Biofactors - Volume 12, issue 1-4

Authors: Hajime Ohigashi, | Toshihiko Osawa, | Junji Terao, | Shaw Watanabe, | Toshikazu Yoshikawa,

Article Type: Other

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

Authors: Paul Talalay,

Article Type: Research Article

Abstract: Induction of Phase 2 enzymes is an effective and sufficient strategy for achieving protection against the toxic and neoplastic effects of many carcinogens. It is proposed that the concept of Phase 2 enzymes as being responsible only for the conjugation of functionalized xenobiotics with endogenous cellular ligands such as glutathione (glutathione S-transferases) and glucuronic acid (UDP-glucuronosyltransferases) be expanded to include proteins with the following common characteristics: (a) coordinate induction by a broad …range of chemical agents that all have the capacity to react with sulfhydryl groups; (b) possible regulation by common promoter elements; and (c) catalysis of reactions that lead to comprehensive protection against electrophile and reactive oxygen toxicities, by a wide variety of mechanisms. These mechanisms include: conjugation with endogenous ligands, chemical modification of reactive features of molecules that can damage DNA and other macromolecules, and generation or augementation of cellular antioxidants. In addition to the above conjugating enzymes, a provisional and partial list of Phase 2 proteins might include: NAD(P)H:quinone reductase, epoxide hydrolase, dihydrodiol dehydrogenase, \gamma -glutamylcysteine synthetase, heme oxygenase-1, leukotriene B_4 dehydrogenase, aflatoxin B_1 dehydrogenase, and ferritin. Show more

Keywords: glutathione transferase, glutathione, NAD(P)H:quinone reductase, heme oxygenase, \gamma-glutamylcysteine synthetase, epoxide hydrolase, ferritin, electrophile toxicity, redox cycling, antioxidants, reactive oxygen species

Citation: BioFactors, vol. 12, no. 1-4, pp. 5-11, 2000

Authors: Soichi Arai,

Article Type: Research Article

Abstract: In 1984, a new science related to functional food was initiated by a National Project team under the auspices of the Japan Ministry of Education and Science. It was followed by a great many academic and industrial studies to occupy a central position in the field of food and nutritional sciences. In 1993, the Ministry of Health and Welfare established a policy of ``Foods for Specified Health Uses'' (FOSHU) by which health claims of some selected …functional foods are legally permitted. Up to now (November 22, 1999), 167 FOSHU products have been born. Since the time (1984) when the concept of ``functional food'' was proposed, it seems that the science in Japan has been progressing along, among others, a unique path of development. The uniqueness is seen in the development of functional foods by minimizing undesirable as well as maximizing desirable food factors. Hypoallergenic foods, developed from their materials by removing allergens, offer a good example. Another characteristic may be found in the field of sensory science which aims at elucidating a molecular logic of the senses of taste and smell in reference to their effects on physiological systems in the body. The paper discusses some characteristics of functional food science in Japan, with special emphasis on these topics. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 13-16, 2000

Authors: Zigang Dong,

Article Type: Research Article

Abstract: Consumption of plant-derived foods, especially fruits and vegetables, has been linked to decreased risk of cancer. Laboratory studies with animals and cells in culture have shown cancer preventive activity of chemicals isolated from soy, tea, rice and many green, yellow and orange fruits and vegetables. Using cell culture, transgenic mice and knockout mice models to examine the anti-cancer effects of these dietary factors at the molecular level, we found that (1) (- )-epigallocatechin gallate …(EGCG), the major active polyphenol in green tea, and theaflavins, the major active components in black tea, inhibit epidermal growth factor (EGF)- or 12-O -tetradecanoylphorbol-13-acetate (TPA)-induced JB6 cell transformation. At the same dose range that inhibited cell transformation, EGCG and theaflavins inhibited activator protein-1 (AP-1) activation. These compounds also inhibited ultraviolet B (UVB)-induced AP-1 and nuclear factor kappa B (NF\kappa B)-dependent transcriptional activation; (2) resveratrol, found at high levels in grapes, inhibited cell transformation through the induction of apoptosis, mediated through JNK and p53-dependent pathways; (3) inositol hexaphosphate (InsP6), an active compound from rice and other grains, inhibited TPA- or EGF-induced transformation and signal transduction through its effects on phosphatidylinositol-3 kinase (PI-3) kinase; (4) phenethyl isothiocyanate (PEITC), which occurs as a conjugate in certain cruciferous vegetables, inhibited cell transformation corresponding with the induction of apoptosis. An elevation of p53 is required for PEITC-induced apoptosis. Our studies indicated that the chemopreventive effect of these food factors may be mediated by their effects on different signal transduction pathways; (5) retinoids (vitamin A and its metabolites) inhibited tumor promoter-induced cell transformation and tumor promotion in transgenic mice through the inhibition of AP-1 action but not through the activation of retinoic acid response element (RARE). Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 17-28, 2000

