Anesthetic Propofol Reduces Endotoxic Inflammation by Inhibiting Reactive Oxygen Species-regulated Akt/IKKβ/NF-κB Signaling

BACKGROUND: Anesthetic propofol has immunomodulatory effects, particularly in the area of anti-inflammation. Bacterial endotoxin lipopolysaccharide (LPS) induces inflammation through toll-like receptor (TLR) 4 signaling. We investigated the molecular actions of propofol against LPS/TLR4-induced inflammatory activation in murine RAW264.7 macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Non-cytotoxic levels of propofol reduced LPS-induced inducible nitric oxide synthase (iNOS) and NO as determined by western blotting and the Griess reaction, respectively. Propofol also reduced the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 as detected by enzyme-linked immunosorbent assays. Western blot analysis showed propofol inhibited LPS-induced activation and phosphorylation of IKKβ (Ser180) and nuclear factor (NF)-κB (Ser536); the subsequent nuclear translocation of NF-κB p65 was also reduced. Additionally, propofol inhibited LPS-induced Akt activation and phosphorylation (Ser473) partly by reducing reactive oxygen species (ROS) generation; inter-regulation that ROS regulated Akt followed by NF-κB activation was found to be crucial for LPS-induced inflammatory responses in macrophages. An in vivo study using C57BL/6 mice also demonstrated the anti-inflammatory properties against LPS in peritoneal macrophages. CONCLUSIONS/SIGNIFICANCE: These results suggest that propofol reduces LPS-induced inflammatory responses in macrophages by inhibiting the interconnected ROS/Akt/IKKβ/NF-κB signaling pathways

What Does It Take to Synergistically Combine Sub-Potent Natural Products into Drug-Level Potent Combinations?

10.1371/journal.pone.0049969PLoS ONE711

Epstein-Barr Virus-Encoded LMP1 Interacts with FGD4 to Activate Cdc42 and Thereby Promote Migration of Nasopharyngeal Carcinoma Cells

Epstein-Barr virus (EBV) is closely associated with nasopharyngeal carcinoma (NPC), a human malignancy notorious for its highly metastatic nature. Among EBV-encoded genes, latent membrane protein 1 (LMP1) is expressed in most NPC tissues and exerts oncogenicity by engaging multiple signaling pathways in a ligand-independent manner. LMP1 expression also results in actin cytoskeleton reorganization, which modulates cell morphology and cell motility— cellular process regulated by RhoGTPases, such as Cdc42. Despite the prominent association of Cdc42 activation with tumorigenesis, the molecular basis of Cdc42 activation by LMP1 in NPC cells remains to be elucidated. Here using GST-CBD (active Cdc42-binding domain) as bait in GST pull-down assays to precipitate active Cdc42 from cell lysates, we demonstrated that LMP1 acts through its transmembrane domains to preferentially induce Cdc42 activation in various types of epithelial cells, including NPC cells. Using RNA interference combined with re-introduction experiments, we identified FGD4 (FYVE, RhoGEF and PH domain containing 4) as the GEF (guanine nucleotide exchange factor) responsible for the activation of Cdc42 by LMP1. Serial deletion experiments and co-immunoprecipitation assays further revealed that ectopically expressed FGD4 modulated LMP1-mediated Cdc42 activation by interacting with LMP1. Moreover, LMP1, through its transmembrane domains, directly bound FGD4 and enhanced FGD4 activity toward Cdc42, leading to actin cytoskeleton rearrangement and increased motility of NPC cells. Depletion of FGD4 or Cdc42 significantly reduced (∼50%) the LMP1-stimulated cell motility, an effect that was partially reversed by expression of a constitutively active mutant of Cdc42. Finally, quantitative RT-PCR and immunohistochemistry analyses showed that FGD4 and LMP1 were expressed in NPC tissues, supporting the potential physiologically relevance of this mechanism in NPC. Collectively, our results not only uncover a novel mechanism underlying LMP1-mediated Cdc42 activation, namely LMP1 interaction with FGD4, but also functionally link FGD4 to NPC tumorigenesis

