Abstract. Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration-and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. IntroductionDespite a declining trend worldwide, colorectal cancer still remains as the third most common cancer among men and the second in women (1,2). More than one million new cases of colorectal cancer are diagnosed every year (3). A wide variety of natural compounds derived from edible plants have been shown to prevent colon carcinogenesis (4). Carnosol, a diterpene present in rosemary (Rosmarinus officinalis), has been reported to prevent the development of intestinal tumors in APC (adenomatous polyposis coli) min+/+ mice (5) and to induce apoptosis in human colon cancer (COLO 205) cells (6). However, the molecular mechanisms underlying the chemopreventive and/or chemotherapeutic effects of carnosol in colon cancer are yet to be fully elucidated. We, therefore, attempted to investigate the effects of carnosol on human colon cancer (HCT116) cells and to elucidate its underlying mechanisms.One of the hallmarks of cancer is the evasion of tumor cells from apoptosis (7). Numerous naturally occurring polyphenols inhibit proliferation and induce apoptosis in various cancer cells (8). Apoptosis is induced by two cellular mechanisms: intrinsic (mitochondria-dependent) and extrinsic (death receptor-mediated) signaling (9). The intrinsic pathway of apoptosis involves the depolarization of mitochondrial membrane, release of cytochrome c, sequential activation of caspase-9, ...
The antioxidant activities of fermented red ginseng (FRG) were investigated in vitro and in vivo. The contents of total polyphenol and total flavonoid in FRG extracts were 17.01±2.00 μg/mg and 18.42±3.97 μg/mg, respectively. These extracts were capable of directly scavenging α, α-diphenyl-picrylhydrazyl free radicals. The antioxidative effects of the FRG extracts in streptozotocin (STZ)-induced diabetic rats were also investigated. The activities of plasma alanine transaminase, aspartate transaminase, and γ-glutamyltransferase were significantly decreased by extract administration as compared to an STZ control group. Hepatic glutathione content depleted by STZ treatment was significantly increased by treatment of the FRG extracts, but the elevation of lipid peroxide content induced by STZ was significantly decreased by the extracts. Activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase decreased after STZ-treatment were recovered by the treatment of the FRG extracts. These results indicate that FRG extracts have antioxidative effets in STZ-induced diabetic rats.
Fermented red ginseng (FRG) was prepared by inoculating 0.1% Lactobacillus fermentum NUC-C1 and fermenting them at 40°C for 12 hours. The ginsenoside contents of FRG were increased compared with those of red ginseng (RG). Moreover, the levels of the ginsenosides Rg2, Rg3, and Rh2 in FRG increased significantly. In an oral glucose tolerance test (OGTT), blood glucose levels were lower in animals fed with RG and FRG extracts than in normal controls. In particular, FRG extracts in OGTT were superior to RG extracts. The antidiabetic effects of FRG in streptozotocin (STZ)-induced diabetic rats were investigated. Rats were divided into four groups: normal control, diabetes mellitus (DM), FRG administered at 100 mg/kg, and FRG administered at 200 mg/kg groups. FRG extracts were orally administered to each treatment group for 3 weeks, and blood glucose, insulin, and lipid levels of each group were determined. Orally administered FRG extracts significantly reduced blood glucose levels and increased plasma insulin levels in diabetic rats. Additionally, the activities of disaccharidases, including sucrase, lactase, and maltase, were decreased significantly in the FRG groups. FRG groups also had reduced triglyceride and total cholesterol levels, compared with the DM group. These results suggest that FRG may have antidiabetic effects in STZ-induced diabetic rats.
Actinidia polygama Max. was subjected to supercritical fluid extraction (SFE), and the resulting ethanol extract of marc (SFEM) was subjected to sequential fractionation with various solvents. Each extract and fraction was assayed for anti-inflammatory effect. The ethyl acetate fraction (EtOAc) contained the highest level (70.8% inhibition) of anti-inflammatory activity. In order to identify the active constituents, the EtOAc fraction was further fractionated by silica gel and ODS column chromatography. By activity-guided fractionation, an active ceramide was identified as the anti-inflammatory component, and its structure was determined by NMR and MS analysis. The novel ceramide was named actinidiamide, and was found significantly to inhibit nitric oxide (NO) production (30.6% inhibition at 1 µg/mL) in lipopolysaccaride (LPS)-stimulated RAW 264.7 cells and β-hexosaminidase release (91.8% inhibition at 1 µg/mL) in IgE-sensitized RBL-2H3 cells. Thus the presence of actinidiamide conveys allergy and inflammation treatment ability to A. polygama.
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