Authors: Shuichi Kaminogawa,

Article Type: Research Article

Citation: BioFactors, vol. 12, no. 1-4, pp. 29-32, 2000

Authors: Mamoru Nishimuta,

Article Type: Research Article

Abstract: A new concept of grouping of minerals, which will be helpful for understanding the actual status of human health, on the basic of elementological biology.

Keywords: intracellular minerals, extracellular minerals, bone minerals

Citation: BioFactors, vol. 12, no. 1-4, pp. 35-38, 2000

Authors: Gerald F. Combs, Jr.,

Article Type: Research Article

Abstract: Micronutrient deficiencies affect nearly half the world's population, impairing child development, reducing work productivity, and increasing mortality and morbidity rates by affecting both infectious and chronic diseases. To feed a growing world, it will be necessary to consider agriculture in the broad context of a food system as an instrument of public health and, thus, to address nutrient balance while also seeking sustainability. Such efforts would include increasing cropping system diversity, enhancing …micronutrient outputs and promoting environmental sustainability. Example of this approach are presented for the essential trace element selenium (Se), which at high intakes can reduce cancer risks but is deficient in many parts of the world. Food systems-based approaches are discussed for preventing Se deficiency by enhancing intakes of any of several biologically available forms of Se, and for reducing cancer risk by enhancing intakes of forms of the element that support anti-tumorigenic Se-metabolites. Show more

Keywords: food system, micronutrient, selenium, cancer, carcinogenesis, chemoprevention

Citation: BioFactors, vol. 12, no. 1-4, pp. 39-43, 2000

Authors: Mohamed Abdulla, | Per Gruber,

Article Type: Research Article

Abstract: Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and include both genetic and biochemical changes in the cells. At each of these levels, there are several possibilities of intervention in order to prevent, slow down or even halt the gradual march of healthy cells towards malignancy. Diet modification is one such possibility. A number of natural foodstuffs, especially fruits and vegetables contain substantial quantities of molecules that have chemopreventive potential against …cancer development. Such compounds include vitamins, trace elements and a variety of other molecules with antioxidant properties. Carotenoids, flavanoid polyphenols, isoflavones, catechins, and several other components that found in cruciferous vegetables are molecules that are known to protect against the deleterious effect of reactive oxygen species. A number of epidemiological and experimental studies have shown that vitamin C and E, Beta-carotene and the essential trace element selenium can reduce the risk of cancer. Consistent observations during the last few decades that cancer risk is reduced by a diet rich in vegetables, fruits, legumes, grains and green tea have encouraged research to identify several plant components especially phytochemicals that protect against DNA damage. Many of these substances block specific carcinogen pathways. Dietary supplements are part of an overall health program, along with a high intake of fruits and vegetables that help to combat damage to cells, which in turn may initiate cancer development. This paper will review current knowledge concerning diet modification and cancer prevention with special reference to minerals and trace elements. Show more

Keywords: cancer prevention, reactive oxygen species, fruits and vegetables, antioxidants, trace elements

