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.

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