p>Background</p> <p>Target identification is important for modern drug discovery. With the advances in the development of molecular docking, potential binding proteins may be discovered by docking a small molecule to a repository of proteins with three-dimensional (3D) structures. To complete this task, a reverse docking program and a drug target database with 3D structures are necessary. To this end, we have developed a web server tool, TarFisDock (<it>Tar</it>get <it>Fis</it>hing <it>Dock</it>ing) <url>http://www.dddc.ac.cn/tarfisdock</url>, which has been used widely by others. Recently, we have constructed a protein target database, <it>P</it>otential <it>D</it>rug <it>T</it>arget <it>D</it>atabase (PDTD), and have integrated PDTD with TarFisDock. This combination aims to assist target identification and validation.</p> <p>Description</p> <p>PDTD is a web-accessible protein database for <it>in silico </it>target identification. It currently contains >1100 protein entries with 3D structures presented in the Protein Data Bank. The data are extracted from the literatures and several online databases such as TTD, DrugBank and Thomson Pharma. The database covers diverse information of >830 known or potential drug targets, including protein and active sites structures in both PDB and mol2 formats, related diseases, biological functions as well as associated regulating (signaling) pathways. Each target is categorized by both nosology and biochemical function. PDTD supports keyword search function, such as PDB ID, target name, and disease name. Data set generated by PDTD can be viewed with the plug-in of molecular visualization tools and also can be downloaded freely. Remarkably, PDTD is specially designed for target identification. In conjunction with TarFisDock, PDTD can be used to identify binding proteins for small molecules. The results can be downloaded in the form of mol2 file with the binding pose of the probe compound and a list of potential binding targets according to their ranking scores.</p> <p>Conclusion</p> <p>PDTD serves as a comprehensive and unique repository of drug targets. Integrated with TarFisDock, PDTD is a useful resource to identify binding proteins for active compounds or existing drugs. Its potential applications include <it>in silico </it>drug target identification, virtual screening, and the discovery of the secondary effects of an old drug (i.e. new pharmacological usage) or an existing target (i.e. new pharmacological or toxic relevance), thus it may be a valuable platform for the pharmaceutical researchers. PDTD is available online at <url>http://www.dddc.ac.cn/pdtd/</url>.</p

A Multi-Robot Cooperation Framework for Sewing Personalized Stent Grafts

This paper presents a multi-robot system for manufacturing personalized medical stent grafts. The proposed system adopts a modular design, which includes: a (personalized) mandrel module, a bimanual sewing module, and a vision module. The mandrel module incorporates the personalized geometry of patients, while the bimanual sewing module adopts a learning-by-demonstration approach to transfer human hand-sewing skills to the robots. The human demonstrations were firstly observed by the vision module and then encoded using a statistical model to generate the reference motion trajectories. During autonomous robot sewing, the vision module plays the role of coordinating multi-robot collaboration. Experiment results show that the robots can adapt to generalized stent designs. The proposed system can also be used for other manipulation tasks, especially for flexible production of customized products and where bimanual or multi-robot cooperation is required.Comment: 10 pages, 12 figures, accepted by IEEE Transactions on Industrial Informatics, Key words: modularity, medical device customization, multi-robot system, robot learning, visual servoing, robot sewin