Citation: BioFactors, vol. 12, no. 1-4, pp. 45-51, 2000

Authors: Ritsuko Masuyama and Kazuharu Suzuki,

Article Type: Research Article

Abstract: Dietary intake of high phosphorus (P) is well-described to increase serum levels of PTH, however, how this increased serum PTH affects the PTH actions in major target tissues, particularly in kidney, remains uncovered. We therefore undertook to clarify this point in intact animals fed the high-P diet by examining various parameters of the PTH actions. Twelve weanling Wistar male rats were assigned randomly into the groups; a control group Ca:P=1:1 and a high-P group (Ca:P=1:3) fed …the standard AIN 76 diet supplemented with P (0.5 and 1.5 g/100 g diet). After 3 week feeding, in the high-P diet group, we observed that serum Ca is lowered without difference in serum P when compared to those in the control group. Excretion of urine cAMP, an index of the renal PTH action, was also decreased with higher excretion of urine P by feeding the high P diet. In agreement with the decreased cAMP excretion, a clear reduction in the PTH/PTHrP receptor gene expression estimated by Northern blotting was observed in the kidney irrespective of increased levels of serum PTH. Thus, the present study indicated that high P dietary intake rather reduces the PTH actions in kidney though the serum PTH is increased. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 53-58, 2000

Authors: Hiroshi Tsuchita, | Noboru Manabe, | Shinichi Saito,

Article Type: Research Article

Citation: BioFactors, vol. 12, no. 1-4, pp. 59-64, 2000

Authors: Michio Komai, | Tomoko Goto, | Hitoshi Suzuki, | Tomohiko Takeda, | Yuji Furukawa,

Article Type: Research Article

Abstract: The present study was designed to clarify the effect of zinc deficiency on sodium chloride preference, the lingual trigeminal and taste nerves transduction, and carbonic anhydrase (CA) activity of the tongue surface and salivary gland. Male SD rats, 4 weeks old, were divided into four groups, and fed zinc-deficient (Zn-Def), low-zinc (Low-Zn), and zinc-sufficient diets with free access (Zn-Suf) and pair-feeding (Pair-fed). After taking part in the preference tests for 42 days, the rats were provided …for the chorda tympani and lingual trigeminal nerves recordings, then finally sacrificed and the tongue and submandibular gland excised to measure CA activity. Sodium chloride preference increased only after 4 days of the feeding of zinc-deficient and low-zinc diets, which means that the taste abnormality appears abruptly in zinc deficieny and even though in marginal zinc deficiency. Reduced CA activities of the taste-related tissues in zinc-deficient group paralleled well with the decreased taste and lingual trigeminal nerves sensitivities. Show more

Keywords: zinc deficiency, carbonic anhydrase, taste dysfunction, rat

Citation: BioFactors, vol. 12, no. 1-4, pp. 65-70, 2000

Authors: John H. Weisburger,

Article Type: Research Article

Abstract: The transformation of normal cells by DNA reactive, genotoxic carcinogens and the growth promotion and development of mutated cells by enhancing factors is involved in the overall basic mechanism of cancer induction. Thus, discrimination between genotoxic carcinogens and nongenotoxic chemicals is essential. The dose-response curves, reversibility, and organ-and species specificity are distinct. Genotoxic carcinogens are mutagenic, form DNA adducts, induce DNA repair, and form hydroxy radicals and inappropriate peroxidation reactions that antioxidants …such as those in vegetables, fruits, and tea can decrease. In contrast, promoters do not form DNA adducts, but raise cell duplication rates, among other attributes. In the USA, about 35% about 55% decreased by avoiding the formation of carcinogens, reducing their metabolic activation, or increasing their detoxification. Excessive dietary salt, and heterocyclic arylamines formed in cooking of meats or fish, and high intake of 40% vegetables, fruits, tea, soy products, and fibers are protective. We review nutritional factors involved in cancer and chronic disease causation and prevention. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 73-81, 2000

Authors: Hiroyuki Tsuda, | Kazunori Sekine, | Nobuo Takasuka, | Hiroyasu Toriyama-Baba, | Masaaki Iigo,

