Anti-Inflammatory Effects of 3-(4'-Hydroxyl-3',5'-Dimethoxyphenyl)Propionic Acid, an Active Component of Korean Cabbage Kimchi, in Lipopolysaccharide-Stimulated BV2 Microglia.

We investigated the protective ability of 3-(4'-hydroxyl-3',5'-dimethoxyphenyl)propionic acid (HDMPPA), an active principle in Korean cabbage kimchi, against the production of proinflammatory mediators and cytokines, and the mechanisms involved in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. HDMPPA significantly suppressed the production of nitric oxide (NO) and prostaglandin E2, along with the expression of inducible NO synthase and cyclooxygenase-2 in LPS-stimulated BV2 cells, at concentrations with no cytotoxicity. HDMPPA also attenuated the LPS-induced expression and secretion of proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-1ß. Furthermore, HDMPPA inhibited LPS-induced nuclear factor-κB (NF-κB) activation, which was associated with the abrogation of IκB-α degradation and phosphorylation, and subsequent decreases in NF-κB p65 levels. Moreover, the phosphorylation of mitogen-activated protein kinases (MAPKs) and Akt, a downstream molecule of phosphatidylinositol-3-kinase (PI3K), in LPS-stimulated BV2 cells was suppressed markedly by HDMPPA. This effect was associated with a significant reduction in the formation of intracellular reactive oxygen species. The findings in this study suggest that HDMPPA may exert anti-inflammatory responses by suppressing LPS-induced expression of proinflammatory mediators and cytokines through blockage of NF-κB, MAPKs, and PI3K/Akt signaling pathways and oxidative stress in microglia.

Resveratrol analogue HS-1793 induces the modulation of tumor-derived T cells.

Recent advances in the understanding of the mechanisms responsible for tumor progression suggest the possibility to control cancer growth, not only through chemotherapy-induced cancer cell destruction, but also by stimulating anticancer immunity. However, immune tolerance against tumor antigens disturbs diverse forms of immunotherapy. One of the most potent and well-studied tumor-induced immunosuppressive phenotypes found in the tumor microenvironment is the regulatory subpopulation cells (CD4(+)CD25(+)FoxP3(+) Treg cells). Among the great number of natural agents derived from plants and potentially useful for application in the complementary therapy of cancer, resveratrol is gaining attention for its immunomodulating properties in breast cancer, since the ineffectiveness of numerous immunotherapy strategies may be related, in part, to their negative effects on Treg cells. The present study was undertaken to examine whether HS-1793, a synthetic resveratrol analogue free from the restriction of the metabolic instability and high dose requirement of resveratrol, shows a direct effect on immune responses by enhancing lymphocyte proliferation or an immunomodulatory effect by inducing changes in the Treg cell population in FM3A breast tumor-bearing mice. Although HS-1793 had no direct immunostimulatory effect, it dose-dependently decreased IL-2 secretion and increased IL-4 secretion of concanavalin A-stimulated lymphocytes from tumor-bearing mice, which suggest that HS-1793 may induce changes in the subpopulations of tumor-derived T lymphocytes. The CD4(+)CD25(+) cell population from tumor-bearing mice decreased after HS-1793 treatment in a dose-dependent manner, while the CD4(+) T cell population remained unchanged. FoxP3(+)-expressing cells among the CD4(+)CD25(+) population showed a similar pattern. In contrast, the CD8(+) T cell population as well as the interferon (IFN)-γ-expressing CD8(+) T cell population and IFN-γ secretion of splenocytes from tumor-bearing mice were significantly upregulated by HS-1793 treatment. These results suggest that HS-1793 induces the modulation of tumor-derived T lymphocytes, particulary having a suppressive effect on the Treg cell population, likely contributing to enhanced tumor-specific cytotoxic T lymphocyte responses and CD4(+) T cells involving antitumor immunity. Therefore, HS-1793 may serve as a promising adjuvant therapeutic reagent in breast cancer immunotherapy.

Efficacy on anaplastic thyroid carcinoma of valproic acid alone or in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative, or lactacystin.

The present study investigated the mechanism underlying the antitumor activity of the histone deacetylases inhibitor valproic acid (VPA), alone and in combination with doxorubicin, a synthetic chenodeoxycholic acid derivative (HS-1200), or the proteasome inhibitor lactacystin on cultured anaplastic thyroid carcinoma KAT-18 cells. Cell viability was evaluated by trypan-blue exclusion. Western blotting determined caspase and histone deacetylase activities and expression of poly(ADP)-ribose polymerase. Induction of apoptosis was identified by Hoechst staining, DNA electrophoresis, DNA hypoploidy and cell cycle phase analysis, and measurement of mitochondrial membrane potential. Subcellular translocation of apoptosis inducing factor and caspase-activated DNase after treatment was determined by confocal microscopy following immunofluorescent staining. VPA treatment increased apoptotic death of KAT-18 cells. VPA treatment was also associated with degradation of procaspase-3, procaspase-7, and poly(ADP)-ribose polymerase; induction of histone hyperacetylation; condensation of peripheral chromatin; decreased mitochondrial membrane potential and DNA content; and decreased translocation of apoptosis inducing factor and caspase-activated DNase. VPA in combination with doxorubicin, HS-1200, or lactacystin, applied at the highest concentrations that did not induce KAT-18 cell death, efficiently induced apoptosis in KAT-18 cells. The results suggest VPA combination therapy may represent an alternative therapeutic strategy for anaplastic thyroid carcinoma.