Synergistic inhibition of cancer cell proliferation with a combination of δ-tocotrienol and ferulic acid.

Rice bran consists of many functional compounds and thus much attention has been focused on the health benefits of its components. Here, we investigated the synergistic inhibitory effects of its components, particularly δ-tocotrienol (δ-T3) and ferulic acid (FA), against the proliferation of an array of cancer cells, including DU-145 (prostate cancer), MCF-7 (breast cancer), and PANC-1 (pancreatic cancer) cells. The combination of δ-T3 and FA markedly reduced cell proliferation relative to δ-T3 alone, and FA had no effect when used alone. Although δ-T3 induced G1 arrest by up-regulating p21 in PANC-1 cells, more cells accumulated in G1 phase with the combination of δ-T3 and FA. This synergistic effect was attributed to an increase in the cellular concentration of δ-T3 by FA. Our results suggest that the combination of δ-T3 and FA may present a new strategy for cancer prevention and therapy.

Amadori-glycated phosphatidylethanolamine up-regulates telomerase activity in PANC-1 human pancreatic carcinoma cells.

Several lines of experimental data have highlighted a key role of Amadori-glycated phosphatidylethanolamine (Amadori-PE) in the development of diabetic complications. Recent epidemiological studies suggest that diabetes mellitus could be a risk factor for some cancers. A characteristic of cancer cells is their immortal phenotype, and the enzyme telomerase contributes to the infinite replicative potential of cancer cells. The purpose of this study was to obtain new information about the effect of Amadori-PE on the regulation of telomerase in PANC-1 human pancreatic carcinoma cells. Amadori-PE enhanced cellular telomerase in a time- and dose-dependent manner by up-regulating hTERT expression through induction of c-myc. These results provide experimental evidence for a novel role of Amadori-PE in linking diabetes and cancer.

The level of orally ingested vitamin C affected the expression of vitamin C transporters and vitamin C accumulation in the livers of ODS rats.

We investigated the effects of vitamin C administration on vitamin C-specific transporters in ODS/ShiJcl-od/od rat livers. The vitamin C-specific transporter levels increased in the livers of the rats not administered vitamin C and decreased in the livers of those administered vitamin C at 100 mg/d, indicating that these transporter levels can be influenced by the amount of vitamin C administered.

Dose of 3-methylcholanthrene enhances vitamin C accumulation and mRNA expression of its transporter in the liver of ODS rats and in HepG2 cells.

Polycyclic aromatic hydrocarbon (PAH) compounds including 3-methylcholanthrene induce harmful reactive intermediates and reactive oxygen species. This study reports the effect of 3-methylcholanthrene on the accumulation of vitamin C and the expression of vitamin C transporters. ODS rats were given l-ascorbic acid daily and intraperitoneal injections of 10 mg 3-methylcholanthrene in total. On day 10, vitamin C concentrations and the expression of vitamin C transporter in the tissues were measured. As a result, the levels of sodium-dependent vitamin C transporter (SVCTs) 1 and the l-ascorbic acid concentration in 3-methylcholanthrene-treated livers and hepatocytes have increased significantly. However, the content of vitamin C in the urine and TBARS in the liver have not changed. These results suggest that the administration of 3-methylcholanthrene elevates the requirement for vitamin C via (SVCTs) 1 due to xenobitics-metabolizing, such as the induction of cytochrome P450 family.

Glutathione reacts with glyoxal at the N-terminal.

The elevation of such dicarbonyl compounds as glyoxal and the depletion of GSH occur simultaneously in diabetic patients. Enabling a nonenzymatic glycation reaction with GSH and glyoxal is therefore proposed. However, the reaction mechanism for GSH and glyoxal has not been precisely defined. We isolated in this study the major products obtained by the reaction of GSH and glyoxal under physiological conditions, and clarified the chemical structure of these compounds by MS and NMR analyses for the first time. We identified the major product after 24 h as N-[3-(2,5-dioxomorpholin-3-yl)propanoyl]cysteinylglycine, and the one after 30 min as N-glycoloyl-gamma-glutamylcysteinylglycine (the intermediate of the former compound). Our results suggest that GSH reacted with glyoxal at the alpha-NH(2) group of the glutamate residue, but not at the SH group of the cysteine residue.

Influence of cigarette smoke on the L-ascorbic acid metabolism and the activities of drug-metabolizing enzyme in rats.

This study clarified the influence of cigarette smoke on the L-ascorbic acid (AsA) metabolism and the activities of drug-metabolizing enzyme in rats. The test rats (group T) were exposed to weak sidestream smoke from cigarettes for 2 h, everyday for 57 days. AsA concentration in the tissues and excreted amount of AsA in urine of group T tended to be higher than those of control group (group C). The plasma AsA concentration and the activities of aniline hydroxylase and 7-ethoxycoumarin O-deethylase of group T were significantly higher than those of group C. There was no significant difference in the activity of UDP glucuronosyltransferase or in the liver cytochrome P-450 content between these two groups.

Capsaicin inhibits the production of tumor necrosis factor alpha by LPS-stimulated murine macrophages, RAW 264.7: a PPARgamma ligand-like action as a novel mechanism.

