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TRANSFORMING DIETARY SIGNALS INTO GENE EXPRESSION Epigenetics: The Epigenetic Transfer of Phenotype Epigenetics: Molecular Targets for Diet and Cancer Prevention, Sharon A. Ross Diet-influenced Chromatin Modification and Expression of Chemopreventive Genes by the Soy Peptide, Lunasin, Alfredo F. Galvez, Liping Huang, Mark J.M. Magbanua, Kevin Dawson, Somen Nandi and Raymond L. Rodriguez Role of Epigenetics in the Complications Associated with Diabetes and Related Metabolic Disorders, Louisa M. Villevenuve and Rama Natarajan Systems Biology: Cell Signaling Regulation of Gene Expression Systems Biology Approaches to Study Diet x Genome Interactions, Xia Yang, Zhidong Tu and Jun Zhu Modulation of Atherosclerosis by N-3 Polyunsaturated Fatty Acids, Darshan S. Kelley, Yuriko Adkins, Sumeet Sharma, Dawn M. Fedor Nutrigenomic Implications for Nuclear Receptor Coactivators, David M. Lonard and Bert W. O'Malley Nutrigenomics of Fatty Acid Sensing, Sander Kersten The Polyphenol Resveratrol Alters Global Patterns of Gene Regulation and Improves Physiology Through Multiple Potential Pathways, Behzad Varamini and Joseph A. Baur Nutritional Genomics: Cellular Signaling and Molecular Targets, Wayne R. Bidlack GENE LINKED NETWORKS Gene Linked Chronic Disease Mechanisms Mediating Obesity-Induced Inflammation and Insulin Resistance, Simon Schenk, Olivia Osborn and Jerrold M. Olefsky Nutritional Genomics of Vitamin D on Cardiovascular Disease, Sandra F. Williams, Jorge N. Artaza and Keith C. Norris Gene Linked Cancer Prevention Network Analysis of Gene Expression Profiles in Breast Cancer Cell Lines, T. Gregory Dewey, Katie L. Streicher and Stephen P. Ethier Effects of Dietary Effectors on Signal Transduction Pathways Related to Cancer Prevention, Ann M. Bode and Zigang Dong Green Tea Polyphenols, DNA Repair and Prevention of Photocarcinogenesis, Santosh K. Katiyar Bioactive Food Components and the "U" Shaped Health Conundrum: Vitamin D and Folate as Examples of Friends and Foes, John A. Milner Intestinal Microbiome Linked Gene Expression Human Intestinal Microbiome: Etiology of Inflammation Genomics, Roger A. Clemens FOOD NEEDS TO MEET NUTRIGENOMIC HEALTH NEEDS Agriculture's Ability to Enhance Food Quality Calcium Biofortification of Crops, Kendal D. Hirschi and Sean M. Thompson The Use of Genomics-Aided Breeding to Improve the Nutritional Content of Lettuce, David W. Still Food Science and Technology Enhancement of Diet quality Natural Colorants as Bioactive Agents in Functional Foods, Ann Marie Craig Manufacturing Functional Foods: Effects on Quality and Bioavailability, Ryan J. Elijas and John D. Floros New Whole Foods Designed to Deliver Bioactive Components, Cheryl Mitchell Regulatory Oversight Nutritional Genomics and the Future of Food Labeling in the US, Evelyn D. Cadman Index

Lactoferrin: Natural, Multifunctional, Antimicrobial. A.S. Naidu. Boca Raton, FL: CRC Press, 2000.This monograph of 86 pages is well written by one of the leading researchers in the field. He has c...

