BackgroundThe present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA), with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions.Methodology/Principal Findings In vitro studies showed that DHA strongly reduces the viability and DNA synthesis of MCF-7 human breast cancer cells in culture, and also promotes cell death via apoptosis. Mechanistically, accumulation of reactive oxygen species and activation of caspase 8 contribute critically to the induction of apoptotic cell death. Co-presence of antioxidants or selective inhibition or knockdown of caspase 8 each effectively abrogates the cytotoxic effect of DHA. Using athymic nude mice as an in vivo model, we found that feeding animals the 5% fish oil-supplemented diet for 6 weeks significantly reduces the growth of MCF-7 human breast cancer cells in vivo through inhibition of cancer cell proliferation as well as promotion of cell death. Using 3-nitrotyrosine as a parameter, we confirmed that the fish oil-supplemented diet significantly increases oxidative stress in tumor cells in vivo. Analysis of fatty acid content in plasma and tissues showed that feeding animals a 5% fish oil diet increases the levels of DHA and eicosapentaenoic acid in both normal and tumorous mammary tissues by 329% and 300%, respectively.Conclusions/SignificanceDHA can strongly induce apoptosis in human MCF-7 breast cancer cells both in vitro and in vivo. The induction of apoptosis in these cells is selectively mediated via caspase 8 activation. These observations call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of human breast cancer.

Previous investigations have demonstrated that green tea polyphenols and partially hydrolyzed guar gum as dietary fiber have antioxidative and hypolipidemic activity, respectively, supporting their reduction of risk factors in the course of diabetic nephropathy via a hypoglycemic effect and ameliorating the decline of renal function through their combined administration to rats with subtotal nephrectomy plus streptozotocin (STZ) injection. As a further study, we examined whether (Ϫ)-epigallocatechin 3-O-gallate (EGCg), the main polyphenolic compound, could ameliorate the development of diabetic nephropathy. Rats with subtotal nephrectomy plus STZ injection were orally administrated EGCg at doses of 25, 50, and 100 mg/kg body weight/day. After a 50-day administration period, EGCgtreated groups showed suppressed hyperglycemia, proteinuria, and lipid peroxidation, although there were only weak effects on the levels of serum creatinine and glycosylated protein. Furthermore, EGCg reduced renal advanced glycation endproduct accumulation and its related protein expression in the kidney cortex as well as associated pathological conditions. These results suggest that EGCg ameliorates glucose toxicity and renal injury, thus alleviating renal damage caused by abnormal glucose metabolism-associated oxidative stress involved in renal lesions of diabetic nephropathy.

Diabetes is a disorder of excessive urine excretion and chronic hyperglycemia, and glucose participates in diabetic complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Chronic hyperglycemia accelerates activation of the formation of advanced glycation end-products (AGEs), oxidative stress, the polyol pathway, and protein kinase C pathway. These metabolic factors are synergistically correlated with one another; therefore, an effective treatment with wide-spread effects continues to be required.Up to now, there have been many experiments focusing on the treatment of diabetes and its complications with traditional medicines including Chinese prescriptions because of their absence of toxic and/or side-effects. In our previous study, we reported that the Chinese prescriptions Hachimijio-gan and Keishi-bukuryo-gan had potential therapeutic effects against diabetic nephropathy, and had different functions in terms of their effects on metabolic disorders, especially on AGE formation in Hachimi-jio-gan and oxidative stress in Keishi-bukuryo-gan. [1][2][3][4] In addition, we also clarified that administration of dried Rehmanniae Radix (Rehmannia glutinosa LIBOSCH. var. purpurea MAKINO) extract, which is the main constituent of Hachimi-jio-gan, attenuates renal dysfunction in diabetic nephropathy mainly due to its suppression of oxidative stress 5) ; however, for the analysis of this prescription, further characterization of the other constituents is needed. According to the three-dimensional HPLC profile, as previously shown, 2,4) morroniside, loganin, and paeoniflorin were detected as the major compounds in Hachimi-jio-gan. Morroniside and loganin are the components of Corni Fructus (Cornus officinalis SIEB. et ZUCC.) and paeoniflorin is the component of Moutan Cortex (Paeonia suffruticosa ANDREWS) common in Keishi-bukuryogan. Therefore, in order to clarify the source of a particular action of Hachimi-jio-gan, we chose to evaluate the usefulness of one of the crude drugs, Corni Fructus.Corni Fructus has been used as a traditional medicine in Japan and China, and the components of this plant are iridoid total glycoside such as morroniside and loganin and also a few polyphenols such as cornusiin A, B, and C, monomeric and trimeric hydrolysable tannins, and so on.6,7) Recently, it has been reported that Corni Fructus has a plasma glucoselowering action in normal rats, along with anti-neoplastic and anti-microbial effects.8-10) Moreover, Vareed et al. 11) also reported that Corni Fructus has been used for improving liver and kidney functions, and iridoid total glycoside has the effect of preventing the overexpression of transforming growth factor (TGF)-b 1 and matrixes in glomeruli with a diabetic model. 12) However, the mechanisms of Corni Fructus against glucose-associated metabolic disorders in diabetes have yet to be explored. To determine whether Corni Fructus possesses the principal role in Hachimi-jio-gan, which has a strong effect on AGE formation in diabetes and/or diabetic nephropathy, we e...