Phylogeographic Study of Apodemus ilex (Rodentia: Muridae) in Southwest China

BACKGROUND: The Mountains of southwest China have complex river systems and a profoundly complex topography and are among the most important biodiversity hotspots in the world. However, only a few studies have shed light on how the mountains and river valleys promote genetic diversity. Apodemus ilex is a fine model for investigating this subject. METHODOLOGY/PRINCIPAL FINDINGS: To assess the genetic diversity and biogeographic patterns of Apodemus ilex, the complete cytochrome b gene sequences (1,140 bp) were determined from 203 samples of A. draco/ilex that were collected from southwest China. The results obtained suggested that A. ilex and A. draco are sistergroups and diverged from each other approximately 2.25 million years ago. A. ilex could be divided into Eastern and Western phylogroups, each containing two sub-groups and being widespread in different geographical regions of the southern Hengduan Mountains and the western Yunnan - Guizhou Plateau. The population expansions of A. ilex were roughly from 0.089 Mya to 0.023 Mya. CONCLUSIONS: Our result suggested that A. ilex is a valid species rather than synonym of A. draco. As a middle-high elevation inhabitant, the phylogenetic pattern of A. ilex was strongly related to the complex geographical structures in southwest China, particularly the existence of deep river valley systems, such as the Mekong and Salween rivers. Also, it appears that the evolutionary history of A. ilex, such as lineage divergences and population expansions were strongly affected by climate fluctuation in the Late Pleistocene

Genetic Evidence for an Indispensable Role of Somatic Embryogenesis Receptor Kinases in Brassinosteroid Signaling

The authors are grateful to the Arabidopsis Biological Resource Center for providing the T-DNA insertion lines discussed in this work. We thank Dr. Yanhai Yin (Iowa State University) for providing anti-BES1 antibody, Dr. Jiayang Li (Institute of Genetics and Developmental Biology, Chinese Academy of Sciences) for bri1-301 seeds, and Dr. Xing-wang Deng (Yale University) for cop1-4 and cop1-6 seeds as controls.Author Summary Brassinosteroids (BRs) are a group of plant hormones critical for plant growth and development. BRs are perceived by a cell-surface receptor complex including two distinctive receptor kinases, BRI1 and BAK1. Whereas BRI1 is a true BR-binding receptor, BAK1 does not appear to have BR-binding activity. Therefore, BAK1 is likely a co-receptor in BR signal transduction. The genetic significance of BAK1 was not clearly demonstrated in previous studies largely due to functional redundancy of BAK1 and its closely related homologues. It was not clear whether BAK1 plays an essential role or only an enhancing role in BR signaling. In this study, we identified all possible BAK1 redundant genes in the Arabidopsis thaliana genome and generated single, double, triple, and quadruple mutants. Detailed analysis indicated that, without BAK1 and its functionally redundant proteins, BR signaling is completely disrupted, largely because BRI1 has lost its ability to activate downstream components. These studies provide the first piece of loss-of-functional genetic evidence that BAK1 is indispensable to the early events of the BR signaling pathway.Yeshttp://www.plosgenetics.org/static/editorial#pee

Alpha decay half-lives of heavy nuclei within a generalized liquid drop model

Theoretical alpha-decay half-lives of the heaviest nuclei are calculated using the experimental Q value. The barriers in the quasi-molecular shape path is determined within a Generalized Liquid Drop Model (GLDM) and the WKB approximation is used. The results are compared with calculations using the Density-Dependent, M3Y (DDM3Y) effective interaction and the Viola-Seaborg-Sobiczewski (VSS) formulae. The calculations provide consistent estimates for the half-lives of the a decay chains of these superheavy elements. The experimental data stand between the GLDM calculations and VSS ones in the most time.Natural Science Foundation of China 10775061 10505016 1057511

Nanostructure in the p-layer and its impacts on amorphous silicon solar cells

The open circuit voltage (V-oc) of n-i-p type hydrogenated amorphous silicon (a-Si:H) solar cells has been examined by means of experimental and numerical modeling. The i- and p-layer limitations on V-oc are separated and the emphasis is to identify the impact of different kinds of p-layers. Hydrogenated protocrystalline, nanocrystalline and microcrystalline silicon p-layers were prepared and characterized using Raman spectroscopy, high resolution transmission electron microscopy (HRTEM), optical transmittance and activation energy of dark-conductivity. The n-i-p a-Si:H solar cells incorporated with these p-layers were comparatively investigated, which demonstrated a wide variation of V-oc from 1.042 V to 0.369 V, under identical i- and n-layer conditions. It is found that the nanocrystalline silicon (nc-Si:H) p-layer with a certain nanocrystalline volume fraction leads to a higher V-oc. The optimum p-layer material for n-i-p type a-Si:H solar cells is not found at the onset of the transition between the amorphous to mixed phases, nor is it associated with a microcrystalline material with a large grain size and a high volume fraction of crystalline phase. (c) 2006 Elsevier B.V. All rights reserved