Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.tumor suppression | tryptophan metabolism | inflammation control C yclooxygenase-2 (COX-2) is a rate-limiting enzyme in the production of diverse prostanoids with potent biological activities. It is involved in multiple physiological functions and triggers key pathological processes, such as tumorigenesis and inflammation (1, 2). COX-2 is constitutively overexpressed in a wide variety of human cancers and is enhanced by proinflammatory stimuli (3, 4). There is convincing evidence for a causal role of COX-2 in tumorigenesis. Inhibition of COX-2 activities was reported to control human colorectal cancer (5-8). COX-2 induces tumorigenesis by promoting important cellular functions including cell proliferation, migration, and resistance to apoptosis (9-11). The induced COX-2 expression by proinflammatory and mitogenic factors in normal cells is tightly controlled (12) whereas its overexpression in cancer cells is attributed to dysregulated transcription (13). The endogenous control mechanisms for COX-2 expression in normal cells and the mechanisms underlying the dysregulation in cancer cells are poorly understood. We previously identified in the conditioned medium of human fibroblasts small molecules (named cytoguardins) that suppress COX-2 expression induced by proinflammatory mediators (14). NMR analysis of a semipurified fraction revealed compounds with indole moieties (14). However, the exact chemical structures remain elusive. In this study, we elucidated the structure of cytoguardins by comparing the metabolomic profiles between normal and cancer cells. ResultsCytoguardins Inhibit Cancer Cell COX-2. To determine that fibroblast factors are capable of suppressing cancer cell COX-2 expression, we cocultured human Hs68 foreskin fibroblasts (HsFb) with A549 lung cancer cells in a Boyden chamber for 24 h. A549 cells were removed and treated with phorbol 12-myristate 13-acetate (PMA) for 4 h, and COX-2 proteins were analyzed. HsFb suppressed A549 ...

A dielectric elastomer is capable of giant electromechanical actuation but fails at breakdown due to instability under certain conditions with a small deformation. By applying a mechanical pre-stretch, one obtains a stabilized large actuation. In this paper, we measured the dielectric constant and critical voltage of a polyacrylic dielectric elastomer subjected to both equal and unequal biaxial stretch, and modelled its actuation by employing the Gent strain energy function with a microscopic view to characterize the nonlinear stiffening behaviour and the electrostrictive effect in the deformation. The mechanical pre-stretch contributes in several ways to the stabilization of dielectric elastomer, by eliminating the pull-in instability, by generating electrostriction, by improving the breakdown strength, as well as by reducing the membrane thickness which consequently lowers the voltages required for activation.

This paper proposes a free energy model to study the dynamic characteristics of a dielectric elastomer membrane undergoing in-plane deformation, subject to the combined loads of a mechanical press and an electric field. The natural frequency of the small-amplitude perturbation around the state of equilibrium is calculated with focus on the damping effects and the resonance phenomenon. The numerical results, such as the oscillation, phase diagrams and Poincaré maps, are presented to show the influence of the damping on the nonlinear dynamic characteristics of the dielectric elastomer. The numerical results indicate that pre-stresses, damping effects and applied voltages could tune the natural frequency and modify the dynamic behavior of the dielectric elastomer. There is a stability transition when taking the damping effect into account. The damping effect could cause the dynamic responses to constant vibration and decrease the amplitude. These conclusions may guide the exploration of high-performance dielectric elastomers under dynamic mechanical and electrical loads.

The dielectric constant of elastomeric dielectric material is an essential physical parameter, whose value may affect the electromechanical deformation of a dielectric elastomer actuator. Since the dielectric constant is influenced by several external factors as reported before, and no certain value has been confirmed to our knowledge, in the present paper, on the basis of systematical comparison of recent past literature, we conducted extensive works on the measurement of dielectric properties of VHB films, involving five influencing factors: prestretch (both equal and unequal biaxial), electrical frequency, electrode material, stress relaxation time and temperature. Experimental results directly show that the dielectric response changes according to these factors, based on which we investigate the significance of each factor, especially the interaction of two external conditions on the dielectric constant of deformable dielectric, by presenting a physical picture of the mechanism of polarization.

Articles you may be interested inPhysical interpretation of deformation evolvement with water content of ionic polymer-metal composite actuator Dynamic model of ion and water transport in ionic polymer-metal composites AIP Advances 1, 040702 (2011); 10.1063/1.3668286 An explicit physics-based model of ionic polymer-metal composite actuatorsWater-based ionic polymer-metal composites (IPMCs) exhibit complex deformation properties, especially with decreasing water content. Based on our experimental understanding, we developed a systemic actuation mechanism for IPMCs in which the water swelling was taken as the basic cause of deformation. We focused on Nafion-IPMC, and formulated a multiphysical model to describe the complicated deformation properties. The model emphasizes pressure-induced convection fluxes and the significance of the water distribution on deformation. It shows that there are three eigen stresses activated by the migration of ions and water, namely, osmotic pressure, electrostatic stress, and capillary pressure. The model also provides a convenient way of simultaneously handling the internal eigen stresses and the external mechanical load. In this paper, we used a fundamental model, which only considered the hydrostatic pressure in the multiphysical model, to analyze the general transport properties of cations and water by numerical methods. Three effects were investigated: (1) the inter-coupling effects between cations and water, which slow down cation migration and attenuate the back-diffusion of water; (2) the pressure effect, which rarely influences the electric field and the cation distribution, but greatly changes the profile of the water concentration and then the deformation behavior; and (3) the hydration effect, which has a significant impact on the distribution profiles of the cations and the electrical potential. In contrast to the findings of traditional studies, the water concentration displays an almost uniform gradient across the thickness in the bulk, and the cation concentration at the cathode is greatly reduced by the volume effect of the hydrated cations. V C 2013 AIP Publishing LLC.

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An analytical treatment is presented for the propagation of harmonic waves in magneto-electro-elastic multilayered plates, where the general anisotropic and three-phase coupled constitutive equations are used. The state-vector approach is employed to derive the propagator matrix which connects the field variables at the upper interface to those at the lower interface of each layer. The global propagator matrix is obtained by propagating the solution in each layer from the bottom of the layered plate to the top using the continuity conditions of the field variables across the interfaces. From the global propagator matrix, we finally obtain the dispersion relation by imposing the traction-free boundary condition on the top and bottom surfaces of the layered plate. Dispersion curves, modal shapes, and natural frequencies are presented for layered plates made of orthotropic elastic (graphite-epoxy), transversely isotropic PZT-5A, piezoelectric BaTiO 3 and magnetostrictive CoFe 2 O 4 materials. While the numerical results show clearly the influence of different stacking sequences as well as material properties on the field response, the general methodology presented in the paper could be useful to the analysis and design of layered composites made of smart piezoelectric and piezomagnetic materials.

For dielectric elastomers (DEs), the inherent viscoelasticity leads to a time-dependent deformation during actuation. To describe such a viscoelastic behavior, a constitutive model is developed by utilizing a combined Kelvin-Voigt-Maxwell (KVM) model. The established model captures both the initial jumping deformation and the following slow creeping. Subsequently, with an employment of VHB 4910 elastomer, experiments are performed to validate the viscoelastic KVM model. The results indicate a good agreement between the simulation and experimental data. Effect of the parameters in KVM model on the viscoelastic deformation of DEs is also investigated.