Article Type: Research Article

Abstract: Bovine lactoferrin (bLF), a milk protein known to have bacteriostatic properties was examined for its preventive effects on colon and other organ carcinogenesis and experimental metastasis. (Experiment 1) The influence on colon carcinogenesis was investigated in male rats treated with azoxymethane (AOM), then received 2 or 0.2% weeks. Significant reduction in the incidence (27% control, respectively) and number of adenocarcinomas of the large intestine was observed. (Experiment 2) In BALB/c mice bearing …subcutaneous (s.c.) implants of colon carcinoma 26 (Co 26Lu), bLF demonstrated significant inhibition of spontaneous lung metastasis (approximately 43% and CD8^+ cells in white blood cells increased (171% control, respectively) after treatment. Results of those experiments indicate that bLF remarkably prevents colon carcinogenesis and lung metastasis of colon carcinoma cells, possibly due to increasing cytotoxic cells in the peripheral blood. Show more

Keywords: lactoferrin, carcinogenesis, prevention, metastasis, rat, mouse

Citation: BioFactors, vol. 12, no. 1-4, pp. 83-88, 2000

Authors: H. Adlercreutz, | W. Mazur, | K. Stumpf, | A. Kilkkinen, | P. Pietinen, | K. Hult\'en, | G. Hallmans,

Article Type: Research Article

Citation: BioFactors, vol. 12, no. 1-4, pp. 89-93, 2000

Authors: Yasuhiro Matsumura, | Nobuo Yoshiike, | Tetsuji Yokoyama, | Heizo Tanaka,

Article Type: Research Article

Abstract: We examined the correlation between the prefectural variation of standardized mortality ratio (SMR) for lung and colon cancer and the consumption of foods using dietary data from National Nutrition Survey in Japan from 1976 to 1995. We found partly the same results on promoting factors and preventing factors of these cancers as the previously reported large scale cohort studies. But, we also found the inconsistent results. This might be partly because of the limitation of data …collection method in the National Nutrition Survey. It was thought that the method of National Nutrition Survey should be modified to monitor nutrition and health conditions to correspond the epidemiological study and to prevent chronic diseases. Show more

Keywords: National Nutrition Survey, standardized mortality ratio, geographic correlation, ecological study

Citation: BioFactors, vol. 12, no. 1-4, pp. 95-99, 2000

Authors: Hideki Mori, | Kunihiro Kawabata, | Kengo Matsunaga, | Jun Ushida, | Keiko Fujii, | Akira Hara, | Takuji Tanaka, | Hiromichi Murai,

Article Type: Research Article

Abstract: Polyphenolic compound chlorogenic acid (CGA) known to be much contained in coffee beans was found to have a regressive effect on induced aberrant crypt foci (ACF) as well as on development of ACF in azoxymethane (AOM)-induced colorectal carcinogenesis in rats. Rice germ and \gamma -aminobutyric acid-enriched defatted rice germ inhibited AOM-induced ACF formation and colorectal carcinogenesis in rats. Ferulic acid (FA) also known to be contained in coffee beans and rice prevented …AOM-induced ACF formation and intestinal carcinogenesis in rats. Both of food factors, coffee and rice may be of benefit to prevention of human colorectal cancers. Show more

Keywords: chlorogenic acid, ferulic acid, coffee, rice, colorectal carcinogenesis

Citation: BioFactors, vol. 12, no. 1-4, pp. 101-105, 2000

Authors: Young-Joon Surh, | Seong Su Han, | Young-Sam Keum, | Hyo-Joung Seo, | Sang Sup Lee,

