Biofactors - Volume 12, issue 1-4

Authors: Marie-H\'el\`ene Siess, | Anne-Marie Le Bon, | Marie-Chantal Canivenc-Lavier, | Marc Suschetet,

Article Type: Research Article

Abstract: Flavonoids, widespread in edible plants, have been studied extensively for their anticarcinogenic properties. However, only few studies have been done with these constituents being administered by the dietary route. In our research, the effects of feeding rats with flavone, flavanone, tangeretin, and quercetin were investigated on two steps of aflatoxin B1 (AFB_1 )-induced hepatocarcinogenesis (initiation and promotion). Nonpolar flavonoids such as flavone, flavanone and tangeretin administered through the initiation period, decreased …the number of \gamma -glutamyl transpeptidase-preneoplastic foci. In the same conditions of administration, quercetin, a polyhydroxylated flavonoid, showed no protective effect. Moreover, feeding rats with flavanone during the phenobarbital-induced promotion step significantly reduced the areas of placental glutathione S-transferase preneoplastic foci. Quercetin, flavone, and tangeretin, administered in the same conditions, caused no significant effect. Therefore flavanone act as an anti-initiator as well as an anti-promotor. Several mechanisms were involved in the anti-initiating effects of flavone, flavanone, and tangeretin: enhancement of enzymes involved in the detoxication of AFB_1 (glutathione S-transferase, UDP-glucuronyl transferase), increase of the formation of AFB_1 -glutathione conjugates and inhibition of the binding of AFB_1 to DNA. Although the relevance of these data to the human situation remains to be demonstrated, they confirm that several flavonoids administered by the dietary route possess promising chemoprotective effects. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 193-199, 2000

Authors: Hitoshi Ashida,

Article Type: Research Article

Abstract: Dioxin type chemicals such as 2,3,7,8-tetrachlorodibenzo-p -dioxin (TCDD) cause a variety of toxicity. Most of the toxicity of TCDD has been attributed to a mechanism by which TCDD is bound to aryl hydrocarbon receptor (AhR) and transforms the receptor. Thus, suppression of the AhR transformation by food factors can suppress the dioxin toxicity. In this study, flavonoids at various concentrations were treated to a rat cytosolic fraction containing AhR before adding …1 nM TCDD. The transformed AhR was detected by an electrophoretic mobility shift assay with a DNA oligonucleotide consensus to dioxin response element. As the results, flavones and flavonols at dietary levels act as the antagonists for AhR and suppress the transformation. The antagonistic IC_{50} values were in a range between 0.14 and 10 \mu M, which are close to the physiological levels in human. These results suggest that a plant-based diet can prevent the dioxin toxicity. Show more

Keywords: dioxin, Ah receptor, flavonoid, hepatocytes

Citation: BioFactors, vol. 12, no. 1-4, pp. 201-206, 2000

Authors: S. Barnes, | B. Boersma, | R. Patel, | M. Kirk, | V.M. Darley-Usmar, | H. Kim, | J. Xu,

Article Type: Research Article

Abstract: Soy and its isoflavones are associated with a reduced risk of chronic disease. The mechanisms of action of isoflavones include their roles as weak estrogens, inhibitors of tyrosine kinase-dependent signal transduction processes and as cellular antioxidants. Although estrogen receptor beta binds genistein with an affinity close to that of 17\beta -estradiol, it remains to be determined whether it is a mediator of genistein's activity in vivo. Genistein's inhibition of protein tyrosine …kinases is not limited to direct effect on these kinases, but may result from alteration in kinase expression. Genistein is not a particularly good scavanger of cellular oxidants; however, it reacts vigorously with the prooxidant hypochlorous acid, produced by neutrophils as part of the inflammatory response. The chlorinated isoflavones may have altered biochemical and biological effects compared to their parent compounds and may provide increased protection against inflammatory disease. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 209-215, 2000