All- trans retinoyl-β-glucuronide, a prominent water-soluble metabolite of all- trans retinoic acid (RA) in animals, is formed by the enzymic transfer of the glucuronyl moiety of uridine diphosphoglucuronic acid to RA. Uridine diphosphoglucuronic acid glucuronosyl transferases (UGTs) of microsomal preparations catalyze this reaction. In noninduced rat liver microsomes, maximal activity was observed in the physiologic range (pH 6.9–7.5) for all- trans -RA, 9- cis -RA, all- trans -4-oxo-RA, and the synthetic retinoid tetramethyl, tetrahydro-anthracenyl-benzoic acid. The activities toward 13- cis -RA and tetramethyl, tetrahydronaphthenyl-propenyl-benzoic acid were maximal between pH 5.4 and 6.9 and toward acitretin [9-(2′,3′,6′ trimethyl, 4′methoxybenzyl-1′) 3,7 dimethyl, nona-2,4,6,8 tetraenoic acid] at pH 8.4. Several organs catalyze this reaction, but the activities of noninduced microsomes from liver, kidney, and testes were higher than those from intestine and lung. Brain microsomes were inactive. During storage at –80°C, the stability of UGTs varied both with the tissue and the retinoid substrate. 3-Methylcholanthrene both induces UGTs and increases the permeability of microsomal preparations to its substrates. The rates of glucuronidation of the less biologically active retinoids all- trans -4-oxo RA and 13- cis -RA were increased relatively more (11-fold and 6-fold, respectively) than those of the natural ligands for nuclear transcription factors all- trans -RA and 9- cis -RA (threefold and twofold, respectively). We conclude that several microsomal UGTs, which are differentially regulated, act on retinoids.

This symposium focused on the research which documents benefit and toxicity in beta-carotene supplementation. Reflecting on past and current studies, the panel of experts discussed: (1) the potential harm of a high intake of beta-carotene on selected populations, (2) biochemical antioxidant/prooxidant mechanisms of beta-carotene at the cellular level, (3) potential benefits of other carotenoids and antioxidants, and (4) future directions for research in beta-carotene and other antioxidants.

The complex of microsomal UDP-glucuronosyl transferases (UGT; EC 2,4.1.17) of rat liver catalyzes the formation of retinoyl β-glucuronide (RAG) from retinoic acid (RA) and retinyl β-glucuronide (ROG) from retinol (ROL) in the presence of UDP-glucuronic acid (UDPGA). The relative rates of formation of β-glucuronides in noninduced microsomes were: 9-cis RA > 13-cis RA > all-trans 4-oxo RA > TTNPB > all-trans RA > CD-367 > 13-cis ROL > 9-cis ROL > acetretin > all-trans ROL. Michaelis constant (KM) for all-trans RA, 13-cis ROL, TTNPB and UDPGA were 130 μM, 300 μM, 210 μM and 2.6 mM, respectively. Galacturonides of RA, but not detectably of ROL, were formed from UDP-galacturonic acid at 11–30% the rate of the β-glucuronides, whereas UDP derivatives of nonionized sugars did not serve as substrates. Pretreatment of rats with 3-methylcholanthrene markedly increased RAG formation in the absence of detergent (Triton X-100), but less so in its presence. Clofibrate pretreatment doubled the rate of RAG formation, whereas phenobarbital pretreatment showed little effect. N-Ethylmaleimide (5 mM) minimized cis-trans isomerization without significantly affecting glucuronidation. Rates of glucuronidation of retinoids clearly depend both on their isomeric states and on their chemical structures. Different UGT enzymes might well act on different geometric isomers of RA.

Carbon tetrachloride metabolism was examined in hepatic microsomes isolated from control and phenobarbital-treated Sprague-Dawley rats to determine the mechanism of pyridine nucleotide synergism. An NADPH generator increased metabolism two fold as determined by lipid peroxidation. Addition of NADH to the reaction system did not alter the maximum velocity, but did decrease the Km for NADPH from 61 microM to 7.6 microM in control and from 21 microM to 6.3 mM PB microsomes. Addition of NAD+ produced an increase in metabolism similar to NADH. Substrates and competitive inhibitors of nucleotide pyrophosphatase also enhanced CCl4 metabolism. A high correlation (r = 0.947) was indicated between the percent inhibition of nucleotide pyrophosphatase and the percent synergism of NADPH-catalyzed CCl4 metabolism. Thus, pyridine nucleotide synergism in CCl4 metabolism appears to result from the increased availability of NADPH produced by a decreased degradation of the NADPH by the nucleotide pyrophosphatase.