Article Type: Research Article

Abstract: Recently, considerable attention has been focused on identifying dietary and medicinal phytochemicals that can inhibit, retard or reverse the multi-stage carcinogenesis. Spices and herbs contain phenolic substances with potent antioxidative and chemopreventive properties. Curcumin, a yellow colouring agent from turmeric and capsaicin, a pungent principle of red pepper exhibit profound anticarcinogenic and antimutagenic activities. Two well-defined eukaryotic transcription factors, nuclear factor-kappa B (NF-\kappa B) and activator protein 1 (AP-1) have been …implicated in pathogenesis of many human diseases including cancer. These transcription factors are known to be activated by a wide array of external stimuli, such as tumor promoter 12-O -tetradecanoylphorbol-13-acetate (TPA), tumor necrosis factor, reactive oxygen species, bacterial lipopolysaccharide, and ultraviolet. In the present study, we found that topical application of TPA onto dorsal skin of female ICR mice resulted in marked activation of epidermal NF-\kappa B and AP-1. Curcumin and capsaicin, when topically applied prior to TPA, significantly attenuated TPA-induced activation of each transcription factor in mouse skin. Likewise, both compounds inhibited NF-\kappa B and AP-1 activation in cultured human promyelocytic leukemia (HL-60) cells stimulated with TPA. Based on these findings, it is likely that curcumin and capsaicin exert anti-tumor promotional effects through suppression of the tumor promoter-induced activation of transcription factors, NF-\kappa B and AP-1. Show more

Keywords: curcumin, capsaicin, NF-\kappaB, AP-1, chemoprevention

Citation: BioFactors, vol. 12, no. 1-4, pp. 107-112, 2000

Authors: Delbert M. Shankel, | S.P. Pillai, | H. Telikepalli, | S.R. Menon, | C.A. Pillai, | L.A. Mitscher,

Article Type: Research Article

Abstract: Recently it has become increasingly clear that chemicals found in our foods and beverages can prevent the genetic damage that leads to cancer initiation. Such substances may also affect subsequent events in the pathways that lead to cancer, and may have the potential to inhibit the mutations that allow tumor cells to become resistant to antitumor agents. We describe here the antimutagenic potential of Glabrene analogs against EMS-induced mutations utilizing modified Ames tests in {\it S. …typhimurium} TA 100 and {\it E. coli} JC 5088. Results of studies of the ability of well-known antioxidants such as EGCG and related compounds to prevent drug resistance mutations in microorganisms are described, and their possible significance in the prevention of chemotherapeutic drug-resistance in tumor cells is discussed. Show more

Keywords: antimutagenesis, anticarcinogenesis, glabrene, catechins, drug-resistance

Citation: BioFactors, vol. 12, no. 1-4, pp. 113-121, 2000

Authors: Kiyomi Kikugawa, | Kazuyuki Hiramoto, | Tetsuta Kato,

Article Type: Research Article

Abstract: Introduction of phenolic antioxidants, thiol compounds and reductones into the heated model system composed of glucose/glycine/creatinine was effective to scavenge the intermediary pyrazine cation radical and to reduce the mutagenicity due to imidazoquinoxaline heterocyclic amines. Addition of a reductone, ascorbate or erythorbate, at 0.3% to ground beef effectively reduced the mutagenicity of cooked hamburger. Mutagenicity of cooked hamburger was also decreased by addition of glucose at more than 0.7% to ground beef.

Keywords: pyrazine cation radical, mutagenicity, cooked hamburger, ascorbate, erythorbate, glucose

Citation: BioFactors, vol. 12, no. 1-4, pp. 123-127, 2000

Authors: Kouji Watanabe, | Toshihiko Kawamori, | Seiichi Nakatsugi, | Keiji Wakabayashi,

Article Type: Research Article

Abstract: Cyclooxygenase (COX)-2 has been suggested to play an important role in colon carcinogenesis. We found that the COX-2 selective inhibitor, nimesulide, reduces azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats and colon carcinogenesis in mice, as well as formation of intestinal polyps in Min mice. Thus, selective inhibitors of COX-2, which catalyzes the synthesis of prostanoids, could be good candidates as chemopreventive agents against colon cancer. Examination of the effect of prostanoid receptor …deficiency and a selective antagonist of prostanoid receptor on the development of AOM-induced ACF in mice revealed the involvement of the EP_1 receptor. Moreover, a selective EP_1 antagonist reduced the number of intestinal polyps in Min mice. These results suggest that PGE_2 contributes to colon carcinogenesis through binding to the EP_1 receptor. Nitric oxide synthase (NOS) is known to be overexpressed in colon cancers of humans and rats, and a NOS inhibitor, L-N^G -nitroarginine methyl ester, was found to inhibit the development of AOM-induced ACF in rats. Thus, NOS including iNOS could also be a good target for chemoprevention of colon cancer, as in the COX-2 case. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 129-133, 2000

