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Abstract. Thiazolidinediones, peroxisome proliferators-activated receptor gamma (PPARγ) ligands, have been recognized as a potential therapeutic agents for the treatment of pathological neovascularization. In the present study, we examined the molecular mechanism by which troglitazone (TROG), a PPARγ agonist, exerts its inhibitory action in vascular endothelial growth factor (VEGF)-induced angiogenesis signaling. In an in vitro angiogenesis model using human umbilical vein endothelial cells, TROG (20 μM) significantly suppressed VEGF-induced cell proliferation and invasion of the cells into the Matrigel basement membrane, which was not reversed by treatment with PPAR antagonists, GW9662 (10 μM) and bisphenol A diglycidyl ether (10 μM). TROG also blocked VEGF-induced reactive oxygen species (ROS) production and its downstream extracellular signal-regulated kinase (ERK) phosphorylation, and this inhibitory effect was not reversed by GW9662 (10 μM). The antiangiogenic activity of TROG correlated with suppression of VEGF-induced matrix metalloproteinase (MMP)-2 and membrane type 1 (MT1)-MMP expression. In addition, the effects of TROG on VEGF-induced MMP-2 and MT1-MMP expression were comparable to those of the NADPH oxidase inhibitor diphenylene iodium (10 μM) and ERK inhibitor PD98056 (10 μM). Furthermore, in an in vivo angiogenesis system using a chick chorioallantoic membrane model, TROG dose-dependently inhibited VEGF-induced angiogenesis, which was similar to the inhibitory effect of N-acetylcysteine on VEGF-induced angiogenesis. The results suggest that the inhibitory effects of TROG on VEGFinduced angiogenesis were mediated through the suppression of VEGF-induced ROS production and ERK phosphorylation.

ABSTRA ABSTRA ABSTRA ABSTRA ABSTRACT CT CT CT CT: : : : : B B B B Bacillus cir acillus cir acillus cir acillus cir acillus circulans culans culans culans culans, , , , , B B B B Br r r r revibacillus br evibacillus br evibacillus br evibacillus br evibacillus brevis evis evis evis evis, , , , , B. . ster ster ster ster sterothermophillus othermophillus othermophillus othermophillus othermophillus were isolated and identified from chungkukjangs (Korean traditional soybean paste fermented for a few day).were isolated and identified from chungkukjangs (Korean traditional soybean paste fermented for a few day). were isolated and identified from chungkukjangs (Korean traditional soybean paste fermented for a few day). were isolated and identified from chungkukjangs (Korean traditional soybean paste fermented for a few day). were isolated and identified from chungkukjangs (Korean traditional soybean paste fermented for a few day). Chungkukjang was prepared on a laboratory scale with soybeans and the isolated strains. Characteristics of the Chungkukjang was prepared on a laboratory scale with soybeans and the isolated strains. Characteristics of the Chungkukjang was prepared on a laboratory scale with soybeans and the isolated strains. Characteristics of the Chungkukjang was prepared on a laboratory scale with soybeans and the isolated strains. Characteristics of the Chungkukjang was prepared on a laboratory scale with soybeans and the isolated strains. Characteristics of the chungkukjangs including slime material content, free amino acid content, sensory qualities, and antimutagenicity chungkukjangs including slime material content, free amino acid content, sensory qualities, and antimutagenicity chungkukjangs including slime material content, free amino acid content, sensory qualities, and antimutagenicity chungkukjangs including slime material content, free amino acid content, sensory qualities, and antimutagenicity chungkukjangs including slime material content, free amino acid content, sensory qualities, and antimutagenicity were determined. The content of slime material, which is an important indicator of the quality of chungkukjang, was were determined. The content of slime material, which is an important indicator of the quality of chungkukjang, was were determined. The content of slime material, which is an important indicator of the quality of chungkukjang, was were determined. The content of slime material, which is an important indicator of the quality of chungkukjang, was were determined. The content of slime material, which is an important indicator of the quality of chungkukjang, was highest in highest in highest in highest in highest in B. licheniformis B. licheniformis B. licheniformis B. licheniformis B. licheniformis-inoculated chungkukjang, and lowest in -inoculated chungkukjang, and lowest in -inoculated chungkukjang, and lowest in -inoculated chungkukjang, and lowest in -inoculated chungkukjang, and lowest in B. sterothermophillus B. sterothermophillus B. sterothermophillus B. sterothermophillus B....

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Increased interleukin (IL)-8 plays an important role not only in activation and recruitment of neutrophils but also in inducing exaggerated angiogenesis at the inflamed site. In the present study, we investigated the fact that clotrimazole (CLT) inhibits intestinal inflammation, and the inhibitory action is mediated through suppression of IL-8 expression. In the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model, CLT dose-dependently protected from the TNBS-induced weight loss, colon ulceration, and myeloperoxidase activity increase. In the lesion site, CLT also suppressed the TNBS-induced angiogenesis, IL-8 expression, and nuclear factor (NF)-B activation. In a cellular model of colitis using tumor necrosis factor (TNF)-␣-stimulated HT29 colon epithelial cells, treatment with CLT significantly suppressed TNF-␣-mediated IL-8 induction and NF-B transcriptional activity revealed by a luciferase reporter gene assay. Furthermore, cotreatment with CLT and pyrrolidine dithiocarbamate, a NF-B inhibitor, synergistically reduced the NF-B transcriptional activity as well as IL-8 expression. In an in vitro angiogenesis assay, CLT suppressed IL-8-induced proliferation, tube formation, and invasion of human umbilical vein endothelial cells. The in vivo angiogenesis assay using chick chorioallantoic membrane also showed that CLT significantly inhibited the IL-8-induced formation of new blood vessels. Taken together, these results suggest that CLT may prevent the progression of intestinal inflammation by not only down-regulating IL-8 expression but also inhibiting the action of IL-8 in both colon epithelial and vascular endothelial cells during pathogenesis of intestinal inflammation.