The role of pyridine nucleotide synergism in CCl4 metabolism was evaluated for its potential contribution to enhanced lipid peroxidation. Male Sprague-Dawley rats receiving either no treatment (control) or treatment with phenobarbital (PB) were used to prepare hepatic microsomes. Metabolism was evaluated in the presence and absence of an NADPH generator system and in the presence and absence of NADH. The generator system produced a greater extent of metabolism for both control and PB microsomes. NADH-catalyzed CCl4 metabolism occurred to a similar extent in control and PB microsomes, amounting to 9-10% and 5-6% of the NADPH rate in control and PB microsomes, respectively. Synergism by NADH occurred at the lowest concentrations of NADPH, apparently decreasing the Km for NADPH and having little effect on the Vmax. Addition of NAD+ produced synergism, as did the addition of 5' AMP, an inhibitor of nucleotide pyrophosphatase. Thus, the synergistic increase in CCl4 metabolism produced by NADH may occur in part from an increased availability of NADPH, as a result of decreased degradation, rather than by electron donation from NADH.

Nutrigenomics: Opportunities and Challenges K. Kornman and C. Fogarty Gene-Diet Interactions, Blood Lipids, and Cardiovascular Disease Risk: The Rise of Nutrigenetics J.M. Ordovas Diet-Disease Interactions at the Molecular Level: An Experimental Paradigm J. Kaput Anti-Inflammatory Phytochemicals: In Vitro and Ex Vivo Evaluation M. Lemay Lipid Peroxidation, Gene Expression, and Resveratrol: Implications in Atherosclerosis Ozgur Kutuk, Dilek Telci, and Huveyda Basaga Adipose Tissue Gene Expression in the Context of Inflammation and Obesity P.A. Kern Gene-Environment Interactions in Obesity: Implications for the Prevention and Treatment of Obesity L. Perusse Saturated Fat Consumption in Ancestral Human Diets: Implications for Contemporary Intakes L. Cordain Plant-Based Diets and Prevention of Cardiovascular Disease: Epidemiologic Evidence F.B. Hu Evolutionary Aspects of Diet, the Omega-6/Omega-3 Ratio, and Gene Expression A.P. Simopoulos Beyond Fiber: Whole Grains and Health J. Slavin Molecular Activities of Vitamin E J.M. Zingg and A. Azzi

The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F(1) mice, the mycotoxin fumonisin B(1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B(1) caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B(1) exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B(1) administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B(1). Fumonisin B(1) is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B(1) may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.

Preface o Strategies for Discovery of Bioactive Phytochemicals, Stephen O. Duke, Ph.D., Agnes M. Rimando, Franck E. Dayan, Camilo Canel, David E. Wedge, Mario R. Tellez, Kevin K. Schrader, Leslie A. Weston, Troy J. Smillie, Rex N. Paul and Mary V. Duke o QSAR and Molecular Modeling of Bioactive Phyto-Phenolics, Eric J. Lien, Ph.D. and Shijun Ren, Ph.D. o Chemoprevention by Phytochemical Modifiers of Carcinogen Metabolism, Stephen S. Hecht, Ph.D. o Clinical Trial Design for Evaluating Phytochemical Bioactivity, Kevin C. Maki, Ph.D. o The Use of Fermentable Fibers to Manage the Gastrointestinal Ecosystem, Randal K. Buddington, Ph.D. o Phytoantimicrobial (PAM) Agents as Multifunctional Food Additives, A.S. Naidu, Ph.D. o The Protective Effect of Tea on Cancer: Human Evidence, Junshi Chen, M.D. and Chi Han, M.D. o Effect of Genistein on Growth of Human Breast Cancer Cells in vitro and in vivo, William Helferich, Ph.D. o Cancer Prevention by Carotenoids and Curcumins, H. Nishino, M.D., Harukuni Tokuda, Michiaki Murakoshi, Yoshiko Satomi, Hirohiko Matsumoto, Mitsuhara Masuda, Ping Bu, Mari Onozuka, Shino Yamagguchi, Yoko Okuda, Junko Takayasu, Atsuko Nishino, Jun Tsuruta, Masato Okuda, Eiichiro Ichiishi, Kazuto Nosaka, Takao Konoshima, Toshimitsu Kato, Zohar Nir, Frederick Khachik, Norihiko Misawa, Tomio Narisawa and Nobuo Takasuka o Alfalfa Saponins: Chemistry and Application, Wieslaw A. Oleszek, Ph.D. o Saw Palmetto: Critical Review, Chemistry and Application, Paul Burbrick, Ph.D., Paul Johnson, B.S. and Kerry Stonebrook, M.S. o Effect of Garlic on Serum Cholesterol Levels, Christopher D. Gardner, Ph.D., Loaine Chatterjee, M.S. and Joseph Carlson, Ph.D., R.D. o Bioactives in Rice Bran and Rice Bran Oil, Rukmini Cheruvanky, Ph.D. o Designing Functional Foods to Enhance Health, Wayne R. Bidlack, Ph.D. and Wei Wang, Ph.D.