Capsaicin, a major ingredient of hot pepper, is considered to exhibit anti-inflammatory properties. Our previous study demonstrated that capsaicin inhibited the production of pro-inflammatory mediators through NF-kappaB inactivation in LPS-stimulated macrophages. In order to further clarify the mechanism underlying the anti-inflammatory action of capsaicin, we investigated whether capsaicin alters PPARgamma activity, which regulates the production of the pro-inflammatory cytokine TNFalpha. Capsaicin significantly inhibited the production of TNFalpha by macrophages in a dose-dependent manner. Simultaneous exposure of the cells to capsaicin and PPARgamma agonist troglitazone or RXR agonist LG100268 resulted in stronger inhibition of TNFalpha production compared to the cells treated with either capsaicin, troglitazone, or LG100268 alone. Luciferase reporter assay revealed that capsaicin induced GAL4/PPARgamma chimera and full length PPARgamma (PPRE) transactivations in a dose-dependent manner. Furthermore, a specific PPARgamma antagonist T0070907 abrogated the inhibitory action of capsaicin on LPS-induced TNFalpha production by RAW 264.7 cells, indicating that capsaicin acts like a ligand for PPARgamma. Our data demonstrate for the first time that the anti-inflammatory action of capsaicin may be mediated by PPARgamma activation in LPS-stimulated RAW 264.7 cells.

Identification and sensory evaluation of volatile compounds in oxidized porcine liver.

Headspace solid phase microextraction (HS-SPME) was used to isolate the off-flavor volatile compounds, which are formed during the oxidation of porcine liver induced by iron. Poly(dimethylsiloxane)/divinylbenzene fiber was used in the HS-SPME. Changes in the volatile compounds of oxidized porcine liver and unsaturated fatty acids induced by iron were examined. Results showed that 1-octen-3-one (metallic), hexanol (weak metallic), 1-octen-3-ol (mushroomlike), (E)-2-nonenal (cardboardlike), and (E,E)-2,4-decadienal (fatty, oily) were the main contributors to the overall off-flavor of porcine liver. The results of the sensory evaluation revealed that oxidized arachidonic acid has a major impact on metallic and liverlike off-flavor and that when liverlike off-flavor is perceived, metallic is also included. Oxidized linolenic acid was the most important contributor to the objectionable fishy off-flavor. Oxidized porcine liver exhibited distinct metallic, liverlike, and weak fishy background notes. Liverlike flavor had a high correlation coefficient with odor characteristics such as metallic (0.839) and fishy (0.777). In this study, it was clearly observed that the stronger the metallic and fishy off-flavor the higher the perception of liverlike off-flavor.

The effect of cigarette smoke exposure and ascorbic acid intake on gene expression of antioxidant enzymes and other related enzymes in the livers and lungs of Shionogi rats with osteogenic disorders.

Cigarette smoking causes many chronic diseases but is a preventable risk factor in developing countries. However, it may be possible to relieve the smoke-induced damage by increasing the protective defense system. As vitamin C intake reduces smoking risk, it is recommended that smokers should take more vitamin C. However, the molecular mechanism of vitamin C intake on smokers has not been thoroughly investigated. We have found there to be suppression of smoke-induced cytochrome P-450 1A1 (CYP1A1) mRNA expression by high-dose ascorbic acid administration. Therefore, we surveyed other genes, the expressions of which were altered by the administration of high-dose ascorbic acid. As cigarette smoking increases oxidative stress, we investigated the effect on antioxidative enzyme expression. The osteogenic disorder Shionogi (ODS) rat, which lacks ascorbic acid synthesis enzyme, was administered either minimal amounts (4 mg/day, S4) or high-dose amounts (40 mg/day, S40) of ascorbic acid, and were exposed to cigarette smoke daily for 25 days. The effect on antioxidative enzymes mRNA expression in the liver was measured by competitive reverse transcription-polymerase chain reaction method (competitive RT-PCR). CuZn-superoxide dismutase (SOD), MnSOD, catalase and protein disulfide isomerase (PDI) were significantly decreased by high-dose ascorbic acid administration, and plasma glutathione peroxidase was also decreased, but not significantly. Cigarette smoke exposure slightly increased gene expression of PDI and catalase, but not significantly. The differently expressed 27 genes in the liver were found by differential display methods. From 27 genes, altered expression of plasma proteinase inhibitor, alpha-1-inhibitor III and CYP1A2 were confirmed by competitive RT-PCR. These results show that ascorbic acid intake influences gene expression of antioxidative enzymes, an ascorbic acid recycle enzyme, and xenobiotic metabolizing enzymes.

Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages.

Capsaicin, a major ingredient of hot pepper, was considered to exhibit an anti-inflammatory property. In order to clarify the signalling mechanism underlying the anti-inflammatory action of capsaicin, we investigated the effect of capsaicin on the production of inflammatory molecules in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The level of PGE2 was measured by EIA. The expression levels of COX-2, iNOS, IkB-a, and vanilloid receptor-1 (VR-1) were determined at the protein and mRNA levels. Significant inhibition of the production of LPS-induced PGE2 by capsaicin was observed in a dose-dependent manner. Capsaicin did not affect the COX-2 expression at either the protein or mRNA level, but inhibited the enzyme activity of COX-2 and the expression of the iNOS protein. Capsaicin completely blocked LPS-induced disappearance of IkB-a and therefore inactivated NF-kB. The inhibitory action of capsaicin on PGE2 production was not abolished by capsazepine, a specific antagonist to VR-1. A high expression level of the VR-1 like protein (VRL-1) was observed in peritoneal macrophages, while the expression of VR-1 was not detected. These findings suggest that the anti-inflammatory action of capsaicin may occur through a novel mechanism, not by a VR-1 receptor-mediated one. Both capsaicin and capsazepine may be a promising drug candidates for ameliorating inflammatory diseases and cancer.