TY - JOUR TI - Terameprocol, a methylated derivative of nordihydroguaiaretic acid, inhibits production of prostaglandins and several key inflammatory cytokines and chemokines AU - Eads, D. AU - Hansen, R. L. AU - Oyegunwa, A. O. AU - Cecil, C. E. AU - Culver, C. A. AU - Scholle, F. AU - Petty, I. T. D. AU - Laster, S. M. T2 - JOURNAL OF INFLAMMATION-LONDON AB - Abstract Background Extracts of the creosote bush, Larrea tridentata , have been used for centuries by natives of western American and Mexican deserts to treat a variety of infectious diseases and inflammatory disorders. The beneficial activity of this plant has been linked to the compound nordihydroguaiaretic acid (NDGA) and its various substituted derivatives. Recently, tetra-O-methyl NDGA or terameprocol (TMP) has been shown to inhibit the growth of certain tumor-derived cell lines and is now in clinical trials for the treatment of human cancer. In this report, we ask whether TMP also displays anti-inflammatory activity. TMP was tested for its ability to inhibit the LPS-induced production of inflammatory lipids and cytokines in vitro . We also examined the effects of TMP on production of TNF-α in C57BL6/J mice following a sublethal challenge with LPS. Finally, we examined the molecular mechanisms underlying the effects we observed. Methods RAW 264.7 cells and resident peritoneal macrophages from C57BL6/J mice, stimulated with 1 μg/ml LPS, were used in experiments designed to measure the effects of TMP on the production of prostaglandins, cytokines and chemokines. Prostaglandin production was determined by ELISA. Cytokine and chemokine production were determined by antibody array and ELISA. Western blots, q-RT-PCR, and enzyme assays were used to assess the effects of TMP on expression and activity of COX-2. q-RT-PCR was used to assess the effects of TMP on levels of cytokine and chemokine mRNA. C57BL6/J mice injected i.p. with LPS were used in experiments designed to measure the effects of TMP in vivo . Serum levels of TNF-α were determined by ELISA. Results TMP strongly inhibited the production of prostaglandins from RAW 264.7 cells and normal peritoneal macrophages. This effect correlated with a TMP-dependent reduction in levels of COX-2 mRNA and protein, and inhibition of the enzymatic activity of COX-2. TMP inhibited, to varying degrees, the production of several cytokines, and chemokines from RAW 264.7 macrophages and normal peritoneal macrophages. Affected molecules included TNF-α and MCP-1. Levels of cytokine mRNA were affected similarly, suggesting that TMP is acting to prevent gene expression. TMP partially blocked the production of TNF-α and MCP-1 in vivo in the serum of C57BL6/J mice that were challenged i.p . with LPS. Conclusion TMP inhibited the LPS-induced production of lipid mediators and several key inflammatory cytokines and chemokines, both in vitro and in vivo , raising the possibility that TMP might be useful as a treatment for a variety of inflammatory disorders. DA - 2009/1/8/ PY - 2009/1/8/ DO - 10.1186/1476-9255-6-2 VL - 6 SP - SN - 1476-9255 ER - TY - JOUR TI - Modified vaccinia virus Ankara can activate NF-kappa B transcription factors through a double-stranded RNA-activated protein kinase (PKR)-dependent pathway during the early phase of virus replication AU - Lynch, Heather E. AU - Ray, Caroline A. AU - Oie, Katrina L. AU - Pollara, Justin J. AU - Petty, Ian T. D. AU - Sadler, Anthony J. AU - Williams, Bryan R. G. AU - Pickup, David J. T2 - VIROLOGY AB - Modified vaccinia virus Ankara (MVA), which is a promising replication-defective vaccine vector, is unusual among the orthopoxviruses in activating NF-κB transcription factors in cells of several types. In human embryonic kidney (HEK 293T) cells, the MVA-induced depletion of IκBα required to activate NF-κB is inhibited by UV-inactivation of the virus, and begins before viral DNA replication. In HEK 293T, CHO, or RK13 cells, expression of the cowpox virus CP77 early gene, or the vaccinia virus K1L early gene suppresses MVA-induced IκBα depletion. In mouse embryonic fibroblasts (MEFs), MVA induction of IκBα depletion is dependent on the expression of mouse or human double-stranded RNA-activated protein kinase (PKR). These results demonstrate that events during the early phase of MVA replication can induce PKR-mediated processes contributing both to the activation of NF-κB signaling, and to processes that may restrict viral replication. This property may contribute to the efficacy of this vaccine virus. DA - 2009/9/1/ PY - 2009/9/1/ DO - 10.1016/j.virol.2009.06.012 VL - 391 IS - 2 SP - 177-186 SN - 0042-6822 KW - Vaccinia KW - MVA KW - NF-kappaB KW - I-kappaB KW - K1L KW - CP77 KW - Cowpox KW - PKR KW - Orthopoxvirus KW - Vaccine ER - TY - JOUR TI - Visualization and analysis of microstructure in three-dimensional discrete numerical models AU - Evans, T. M. AU - Chall, S. AU - Zhao, X. L. AU - Rhyne, T. M. T2 - Journal of Computing in Civil Engineering AB - A computer program has been developed to allow for the virtual slicing of irregularly spaced and irregularly shaped three-dimensional image data. The program was used to virtually slice three-dimensional particle assemblies from discrete element method (DEM) simulations, allowing, for the first time, direct comparison to two-dimensional slices extracted from solidified physical specimens. Based on slices obtained from the numerical specimens, it is possible to compare quantitatively numerical microstructure directly to its physical analog, which should lead to greatly improved calibrations of granular mechanics models, and could facilitate the calibration of models across all scales of interest rather than solely at specimen boundaries. Improved confidence in the ability of the DEM to realistically simulate the microstructure of granular assemblies (through improved multiscale calibration) should result in increased confidence in microstructural parameters measurable in numerical simulations but inaccessible in the laboratory. Algorithm development within the framework of the open-source Visualization Toolkit is described and performance of the algorithm is quantified for two platforms. Results from virtual slices of a test assembly with regular particle packing are verified against known analytical solutions. A slice of a more complex assembly comprised of nearly 40,000 spheres is quantified statistically and compared to an analogous slice from a physical specimen of uniform sand. DA - 2009/// PY - 2009/// DO - 10.1061/(ASCE)0887-3801(2009)23:5(277) VL - 23 IS - 5 SP - 277-287 ER -