This work aims to evaluate the encapsulation of a flavonoid-rich Allium cepa L. var. agrogatum Don extract (ACADFE) in ?-cyclodextrin (?-CD) by analyzing the percutaneous penetration in vitro and in vivo, leading to an explanation of the physical mechanism during transdermal transport. The optimal inclusion compound containing ACADFE in ?-CD was prepared in a 1:3 molar ratio. The physicochemical characterization of the inclusion complex was performed using IR, UV-vis, simultaneous thermogravimetry (TG), and differential thermal analysis (DTA) studies. It was concluded that the inclusion complex could improve the aqueous solubility and bioavailability of ACADFE. The inclusion complex exhibited significant enhancement of percutaneous absorption both in vitro and in vivo. The dorsal skins of hairless mice were photographed using a confocal scanning laser microscope. Confocal scanning laser microscopy shows that penetration of the ACADFE-?-CD inclusion complex proceeds across skin via both follicular and transcellular routes.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death in various types of cancer cells but has little or no effects on normal cells. Unfortunately, not all cancer cells respond to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. Here, we reported that 6-(4-N,N-dimethylaminophenyltelluro)-6-deoxy-?-cyclodextrin (DTCD), a cyclodextrin-derived diorganyl telluride which has been identified as an excellent inhibitor of thioredoxin reductase (TrxR), could sensitize TRAIL resistant human ovarian cancer cells to undergo apoptosis. In vitro, DTCD enhanced TRAIL-induced cytotoxicity in human ovarian cancer cells through up-regulation of DR5. Luciferase analysis and CHIP assays showed that DTCD increased DR5 promoter activity via Sp1 activation. Additionally, DTCD stimulated extracellular signal-regulated kinase (ERK) activation, while the ERK inhibitor PD98059 blocked DTCD-induced DR5 expression and suppressed binding of Sp1 to the DR5 promoter. We further demonstrated that DTCD could induce the release of ASK1 from its complex with Trx-1, and recovered its kinase activity. Meanwhile, suppression of ASK1 by RNA interference led to decreased ERK phosphorylation induced by DTCD. The underlying mechanisms reveal that Trx-1 is heavily oxidized in response to DTCD treatment, in accordance with the fact that DTCD could inhibit the activity of TrxR that reduces oxidized Trx-1. Moreover, using an A2780 xenograft model, DTCD plus TRAIL significantly inhibited the growth of tumor in vivo. Our results suggest that Trx/TrxR system inhibition may play a critical role in apoptosis by combined treatment with DTCD and TRAIL, and raise the possibility that their combination may be a promising strategy for ovarian carcinoma treatment.
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity via membrane receptors on cancer cells without deleterious side-effects for normal tissue. Unfortunately, like many other cancer types, breast cancer cells develop resistance to TRAIL; therefore, TRAIL-sensitising agents are currently being explored. In this study, we report that seleno-cyclodextrin (2-selenium-bridged ?-cyclodextrin, 2-SeCD), a seleno-organic compound with glutathione peroxidase (GPx)-mimetic activity, sensitises TRAIL-resistant human breast cancer cells and xenograft tumours to undergo apoptosis. In vitro, 2-SeCD reduces the viability of cancer cells by inducing cell cycle arrest in G(2)/M phase. Furthermore, 2-SeCD efficiently sensitises MDA-MB-468 and T47D cells but not untransformed human mammary epithelial cells to TRAIL-mediated apoptosis, as evidenced by enhanced caspase activity and poly-ADP-ribose-polymerase (PARP) cleavage. From a mechanistic standpoint, we show that 2-SeCD induces the expression of TRAIL receptors DR5 but not DR4 on both mRNA and protein levels in a dose-dependent manner. Moreover, 2-SeCD treatment also suppresses TRAIL-induced nuclear factor-?B (NF-?B) pro-survival pathways by preventing cytosolic I?B? degradation and p65 nuclear translocation. Consequently, the combined administration suppresses anti-apoptotic proteins transcriptionally regulated by NF-?B. In vivo, 2-SeCD and TRAIL are well tolerated in mice, and their combination significantly inhibits the growth of MDA-MB-468 xenografts and promotes apoptosis. Up-regulation of DR5 and down-regulation of NF-?B by dual treatment were also observed in tumour tissues. Overall, 2-SeCD sensitises resistant breast cancer cells to TRAIL-based apoptosis in vitro and in vivo. These findings provide strong evidence for the therapeutic potential of this combination against breast cancers.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumor activity via membrane receptors on cancer cells without deleterious side effects for normal tissue. Unfortunately, breast cancer cells, as many other cancer types, develop resistance to TRAIL; therefore, TRAIL sensitizing agents are currently being explored. 2-Tellurium-bridged ?-cyclodextrin (2-TeCD) is a synthetic organotellurium compound, with both glutathione peroxidase-like catalytic ability and thioredoxin reductase inhibitor activity. In the present study, we reported that 2-TeCD sensitized TRAIL-resistant human breast cancer cells and xenograft tumors to undergo apoptosis. In vitro, 2-TeCD efficiently sensitized MDA-MB-468 and T47D cells, but not untransformed human mammary epithelial cells, to TRAIL-mediated apoptosis, as evidenced by enhanced caspase activity and poly (adenosine diphosphate-ribose) polymerase cleavage. From a mechanistic standpoint, we showed that 2-TeCD treatment of breast cancer cells significantly upregulated the messenger RNA and protein levels of TRAIL receptor, death receptor (DR) 5, in a transcription factor Sp1-dependent manner. 2-TeCD treatment also suppressed TRAIL-induced nuclear factor-?B (NF-?B) prosurvival pathways by preventing cytosolic I?B? degradation, as well as p65 nuclear translocation. Consequently, the combined administration suppressed anti-apoptotic molecules that are transcriptionally regulated by NF-?B. In vivo, 2-TeCD and TRAIL were well tolerated in mice and their combination significantly inhibited growth of MDA-MB-468 xenografts and promoted apoptosis. Upregulation of DR5 and downregulation of NF-?B by the dual treatment were also observed in tumor tissues. Overall, 2-TeCD sensitizes resistant breast cancer cells to TRAIL-based apoptosis in vitro and in vivo. These findings provide strong evidence for the therapeutic potential of this combination against breast cancers.
A practical and nontarnishing method for the determination of trace nickel (Ni) in hydrogenated cottonseed oil by inductively coupled plasma/mass spectrometry (ICP/MS) was developed. In order to avoid tarnishing in the pretreatment of samples, the technology of pressurized PTFE vessel acid digestion was applied. The temperature and acid content in the digestion were optimized. The results showed that hydrogenated cottonseed oil could be digested completely by the proposed method. Compared with the U.S. Pharmacopeia 28 and British Pharmacopoeia 2003 methods, the developed method avoided the risk of using platinum and the tarnish from silica crucibles. In addition, the analytical cycle of the test solution was shortened by the use of ICP/MS instead of graphite furnace atomic absorption spectrophotometry.
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