The practice of supplementing milk replacers fed to neonatal calves with high concentrations of vitamin A has raised concerns regarding the effect of excess vitamin A on the bioavailability of vitamin E. A 4 x 2 factorial experiment evaluated the effects of four dietary amounts of vitamin A [0, 1.78 [National Research Council (NRC)(6) requirement, control], 35.6 and 71.2 micromol daily as retinyl acetate] and two forms of vitamin E (RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate, 155 micromol daily) on plasma RRR-alpha-tocopherol and RRR-gamma-tocopherol and RRR-alpha-tocopherol associated with plasma lipoproteins (Lp) from milk replacer-fed Holstein calves from birth to 28 d of age. The VLDL, LDL, HDL and very high-density lipoprotein (VHDL) fractions were separated by ultracentrifugal flotation, and the amount of vitamin E associated with each fraction was determined by normal-phase HPLC. The amount and distribution of RRR-alpha-tocopherol in Lp fractions were unaffected by the form of dietary vitamin E. Plasma and Lp RRR-alpha-tocopherol concentrations increased with age (P0.0001) and were maximal at 28 d of age. Concentrations of RRR-alpha-tocopherol associated with Lp were 25% (P0.01) to 39% (P0.0001) lower in calves fed 35.6 and 71.2 micromol of vitamin A daily than in control calves at 28 d of age. The RRR-gamma-tocopherol concentrations were unaffected by dietary vitamin A (P/= 0.05). In conclusion, dietary vitamin A modulated the amount and distribution of RRR-alpha-tocopherol in the circulation of milk replacer-fed neonatal calves. Because of the essential antioxidant role of vitamin E, the health-related consequences associated with the depression of the LP RRR-alpha-tocopherol concentrations in calves fed vitamin A at 35.6 and 71.2 micromol need to be investigated.

