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Abstract: Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we show that rosiglitazone sensitizes human renal cancer cells to TRAIL-mediated apoptosis, but not normal human mesangial cells. Furthermore, because rosiglitazone-enhanced TRAIL-mediated apoptosis is induced in various types of cancer cells but is not interrupted by Bcl-2 overexpression, this combinatory treatment may provide an attractive strategy for cancer treatment. We found that treatment with rosiglitazone significantly induces DR5 expression at both its mRNA and its protein levels, accompanying the generation of reactive oxygen species (ROS). Both treatment with DR5/Fc chimeric protein and silencing of DR5 expression using small interfering RNAs attenuated rosiglitazone plus TRAIL-induced apoptosis, showing the critical role of DR5 in this cell death. Pretreatment with GSH significantly inhibited rosiglitazone-induced DR5 up-regulation and the cell death induced by the combined treatment with rosiglitazone and TRAIL, suggesting that ROS mediate rosiglitazone-induced DR5 up-regulation, contributing to TRAIL-mediated apoptosis. However, both DR5 up-regulation and sensitization of TRAIL-mediated apoptosis induced by rosiglitazone are likely PPARγ-independent, because a dominant-negative mutant of PPARγ and a potent PPARγ inhibitor, GW9662, failed to block DR5 induction and apoptosis. Interestingly, we also found that rosiglitazone treatment induced down-regulation of cellular FLICE-inhibitory protein (c-FLIPs), and ectopic expression of c-FLIPs attenuated rosiglitazone plus TRAIL-mediated apoptosis, demonstrating the involvement of c-FLIPs in this apoptosis. Taken together, the results of this study demonstrate that rosiglitazone enhances TRAIL-induced apoptosis in various cancer cells by ROS-mediated DR5 up-regulation and down-regulation of c-FLIPs. [Copyright &y& Elsevier]

Abstract Ethnopharmacological relevance Astragali Radix (AR), the root of Astragalus mongholicus Bunge, is widely applied in traditional medicine to promote skin health and tissue regeneration. Aim of the study This study investigated the effects of AR and its active compound, formononetin (FMT), on skin barrier defects in keratinocytes exposed to diesel particulate matter (PM). Materials and methods HaCaT cells and three-dimensional (3D) human skin reconstructed model were pre-treated with AR (50, 100 μg/ml) and FMT (30, 50 μM), then treated with PM (200 μg/ml). Results AR and FMT significantly enhanced the expression of Keratin (KRT) 16 in PM stimulated HaCaT cells. PM increased p53 and Bax expression as well as the subsequent cleavage of caspase 3 and PARP in HaCaT cells, while this was inhibited by AR and FMT treatment. In vitro studies using the PM stimulated 3D human skin reconstructed model revealed that AR and FMT increased the expression of KRT 16 and KRT 17. Histological examination of the 3D human skin reconstructed model showed that AR and FMT up-regulated the expression of Ki67, but down-regulated the expression of cleaved caspase 3. Both AR and FMT significantly inhibited phosphorylation of ERK, but not JNK and p38 MAPK in PM stimulated HaCaT cells. Conclusions These results suggest that AR and FMT act as anti-pollution agents and alleviate PM induced skin barrier defects through regulation of apoptosis and proliferation in keratinocytes. Graphical abstract fx1 [ABSTRACT FROM AUTHOR]

Abstract: Quercetin, a natural product derived from grapes, has been shown to prevent carcinogenesis in murine models. We report here that quercetin induces anti-proliferation and arrests G2/M phase in U937 cells. The G2/M phase accumulation was accompanied by an increase in the level of the cyclin B. In contrast, the level of the cyclin D, cyclin E, E2F1, and E2F2 was marked decreased in quercetin-treated U937 cells. Removal of quercetin from the culture medium stimulates U937 cells to synchronously re-enter the cell cycle, decrease expression level of cyclin B, and increased the expression level of cyclin D and cyclin E. These data demonstrate that quercetin causes reversible G2/M phase arrest, which was related with dramatic changes in the level of cyclin B, cyclin D, and cyclin E. Quercetin-induced down-regulation of cyclin D and cyclin E was associated with suppression of transcriptional levels but not protein stability. In addition, quercetin-treated U937 cells showed DNA fragmentation, increased sub-G1 population, and generated a 60kDa cleavage product of PLC-γ1 in a dose-dependent manner, which were significantly inhibited by z-VAD-fmk. These data clearly indicate that quercetin-induced apoptosis is associated with caspase activation. In summary, the growth inhibition of the quercetin is highly related to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis in human promonocytic U937 cells. [Copyright &y& Elsevier]