Authors: M. Smriga, | H. Murakami, | M. Mori, | K. Torii,

Article Type: Research Article

Abstract: Rats readily recognize an amino acid deficient diet, presumably via central mechanisms that involve hypothalamic circuits. Presently, effects of the essential amino acid L-lysine deficiency on the ventromedial (VMH) and lateral (LH) hypothalamus norepinephrine (NE) release were evaluated in free moving rats. Microdialysis measurement was undertaken once in 48 h (12:00 noon--14:00) in rats that had free access to food and drink. Significant decline in the food intake and VMH NE release were found in rats …fed L-lysine diet. No changes were identified in LH NE release. Additionally, no significant differences in diet-induced spatial thermogenesis between normal and L-lysine deficient non-stressed rats were found in vivo. The results suggested that the VMH NE release was specifically involved in the integration of signals about amino acid deficiency. However, the decrease in VMH NE was not translated into changes of thermogenic responses to diet. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 137-142, 2000

Authors: Masaaki Yoshikawa, | Hiroyuki Fujita, | Nobuyuki Matoba, | Yasuyuki Takenaka, | Taichi Yamamoto, | Rena Yamauchi, | Hirotaka Tsuruki, | Kyoya Takahata,

Article Type: Research Article

Abstract: Many kinds of bioactive peptides which might prevent lifestyle-related diseases are released from food proteins after enzymatic digestion. Inhibitory peptides for angiotensin I-converting enzyme (ACE) having anti-hypertensive effect have been isolated from enzymatic digests of various food proteins. LKPNM, which was isolated from the thermolysin digest of dried bonito was activated 8-fold by ACE itself and showed a prolonged effect after oral administration. Two vasorelaxing peptides, ovokinin and ovokinin(2--7), showing antihypertensive effect …after oral administration were obtained from ovalbumin digests. We found that low molecular weight peptides derived from food proteins lowered serum cholesterol without increasing excretion of cholesterol and bile acids. An immunostimulating peptide isolated from an enzymatic digest of soybean protein prevented alopecia induced by cancer chemotherapy. Show more

Keywords: peptide, lifestyle-related diseases, angiotensin I-converting enzyme inhibitor, vasorelaxation, cholesterol, immunostimulation, ovalbumin, soybean, \beta-lactoglobulin

Citation: BioFactors, vol. 12, no. 1-4, pp. 143-146, 2000

Authors: A.W. Lipkowski, | B. Baranowska, | E. Marczak, | B. Kwiatkowska-Patzer, | B. Gajkowska, | M. Walski,

Article Type: Research Article

Abstract: To induce oral tolerance in multiple sclerosis treatment, we proposed to use the predigested protein of pig spinal cord. The most biologically active composition was obtained from the hydrolysis of an undenaturated homogenate of proteins digested with pepsin. Feeding the rats with our preparation, before or after immunization with MS antigens, strongly reduced development of the experimental autoimmune encephalomyelitis (EAE). The biological results obtained in animals suggest that the developed method of …induction of the oral tolerance should be effective in human treatment, at least as a support mechanism in combination with other treatment methods. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 147-150, 2000

Authors: Song E Kim, | Hyuck Hwa Kim, | Ji Yeon Kim, | Young Im Kang, | Hee Jong Woo, | Hyong Joo Lee,