Nutrition and food science have each enhanced the development of an abundant, nutritious, safe food supply. A healthy diet should contain all of the required nutrients and sufficient calories to balance energy expenditure and provide for growth and maintenance throughout the life cycle. Importantly, dietary factors are associated with 5 of the 10 leading causes of death, including coronary heart disease, certain types of cancer, stroke, noninsulin dependent diabetes mellitus and atherosclerosis. National health care expenditures for 1990 totaled $666 billion of which 30% are related to inappropriate diet. Identification of external factors that contribute to premature death would aid preventive efforts, improve the quality of life, and reduce health care costs. Even though genetic predisposition increases susceptible people's risk for many of these chronic diseases, these conditions may be diminished or prevented by improvements in the American diet. Each stage of the life cycle has specific nutrient needs. Throughout infancy, childhood and adolescence nutrients are required to meet the growth processes as well as cognitive function. During pregnancy nutrients are required for both mother and developing infant needs. Adult nutrition focuses on tissue maintenance, nutrient and energy needs, and disease prevention. As the population of elderly increase in number and greater age, nutritional needs must be met to minimize certain disease states and assure the quality of life. Nutrition associated health risks have been identified for coronary heart disease, cancer and diabetes mellitus. Recommendations for each includes a decrease in dietary fat, awareness of caloric intake and enhancement of nutrient density including an increase in fruit and vegetables. These recommendations also impact obesity and diminish the compounding of other disease states affected by excessive body weight. Calcium intake at early ages affects development of bone density and manifestation of osteoporosis. Current gaps in knowledge are also identified that could improve health. Numerous nutrients are being examined for their regulation of specific gene expressions and in the processes of transcription and translation. To offer food products with greater nutrient density or improved functional health ingredients, modification of existing foods is needed to assure an improved diet. Policies to improve health require integration of nutrition needs with economic growth and development, agriculture and food production, processing, marketing, health care and education, and includes changing life styles and food choices. Increased research support is required to achieve national health goals with emphasis on nutrition and food sciences. Education methods must be improved to better inform consumers, to encourage food producers and manufactures to produce healthier foods, to assure training of future professionals and to provide legislators with the basis to make informed decisions. Recommendations to CFERR are identified. Improved quality and availability of nutritious foods will result in a healthier, more productive population. A decrease in the occurrence and duration of chronic disease should diminish the cost of health care and allow these resources to further benefit the nation. International concerns about undernutrition include 780 million people who are malnourished, lacking sufficient food to meet their basic nutritional needs for protein and energy, and 2 billion people who subsist on diets lacking essential nutrients needed for growth, development and physiological maintenance. National concerns about undernutrition exist based on incomplete data identified by indices of hunger and characterized by an increased demand for food assistance for women, children and the elderly. Major health problems in the US impacted by diet and nutrition include coronary heart disease, atherosclerosis, some types of cancer, non-insulin dependent diabetes mellitus, hypert

Several good books exist in many fields. However, there is in each case only one book that becomes the seminal volume that represents all the key issues. Casarett & Doull’s Toxicology has become th...

Scientific research continues to point to the health benefits of including more fruits and vegetables in the diet. At the same time, some groups claim that pesticides used in their production pose significant health risks. This article reviews some of the position statements, describes the principles of risk and hazard assessment, and identifies regulatory processes to assure the safe use of pesticides.

This well-written text integrates the relationships between nutrients from food and the chemistry of living organisms. The sequential presentation, the figures and tables, the case studies, the app...

As the US population continues to age and live longer, it becomes readily apparent that health professionals need to have a clearer understanding of the health and nutritional problems of the geria...

Male Sprague-Dawley rats were pair fed either a control magnesium diet (480 mg/kg) or a magnesium-deficient diet (30 mg/kg) for 10 days to produce magnesium depletion. Serum magnesium concentration declined 60%, but tissue magnesium deficiency was not apparent. Hepatic parenchymal cells and microsomal membranes were isolated to evaluate in vitro metabolism of p-nitroanisole and conjugation of its metabolite, p-nitrophenol (pNP). O-Demethylation of p-nitroanisole was decreased slightly in both magnesium depletion hepatocytes and microsomal membranes. However, pNP glucuronide formation was specifically decreased 50% in the magnesium depletion cells at all p-nitroanisole concentrations. Similar results were found in the microsomal reaction system measuring pNP conjugation. Thus, early stages of magnesium depletion may result in a specific decrease in the pNP UDP-glucuronyl transferase activity.

Metal Ions in Biological System, Volume 36: Interrelations Between Free Radicals and Metal Ions in Life Processes. Astrid Sigel and Helmut Sigel, eds. New York: Marcel Dekker, Inc., 797 pp, 1999.Nu...

(1994). The Retinoids: Biology, Chemistry and Medicine, 2nd ed. Journal of the American College of Nutrition: Vol. 13, No. 6, pp. 675-676.

Green Tea: Health Benefits and Applications. edited by Yukihiko Hara. New York: Marcel Dekker, 252 pp, 2001.Since the late 1980’s green tea, green tea extracts and tea flavonoids have been studied ...

Introduction to Clinical Nutrition, by Vishwanath M. Sardesai, Marcel Dekker, Inc., New York, NY, 1997, 488 pages $75.Nutrition has evolved as a requisite part of the nation’s health over the last ...