Authors: Mariko Uehara, | Yusuke Arai, | Shaw Watanabe, | Herman Adlercreutz,

Article Type: Research Article

Abstract: Time-resolved fluoroimmunoassays (TR-FIA), with europium labeled phytoestrogens as tracers, were developed for the quantitative measurement of genistein, daidzein and enterolactone in plasma and urine for the purpose of screening large populations and studies on possible correlation between the values in biological fluids and the risk of western diseases. The mean values of the three phytoestrogens in plasma as determined by TR-FIA were similar to those obtained by gas chromatography-mass spectrometry (GC-MS). The urinary excretion …levels of total individual phytoestrogens were higher than those obtained by GC-MS, with the exception of the daidzein values. However, comparing the assay results obtained by the present method and those obtained by GC-MS, a strong correlation was evident (r=0.87-0.99, p<0.001 ). We measured plasma levels of genistein, daidzein and enterolactone in 111 healthy Japanese women. The mean and median levels of genistein were 406.8 and 306.3 nmol/l, respectively, and those of daidzein were 118.4 and 76.8 nmol/l, respectively. These levels are higher than those reported for Americans and Western Europeans. Isoflavone intake as calculated from dietary records (genistein: mean, 86.5 \mu mol/day and daidzein: mean, 57.4 \mu mol/day) was correlated with the plasma concentrations observed (genistein: r=0.287, p<0.01 and daidzein: r=0.313, p<0.01 ). Plasma enterolactone levels were low in Japanese women (mean, about 10 nmol/l). The levels of urinary excretions of genistein, daidzein were also measured and it was found that, in the majority, the levels ranged between 5--25 and 5--50 \mu mol/24 h, respectively. In contrast, healthy Finnish women showed very low values of isoflavones (below 10~nmol/l in plasma (n=87 ) and below 0.6 \mu mol/24~h in urine (n=126 ) for both compounds) and high levels of enterolactone in both plasma and urine (plasma: mean, 25~nmol/l and urine: majority range, 1--7 \mu mol/24 h). Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 217-225, 2000

Authors: Shaw Watanabe, | Ryota Haba, | Kayoko Terashima, | Yusuke Arai, | Tsutomu Miura, | Hiroshige Chiba, | Kiyoharu Takamatsu,

Article Type: Research Article

Abstract: Antioxidative activity of isoflavones has not been shown in humans. Newly-developed isoflavone-rich soya hypocotyl tea contains about 12 mg isoflavones per liter. 15 tea drinkers and 23 control young female students were randomly selected from volunteers, and underwent physical examination, blood chemistry and urinary analysis before and after one month of tea drinking. A three-day dietary record was taken before each physical examination. The tea drinkers showed a lower level of phosphatidylcholine …hydroperoxide (PCOOH) and phosphatidyl-ethanolamine hydroperoxide (PEOOH) in the red blood cells and a significant reduction of 8-hydroxydeoxyguanine (^8 ohdG) in the urine compared to the controls. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 227-232, 2000

Authors: Shaw Watanabe, | Kayo Terashima, | Yuho Sato, | Sinsuke Arai, | Akira Eboshida,

Article Type: Research Article

Abstract: Effects of the isoflavone supplement on hormonal states in young premenopausal women were studied by cross-over study design. Administration of 20 mg or 40 mg isoflavones (IF) by tablets, of which 1 g contained 43.5 mg daidzein, 6.0 mg genistein, 24.0 mg glycitein, to 40 young female students for one month caused a prolonged menstruation in 60% in 20% irregular. Larger dose tended to elongate more, but 17beta-estradiol levels in both follicular and luteal phages were …not different between 20 mg and 40 mg isoflavone intake. Equor excreters tended to show low plasma progesteron level in the luteal phase. Detailed hormonal analysis on 3 of students by a cross over study design showed decreased level of 17beta-estradiol throughout the menstruation cycle. SHBG significantly increased about 10% androstendione, and testosterone showed different responses according to the follicular or luteal phase. T3 and T4 increased as a result of isoflavone tablet administration in the follicular phase, but it decreased in the luteal phase. These changes suggest that isoflavones influence not only estrogen receptor-related functions but the hypothalamo-hypophysis-gonadal axis. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 233-241, 2000

Authors: Helen Kim, | Hongli Xia, | Lin Li, | John Gewin,

Article Type: Research Article

Abstract: Epidemiological studies show that postmenopausal women who undertake estrogen-replacement therapy have significantly lower risk for the onset of Alzheimer's disease (AD) than women who do not. Animal behavior studies have shown that ovariectomy results in the development of cognitive dysfunction that is prevented by estrogen-replacement, suggesting that normal mammalian cognitive function is impaired by estrogen reduction. Soy isoflavones in particular genistein have been demonstrated to have weak and selective estrogenic actions in …various models of human chronic diseases. A hallmark of several human dementias including AD and fronto temporal dementia with Parkinsonism on chromosome 17 (FTDP-17) is the hyperphosphorylation of the microtubule-associated protein tau. Preliminary experiments are discussed here which show that isoflavones delivered in a soy protein matrix attenuated selected AD-relevant tau phosphorylations in a primate model of menopause. The rationale is discussed for the use of soy-based foods for protection against postmenopausal neurodegeneration. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 243-250, 2000