BackgroundResearch has been conducted with regard to the development of methods for improving the pharmaceutical effect of ginseng by conversion of ginsenosides, which are the major active components of ginseng, via high temperature or high-pressure processing.MethodsThe present study sought to investigate the anticancer effect of heat-processed American ginseng (HAG) in human gastric cancer AGS cells with a focus on assessing the role of apoptosis as an important mechanistic element in its anticancer actions.Results and ConclusionHAG significantly reduced the cancer cell proliferation, and the contents of ginsenosides Rb1 and Re were markedly decreased, whereas the peaks of less-polar ginsenosides [20(S,R)-Rg3, Rk1, and Rg5] were newly detected. Based on the activity-guided fractionation of HAG, ginsenoside 20(S)-Rg3 played a key role in inducing apoptosis in human gastric cancer AGS cells, and it was generated mainly from ginsenoside Rb1. Ginsenoside 20(S)-Rg3 induced apoptosis through activation of caspase-3, caspase-8, and caspase-9, as well as regulation of Bcl-2 and Bax expression. Taken together, these findings suggest that heat-processing serves as an increase in the antitumor activity of American ginseng in AGS cells, and ginsenoside 20(S)-Rg3, the active component produced by heat-processing, induces the activation of caspase-3, caspase-8, and caspase-9, which contributes to the apoptotic cell death.

It was reported recently that resveratrol could sensitize a number of cancer cell lines to the anticancer actions of several other cancer drugs, including paclitaxel. In the present study, we further investigated whether resveratrol could sensitize human breast cancer cells to paclitaxelinduced cell death. Unexpectedly, we found that resveratrol strongly diminished the susceptibility of MDA-MB-435s, MDA-MB-231 and SKBR-3 cells to paclitaxel-induced cell death in culture, although this effect was not observed in MCF-7 cells. A similar observation was made in athymic nude mice using MDA-MB-435s cells as a representative model. Mechanistically, the modulating effect of resveratrol was partially attributable to its inhibition of paclitaxel-induced G 2 /M cell cycle arrest, together with an accumulation of cells in the S-phase. In addition, resveratrol could suppress paclitaxel-induced accumulation of reactive oxygen species and subsequently the inactivation of anti-apoptotic Bcl-2 family proteins. These observations suggest that the strategy of concomitant use of resveratrol with paclitaxel is detrimental in certain types of human cancers. Given the widespread use of resveratrol among cancer patients, this study calls for more preclinical and clinical testing of the potential benefits and harms of using resveratrol as a dietary adjuvant in cancer patients.

The root of ginseng is a famous functional food and a herbal medicine. Research into the development of a method for increasing the pharmaceutical effect of ginseng by conversion of ginsenosides, the major active components of ginseng, by high-temperature and high-pressure thermal processing has been conducted. However, changes in the structures of each ginsenoside by heat processing and their contributions to anticancer activity have not yet been fully elucidated. Here, we investigated whether anticancer activity of ginsenosides, such as Rb1, Rb2, Rc, Rd, and Re, was associated with changes in the structures of each ginsenoside by heat processing in human stomach cancer AGS cells. Upon heat processing at 120 °C, most peaks of ginsenosides Rb1, Rb2, Rc, and Rd disappeared and the contents of less-polar ginsenosides 20(S,R)-Rg3, Rk1, and Rg5 were newly detected. From the quantitative analysis of ginsenosides, the generated amounts of less-polar ginsenosides were the highest after heat processing of ginsenoside Rd. After heat processing, the diol-type ginsenosides Rb1, Rb2, Rc, and Rd gained significant antiproliferative activity. In particular, ginsenoside Rd induced the strongest cell death among the diol-type ginsenosides, whereas the triol-type gisenoside Re showed weak antiproliferative activity. Ginsenoside Rd-induced cell death was associated with caspase-dependent apoptosis. Taken together, these results demonstrate that deglycosylation of Rd contributes to improved anticancer activity of ginseng and provide new insight on the mechanism of increased anticancer effects of ginsenosides upon heat processing.

Diabetic nephropathy is one of the serious complications in patients with either type 1 or 2 diabetes mellitus but current treatments remain unsatisfactory. Results of clinical research studies demonstrate that Panax ginseng can help adjust blood pressure and reduce blood sugar and may be advantageous in the treatment of tuberculosis and kidney damage in people with diabetes. The heat-processing method to strengthen the efficacy of P. ginseng has been well-defined based on a long history of ethnopharmacological evidence. The protective effects of P. ginseng on pathological conditions and renal damage associated with diabetic nephropathy in the animal models were markedly improved by heat-processing. The concentrations of less-polar ginsenosides (20(S)-Rg3, 20(R)-Rg3, Rg5, and Rk1) and maltol in P. ginseng were significantly increased in a heat-processing temperature-dependent manner. Based on researches in animal models of diabetes, ginsenoside 20(S)-Rg3 and maltol were evaluated to have therapeutic potential against diabetic renal damage. These effects were achieved through the inhibition of inflammatory pathway activated by oxidative stress and advanced glycation endproducts. These findings indicate that ginsenoside 20(S)-Rg3 and maltol are important bioactive constituents of heat-processed ginseng in the control of pathological conditions associated with diabetic nephropathy.

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