Article Type: Research Article

Abstract: An anticancer peptide from soy protein was purified and isolated. Defatted soy protein was hydrolyzed with thermoase and hydrophobic peptides were extracted with ethanol. The peptide extract was fractionated by XAD-2 hydrophobic, gel filtration chromatography, and different C18 HPLCs. Anticancer activity of each fraction was assayed by measuring in vitro cytotoxicity on P388D1, a mouse monocyte macrophage cell line. IC_{50} value of a peptide fraction from Sephadex G-25 chromatography was 0.16 mg/ml. This …peptide fraction at 1 mg/ml significantly affected cell cycle progression by arresting P388D1 at G2/M phases. Finally purified peptide from analytical C18 HPLC was nonapeptide of which molecular weight was 1157 Da and the sequence was X-Met-Leu-Pro-Ser-Tye-Ser-Pro-Tyr. Show more

Keywords: anticancer, peptide, thermoase hydrolyzates, soy protein

Citation: BioFactors, vol. 12, no. 1-4, pp. 151-155, 2000

Authors: Yukio Kawamura, | Mariko Manabe, | Kazumi Kitta,

Article Type: Research Article

Abstract: Antitumor protein (AP) from a mushroom, induced the morphological changes typical to apoptosis such as nuclear condensation, aneuploidity, and DNA fragmentation at concentrations as low as 5--20 ng/ml to cancer cells. Molecular alterations related to cell cycle. Molecular alterations related to cell cycle, especially G1/S transition were investigated with a human keratinocyte transformed with oncoproteins, E6 and E7 of human pappiloma virus(HPV)-16. AP didn't alter significantly and oncosuppressor p53 level, but induced …hyperphosphorylation of pRb. Time-dependent change of G1 cyclins, cdk2 and cdk4 after addition of AP showed that expression level of cdk inhibitors, INK4 family, and p27^{\rm KIP1} did not altered, while that of p21^{\rm WAF1} was downregulated. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 157-160, 2000

Authors: Misao Miwa,

Article Type: Research Article

Keywords: physiological function, FOSHU, branched-chain amino acids, hypertension

Citation: BioFactors, vol. 12, no. 1-4, pp. 161-165, 2000

Authors: Christine Morand, | Claudine Manach, | Vanessa Crespy, | Christian Remesy,

Article Type: Research Article

Abstract: A large number of flavonoids, mostly O-glycosides, are found in foods of plant origin. The bound sugar moiety is known to influence their bioavailability. We examined here the effect of the nature of the sugar on the absorption of the glycosides. Four groups of rats (n=6 ) received a meal containing 20 mg of quercetin equivalents supplied as aglycone, quercetin 3-glucoside, quercetin 3-rhamnoside or rutin. Plasma were hydrolysed by a \beta -glucuronidase/sulfatase and analyzed …by HPLC coupled to UV detection at 370 nm. Four hours after the beginning of the meal, the quercetin metabolites present in plasma were identical in all groups but their total concentrations were quite different. With pure quercetin the circulating levels were 11.7\pm 1.8 \mu M, but this level was three fold higher when quercetin was supplied as quercetin 3-glucoside (33.2\pm 3.5 \mu M). By contrast, the plasma concentrations of quercetin metabolites was quite low with the rutin meal (about 3 \mu M) and undetectable after the quercetin 3-rhamnoside meal. These data suggest that the 3-O-glucosylation improves the absorption of quercetin in the small intestine, whereas the binding of a rhamnose or of a glucose-rhamnose moiety to the aglycone markedly depressed its absorption. Additionnal experiments have shown that the higher plasma levels measured after the meal containing quercetin 3-glucoside compared to quercetin were maintained throughout a 24 hour period following the meal. In conclusion, the nature of the glycosylation markedly influences the efficiency of quercetin absorption in rats. Quercetin 3-glucose can be absorbed in the small intestine and is better absorbed than quercetin itself. By contrast, glycosides containing a rhamnose moiety could not be absorbed in the small intestine. Show more

Keywords: quercetin, quercetin glycosides, intestinal absorption, plasma metabolites