Authors: R. Mackey, | A. Ekangaki, | J.A. Eden,

Article Type: Research Article

Abstract: Fifty four postmenopausal women with elevated cholesterol were recruited for a randomised, double-blind controlled trial of soy protein containing isoflavones. (ISP+ ) or a soy protein with a low isoflavone content (ISP- ), taken daily for 12 weeks. There was an overall reduction after 12 weeks in total cholesterol (TC), LDL cholesterol (LDL-C), sex hormone binding globulin (SHBG), and luteinizing hormone (LH). There were no significant differences between treatment groups. …In a separate study 27 male subjects with a TC > 5.5 mmol/l were given ISP+ for 12 weeks. In this male study there was a significant increase in HDL cholesterol (HDL-C) and SHBG. Soy protein has a cholesterol lowering effect in both women and men. These studies suggest that this effect is independent of isoflavones. Soy protein also reduces SHBG levels in both sexes. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 251-257, 2000

Authors: James E. Trosko, | Chia Cheng Chang,

Article Type: Research Article

Abstract: Chemopreventive or chemotherapeutic agents have been those that either kill cancer cells to a differential degree over the non-cancer cells or those chemicals that either block the induction of tumors in carcinogen-treated animals or retard transplanted tumors in animals. Carcinogenesis is a multi-stage, multi-mechanism process, involving the irreversible alteration of a stem cell (``initiation''), followed by the clonal proliferation of the initiated cell (``promotion''). To develop a strategy for intervention with chemoprevention/chemotherapeutic …chemicals, the basic mechanism(s) of carcinogenesis must be understood. Gap junction intercellular communication (GJIC) regulates cell growth, differentiation, apoptosis and adaptive functions of differentiated cells. Normal cells have functional GJIC while cancer cells do not. Tumor promoters and oncogenes inhibit GJIC, while anti-tumor promoter and anti-oncogene drugs can reverse the down-regulation of GJIC. Transfection of gap junction genes (connexins) has been shown to reverse the tumorigenic phenotype. If prevention/treatment of cancer is to occur, prevention of the chronic down regulation of GJIC by tumor promoters in non-tumorigenic but initiated cells or the up-regulation of GJIC in stably down-regulated GJIC in tumor cells must occur to prevent or to treat cancers. Show more

Keywords: gap junctions, connexins, anti-promoters, chemoprevention

Citation: BioFactors, vol. 12, no. 1-4, pp. 259-263, 2000

Authors: Masato Nagaoka, | Hideyuki Shibata, | Itsuko Kimura-Takagi, | Shusuke Hashimoto,, | Ritsuo Aiyama, | Sadao Ueyama, | Teruo Yokokura,

Article Type: Research Article

Citation: BioFactors, vol. 12, no. 1-4, pp. 267-274, 2000

Authors: Masashi Mizuno,

Article Type: Research Article

Abstract: The changes in the contents of an anti-tumor polysaccharide from {\it Lentinus edodes} (lentinan) and {\it Grifola frondosa} (GGF) during storage were investigated using by an ELISA inhibition assay. When the mushrooms were stored at low temperature, the contents of their anti-tumor polysaccharides show hardly any changes, but their contents decreased markedly at higher temperature (20^{\circ} C). Moreover, the effect of the extract from {\it Lentinus edodes} stored at different temperatures on …tumor necrosis factor (TNF)-\alpha and nitric oxide (NO) productions from macrophages was investigated to confirm the influence to the stimulation of macrophages. Because lentinan stimulates macrophages to augment their antitumor activity. Their productions showed little difference between {\it Lentinus edodes} stored at low temperature and the fresh mushroom, although the cytokine production decreased significantly in {\it Lentinus edodes} stored at 20^{\circ} C. These results suggest that low-temperature storage is more effective in maintaining not only the quality of the mushrooms but also the contents of anti-tumor polysaccharides as health-beneficient foods. Show more

Keywords: anti-tumor polysaccharide, tumor necrosis factor (TNF)-\alpha, nitric oxide (NO), ELISA, {\it Lentinus edodes}, {\it Grifola frondosa}

