Our previous studies have clearly shown that the angiogenic enzymes, matrix metalloproteinase (MMP) -2/9, are directly involved in human hepatic tumorigenesis and metastasis and suggest that the MMP-2/9 inhibitors, which have dual inhibitory activities on enzyme activity and transcription, represent the best candidates for achieving tumor regression. Many anti-cancer drugs have strong cellular cytotoxicity and side effects, indicating that strong anti-cancer drugs that have no or minimal cytotoxicity and side effects need to be developed. The specific aim of the present study was to develop powerful anti-cancer drugs with specific tumor regression and anti-metastatic potential having the dual inhibitory activities of specific MMP-2 and -9 enzyme activities and gene transcription at the molecular level. Caffeic acid (CA), a strong and selective MMP-9 activity and transcription inhibitor, was isolated from the plant Euonymus alatus and its derivative, caffeic acid phenethyl ester (CAPE), was synthesized. CA and CAPE selectively inhibited MMP-2 and -9 but not -1, -3, -7, or cathepsin K. Treatment of HepG2 cells with CA (100 microg/mL) and CAPE (5 microg/mL) suppressed phorbol 12-myristate 13-acetate (PMA) -induced MMP-9 expression by inhibiting the function of NF-kappaB, but not AP-1. We confirmed that CA and CAPE suppressed the growth of HepG2 tumor xenografts in nude mice in vivo. The subcutaneous and oral administrations of CA and CAPE significantly reduced the liver metastasis. These results confirm the therapeutic potential of the compounds and suggest that the anti-metastatic and anti-tumor effects of CA and CAPE are mediated through the selective suppression of MMP-9 enzyme activity and transcriptional down-regulation by the dual inhibition of NF-kappaB as well as MMP-9 catalytic activity.
This paper presents the development of an unmanned underwater vehicle (UUV) platform, especially the derivation of the vehicle's simulation model and its control method to overcome strong sea current. The platform is designed to have a flattened ellipsoidal exterior so as to minimize the hydrodynamic damping on the horizontal plane. Four horizontal thrusters with the identical specifications are symmetrically mounted on the horizontal plane, and each of them has the same thrust dynamics in both forward and reverse directions. In addition, there are three vertical thrusters used to handle the vehicle's roll, pitch and heave motions. Control strategy proposed in this paper to overcome strong current is that: maximizing the vectored horizontal thrust force against the sea current without or with the least of the vehicle's rotation on the horizontal plane. For the vehicle model, due to it being symmetric in all of three axes, the vehicle dynamics can be simplified and all of hydrodynamic coefficients are calculated through both of theoretical and empirically-derived formulas. Numerical simulations and experimental studies in both of the water tank and the circulating water channel are carried out to demonstrate the vehicle's capability of overcoming strong current.
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