Citation: BioFactors, vol. 12, no. 1-4, pp. 169-174, 2000

Authors: Mariusz K. Piskula,

Article Type: Research Article

Abstract: In experiments on rats, some of the factors affecting flavonoids absorption (solubility, glycosylation and nutritional status: fasted and not-fasted animals) were examined. Administration of quercetin with different solubilization degree showed no direct correlation between the quercetin absorption extent and solubility, i.e. despite 3 orders of difference in solubilization degree, the extent of absorption varied only about 4-fold. Absorption comparison of genistein and its glycoside genistin showed no difference in the extent of …absorption; however, aglycone, in contrast to glycoside, was absorbed already from the rat stomach. Conjugation patterns (sulfation and glucuronization) of genistein metabolites demonstrated that the plasma of animals fasted prior to isoflavone administration contained significantly more sulfates and less glucuronides and mixed sulfates/glucuronides conjugates than the plasma of non-fasted animals. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 175-180, 2000

Authors: Kayoko Shimoi, | Noriko Saka, | Kazuhiko Kaji, | Ryushi Nozawa, | Naohide Kinae,

Article Type: Research Article

Abstract: Luteolin has been shown to possess potent antioxidant and anti-inflammatory/anti-allergic activities. In order to evaluate a chemopreventive role of luteolin in inflammatory responses involved in the pathogenesis of atherosclerosis and cancer etc., the metabolic fate of luteolin in rats and humans was investigated by HPLC analysis, and its effect on cell surface expression of adhesion molecules in human umbilical vein endothelial cells(HUVECs) was examined by ELISA. Luteolin monoglucuronide, which was a main …metabolite, and free luteolin were detected in rat plasma and human serum. Luteolin monoglucuronide was hydrolyzed to free luteolin by \beta -glucuronidase released from neutrophils stimulated with Ionomycin and Cytocharasine B. Luteolin suppressed the TNF-\alpha induced ICAM-1 expression significantly. Among nine flavonoids (40 \mu M) examined, chrysin, apigenine, quercetin and galangin also demonstrated suppressive effct on it. These results suggest the posssibility that deconjugation of luteolin monoglucuronide occurs and that free luteolin showed functional acyivities such as suppression of TNF-\alpha induced ICAM-1 expression at inflammation site. Show more

Keywords: luteolin, neutrophils, \beta-glucuronidase, ICAM-1

Citation: BioFactors, vol. 12, no. 1-4, pp. 181-186, 2000

Authors: Akira Murakami, | Yoshimasa Nakamura, | Yoshimi Ohto, | Masamichi Yano, | Teruaki Koshiba, | Koichi Koshimizu, | Harukuni Tokuda, | Hoyoku Nishino, | Hajime Ohigashi,

Article Type: Research Article

Abstract: Citrus fruit intake is known to be associated with a reduction of cancer incidence. Free radicals, including superoxide (O_2\! ^- ) and nitric oxide (NO), are involved in some epithelial carcinogenesis processes. In the present study, we screened thirty-one citrus fruits for their suppressive activities toward three lines of free radical generating systems: 1) O_2\! ^- generation by the xanthine (XA)-xanthine oxidase (XOD) system; 2) O_2\! ^- generation …induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic HL-60 cells; and 3) NO generation in murine macrophage RAW264.7 cells stimulated with lipopolysaccharide (LPS) and interferon (IFN)-\gamma . As a result, the inhibitory activities of peel parts were largely found to be higher than those of the corresponding juice sac parts. In particular, the peel portion of Dancy tangerine ({\it Citrus tangerina}) showed marked anti-oxidative activities in these systems. In addition, nobiletin, a polymethoxyflavonoid isolated from {\it C. nobilis}, showed a higher anti-inflammatory activity than indomethacin in a TPA-induced edema formation test in mouse ears. These results indicate that citrus fruits could be notable sources of anti-oxidative, anti-inflammatory, and cancer preventive compounds. Show more

Citation: BioFactors, vol. 12, no. 1-4, pp. 187-192, 2000

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