Citation: BioFactors, vol. 12, no. 1-4, pp. 275-281, 2000

Authors: Yoshihiro Sowa, | Toshiyuki Sakai,

Article Type: Research Article

Abstract: Recent progress in molecular genetics has facilitated understanding of the mechanisms of carcinogenesis. However, there is not yet any effective therapy or prevention for cancer based on the molecular mechanisms of carcinogenesis. So-called ``gene therapy'' for cancer is expected to become a new method of treatment, but there are still several serious problems with gene therapy. As a matter of fact, it seems impossible to adopt gene therapy for prevention. We therefore tried to develop a …different method of cancer prevention or therapy based on the molecular mechanisms of carcinogenesis. For instance, the tumor-suppressor gene p53 is mutated in about 50% malignancies. It is known that p53 stimulates the promoter activities of p21/WAF1, gadd45 and bax genes, resulting in cell cycle arrest, DNA repair and apoptosis, respectively. Therefore, chemical compounds that can stimulate these genes should compensate for the function of p53. As a model of this, we found that histone deacetylase inhibitors such as butyrate or trichostatin A dramatically stimulate the p21/WAF1 gene promoter through the Sp1 sites, resulting in cell cycle arrest. Interestingly, another group has recently reported that phenylbutyrate, which is also known as a histone deacetylase inhibitor, is very effective for leukemia patients. We therefore consider methods of up-regulating p21/WAF, gadd45 or bax genes should be useful for cancer therapy and termed this method ``Gene-regulating chemotherapy''. Theoretically, the chemicals up-regulating such genes should be also useful for chemoprevention, and we also termed it as ``Gene-regulating chemoprevention''. In conclusion, we propose that ``Gene-regulating chemotherapy or chemoprevention'' may be a promising new method for cancer therapy or prevention and histone deacetylase inhibitor is a good candidate for this method. Show more

Keywords: Gene-regulating chemoprevention, Gene-regulating chemotherapy, histone deacetylase inhibitor, colorectal cancer, dietary fiber, butyrate, p21/WAF1

Citation: BioFactors, vol. 12, no. 1-4, pp. 283-287, 2000

Authors: Leon Prosky,

Article Type: Research Article

Abstract: Before answering the question of when dietary fiber can be considered a functional food we must first decide what can be called a dietary fiber. The generally accepted definition of dietary fiber is that of Trowell that dietary fiber consists of the remnants of edible plant cells polysaccharides, lignin, and associated substances resistant to (hydrolysis) digestion by the alimentary enzymes of humans. In Japan the food tables list the dietary fiber content of animal as well …as plant tissues, while many countries accept saccharides of less than DP-10 as dietary fiber (inulin, oligofructose, Fibersol-2, polydextrose, fructooligosaccharides, galactooligosaccharides etc.). These shorter chain oligosaccharides do not precipitate as dietary fiber in the standard Association of Official Analytical Chemists (AOAC) method, which is accepted by the US Food & Drug Administration, the US Department of Agriculture and the Food & Agriculture Organization of the World Health Organization for nutrition labeling purposes. In the United Kingdom the term dietary fiber has been replaced in nutrition labeling by nonstarch polysaccharides. Therefore the American Association of Cereal Chemists (AACC) commissioned an ad hoc committee of scientists to evaluate continuing validity of the currently used definition, and if appropriate, to modify and update that definition. Obtaining scientific input from the community of analysts, health professionals, and dietary fiber researchers was considered a high priority. To this end three meetings were held in the space of six months to assure input from all persons knowledgeable in the field with the answer expected sometime before 2000. Dietary fiber can be considered a functional food when it imparts a special function to that food aside from the normal expected function and similarly when the dietary fiber is used as an additive to foods. For example, dietary fiber contributes to colonic health, bifidobacterial or lactobacillus stimulation in the gut, coronary artery health, cholesterol reduction, glucose metabolism, insulin response, blood lipids, cancer etc. The author discusses in detail the functional food properties of dietary fiber. Show more

Keywords: total, soluble, insoluble dietary fiber, functional food claims

Citation: BioFactors, vol. 12, no. 1-4, pp. 289-297, 2000

Authors: Hideki Ishikawa, | Ikuko Akedo, | Tomiyo Nakamura, | Kazuko Kimura, | Yasuko Takimoto, | Takaichiro Suzuki, | Shinichi Sato, | Yukio Tanaka, | Toru Otani,

Article Type: Research Article

Abstract: We developed hard biscuit containing 30% bran (WB biscuit) and administered it to 12 volunteers at 7.5 g/day (7.5 g group) or 15 g/day (15 g group) as wheat bran for 12 weeks. After 12 weeks, the dietary fiber intake from foods other than wheat bran decreased slightly in the both groups, in the 15 g group was the decrease notable especially, after the beginning of WB biscuit administration. We suggest that a closest attention to changes in dietary habit …associated with intervention is needed in intervention studies using patients leading a normal life. Show more

Keywords: wheat bran, dietary fiber, diet, cancer prevention, colorectal cancer, volunteer study, intervention study

Citation: BioFactors, vol. 12, no. 1-4, pp. 299-303, 2000

Authors: Arthur Schatzkin,

Article Type: Research Article

Citation: BioFactors, vol. 12, no. 1-4, pp. 305-311, 2000