Identifying the Antiproliferative Effect of Astragalus Polysaccharides on Breast Cancer: Coupling Network Pharmacology With Targetable Screening From the Cancer Genome Atlas

Background:Astragalus polysaccharides (APS), natural plant compounds, have recently emerged as a promising strategy for cancer treatment, but little is known concerning their effects on breast cancer (BC) tumorigenesis.Methods: We obtained breast cancer genetic data from The Cancer Genome Atlas (TCGA) database, network pharmacology to further clarify its biological properties. Survival analysis and molecular docking techniques were implemented for the final screening to obtain key target information. Our experiments focused on the detection of intervention effects of APS on BC cells (MCF-7 and MDA-MB-231), and quantitative RT-PCR (qRT-PCR) was used to assess the expression of key targets.Results: A total of 1,439 differentially expressed genes (DEGs) were identified by TCGA and used to build disease networks. Module analysis, gene ontology and pathway analysis revealed characteristic of the DEGs network. Topological properties were used to identify key targets, survival analysis and molecular docking finally found that the targets of APS regulation of BC cells may be CCNB1, CDC6, and p53. Through cell viability, migration and invasion assays, we found that APS interferes with the development of breast cancer in MCF7 and MDA-MB-231 cells in a dose-dependent manner. Furthermore, qRT-PCR verification suggested that the expression of CCNB1 and CDC6 in breast cancer cells was significantly downregulated in response to APS, while expression of the tumor suppressor gene P53 was significantly increased.Conclusion: Results of this study suggest therapeutic potential for APS in BC treatment, possibly through interventions with CCNB1, CDC6, and P53. Furthermore, these findings illustrate the feasibility of using network pharmacology to connect large-scale target data as a way to discover the mechanism of natural products interfering with disease

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

Methanol electro-oxidation on platinum modified tungsten carbides in direct methanol fuel cells: a DFT study

In exploration of low-cost electrocatalysts for direct methanol fuel cells (DMFCs), Pt modified tungsten carbide (WC) materials are found to be great potential candidates for decreasing Pt usage whilst exhibiting satisfactory reactivity. In this work, the mechanisms, onset potentials and activity for electrooxidation of methanol were studied on a series of Pt-modified WC catalysts where the bare W-terminated WC(0001) substrate was employed. In the surface energy calculations of a series of Pt-modified WC models, we found that the feasible structures are mono- and bi-layer Pt-modified WCs. The tri-layer Pt-modified WC model is not thermodynamically stable where the top layer Pt atoms tend to accumulate and form particles or clusters rather than being dispersed as a layer. We further calculated the mechanisms of methanol oxidation on the feasible models via methanol dehydrogenation to CO involving C-H and O-H bonds dissociating subsequently, and further CO oxidation with the C-O bond association. The onset potentials for the oxidation reactions over the Pt-modified WC catalysts were determined thermodynamically by water dissociation to surface OH∗ species. The activities of these Pt-modified WC catalysts were estimated from the calculated kinetic data. It has been found that the bi-layer Pt-modified WC catalysts may provide a good reactivity and an onset oxidation potential comparable to pure Pt and serve as promising electrocatalysts for DMFCs with a significant decrease in Pt usage

Synchronized replication of genes encoding the same protein complex in fast-proliferating cells

DNA replication perturbs the dosage balance among genes; at mid-S phase, early-replicating genes have doubled their copies while late-replicating ones have not. Dosage imbalance among genes, especially within members of a protein complex, is toxic to cells. However, the molecular mechanisms that cells use to deal with such imbalance remain not fully understood. Here, we validate at the genomic scale that the dosage between early- and late-replicating genes is imbalanced in HeLa cells. We propose the synchronized replication hypothesis that genes sensitive to stoichiometric relationships will be replicated simultaneously to maintain stoichiometry. In support of this hypothesis, we observe that genes encoding the same protein complex have similar replication timing but mainly in fast-proliferating cells such as embryonic stem cells and cancer cells. We find that the synchronized replication observed in cancer cells, but not in slow-proliferating differentiated cells, is due to convergent evolution during tumorigenesis that restores synchronized replication timing within protein complexes. Taken together, our study reveals that the demand for dosage balance during S phase plays an important role in the optimization of the replication-timing program; this selection is relaxed during differentiation as the cell cycle prolongs and is restored during tumorigenesis as the cell cycle shortens

Synchronized replication of genes encoding the same protein complex in fast-proliferating cells

DNA replication perturbs the dosage balance among genes; at mid-S phase, early-replicating genes have doubled their copies while late-replicating ones have not. Dosage imbalance among genes, especially within members of a protein complex, is toxic to cells. However, the molecular mechanisms that cells use to deal with such imbalance remain not fully understood. Here, we validate at the genomic scale that the dosage between early- and late-replicating genes is imbalanced in HeLa cells. We propose the synchronized replication hypothesis that genes sensitive to stoichiometric relationships will be replicated simultaneously to maintain stoichiometry. In support of this hypothesis, we observe that genes encoding the same protein complex have similar replication timing but mainly in fast-proliferating cells such as embryonic stem cells and cancer cells. We find that the synchronized replication observed in cancer cells, but not in slow-proliferating differentiated cells, is due to convergent evolution during tumorigenesis that restores synchronized replication timing within protein complexes. Taken together, our study reveals that the demand for dosage balance during S phase plays an important role in the optimization of the replication-timing program; this selection is relaxed during differentiation as the cell cycle prolongs and is restored during tumorigenesis as the cell cycle shortens