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Despite dietary recommendations that have repeatedly underscored the importance of increasing consumption of fruits and vegetables, intakes worldwide are lower than recommended levels. Consequently, the diets of many individuals may be lacking in nutrients and phytonutrients typical of a diet rich in a variety of fruits and vegetables. In the present study, we estimated phytonutrient intakes by adults categorised by sex, level of fruit and vegetable consumption ( v.≥ 5 servings/d), and geographic diet cluster. Intakes of nine select phytonutrients were estimated from the 2002–4 World Health Survey fruit and vegetable servings intake data (n198 637), the FAO supply utilisation accounts data, and phytonutrient concentration data obtained from the US Department of Agriculture databases and the published literature. Percentage contributions to each phytonutrient intake from fruit and vegetable sources were also estimated. Estimated intakes of phytonutrients from fruits and vegetables varied across the thirteen geographic diet clusters, reflecting regional differences in both numbers and proportions of fruit and vegetable servings consumed, and the specific types of fruits and vegetables available in the diet. The mean phytonutrient intakes by adults consuming ≥ 5 servings/d of fruits and vegetables were approximately 2- to 6-fold the mean phytonutrient intakes by adults with low fruit and vegetable consumption (

Objective In developed countries with westernized diets, the excessive consumption of added sugar in beverages and highly refined and processed foods is associated with increased risk for obesity, diabetes, and cardiovascular diseases. As a major constituent of added sugars, fructose has been shown to cause a variety of adverse metabolic effects, such as impaired insulin sensitivity, hypertriglyceridemia, and oxidative stress. Recent studies have shown that ketohexokinase isoform C is the key enzyme responsible in fructose metabolism that drive’s fructose's adverse effects. The objective of this study was to identify botanical ingredients with potential for inhibitory activity against ketohexokinase-C and fructose-induced metabolic effects by using a series of in vitro model systems. Methods Extracts from 406 botanicals and 1200 purified phytochemicals were screened (initial concentration of 50 μg/mL and 50 μM, respectively) for their inhibitory activity using a cell free, recombinant human ketohexokinase-C assay. Dose response evaluations were conducted on botanical extracts and phytochemicals that inhibited ketohexokinase-C by > 30% and > 40%, respectively. Two different extract lots of the top botanical candidates were further evaluated in lysates of HepG2 cells overexpressing ketohexokinase-C for inhibition of fructose-induced ATP depletion. In addition, extracts were evaluated in intact Hep G2 cells for inhibition of fructose-induced elevation of triglyceride and uric acid production. Results Among the botanical extracts, phloretin (Malus domestica) extracts were the most potent (IC50: 8.9–9.2 μg/mL) followed by extracts of Angelica archangelica (IC50: 22.6 μg/mL—57.3 μg/mL). Among the purified phytochemicals, methoxy-isobavachalcone (Psoralea corylifolia, IC50 = 0.2 μM) exhibited the highest potency against ketohexokinase isoform C activity followed by osthole (Angelica archangelica, IC50 = 0.7 μM), cratoxyarborenone E (Cratoxylum prunifolium, IC50 = 1.0 μM), and α-/γ-mangostin (Cratoxylum prunifolium, IC50 = 1.5 μM). Extracts of Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis exhibited ketohexokinase inhibitory activity and blocked fructose-induced ATP depletion and fructose-induced elevation in triglyerides and uric acid. Conclusions Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis were the top four botanical candidiates identified with inhibitory activity against ketohexokinase-C. Future studies are needed to show proof of mechanism and the efficacy of these botanical extracts in humans to blunt the negative metabolic effects of fructose-containing added sugars.

Objective Although observational studies have shown that genotype may influence nutritional effects on target outcomes, there are few reported studies that stratified subjects by genotype before a nutritional intervention. This proof-of-concept trial determined whether specifically formulated botanical mixtures reduced inflammation in individuals with genetic variations that predispose to overexpression of interleukin-1β (IL-1β) and early heart disease. Methods Healthy adults with elevated C-reactive protein (CRP) were stratified into genetic groups based on being positive (IL1 Pos ) or negative (IL1 Neg ) for the at-risk IL-1 gene variations. IL1 Pos ( n = 39) and IL1 Neg ( n = 40) subjects were then randomized to the candidate botanical formulation or placebo. The botanical formulation included rose hips, a blueberry and blackberry mixture, and a grapevine extract. Results At 12 wk of dosing with the botanical formulation, IL-1β gene expression by stimulated peripheral blood mononuclear cells was significantly lower than at baseline and significantly lower than placebo in IL1 Pos and IL1 Neg subjects. Mean IL-1β gene expression treatment effect over the 12-wk period was greater in IL1 Pos than in IL1 Neg subjects. At 12 wk of dosing the botanical mixture produced no mean change in serum CRP levels. However, in IL1 Pos subjects, significantly more subjects achieved a reduction in CRP with the botanical mixture than with placebo. No CRP effect was observed in the IL1 Neg subjects. Conclusion This study represents one of a few prospective clinical trials in which genetic variations were shown to differentially influence nutrient effects on outcomes.

Background Diacylglyceride acyltransferase 1 (DGAT1) is the enzyme that adds the final fatty acid on to a diacylglyceride during triglyceride (TG) synthesis. DGAT1 plays a key role in the repackaging of dietary TG into circulating TG rich chylomicrons. A growing amount of research has indicated that an exaggerated postprandial circulating TG level is a risk indicator for cardiovascular and metabolic disorders. The aim of this research was to identify a botanical extract that inhibits intestinal DGAT1 activity and attenuates postprandial hypertriglyceridemia in overweight and obese humans. Methods Twenty individual phytochemicals and an internal proprietary botanical extract library were screened with a primary cell-free DGAT1 enzyme assay that contained dioleoyl glycerol and palmitoleoyl Coenzyme A as substrates plus human intestinal microsomes as the DGAT1 enzyme source. Botanical extracts with IC50 values

Background Individuals consuming diets dense in fruits and vegetables consume an array of phytonutrients as well as recognized nutritional components, including vitamins, minerals, and fiber. There is a growing body of evidence that phytonutrients may play positive roles in health. Objective The purpose of this research was to estimate usual intakes of nine individual phytonutrients by Americans consuming recommended levels of fruits and vegetables compared to intakes by adults not meeting these recommendations, and to identify contributions of food sources to total phytonutrient intakes. The phytonutrients examined in this study are found predominantly in fruits and vegetables. Design Food consumption data from the National Health and Nutrition Examination Surveys 2003-2006 and phytonutrient concentration data from US Department of Agriculture databases and the published literature were used to estimate energy-adjusted usual intakes. Student's t tests were used to compare mean energy-adjusted phytonutrient intakes between subpopulations who consumed recommended amounts of fruits and vegetables vs those who did not. Percentage contributions of each phytonutrient by food source were estimated for all adults. Results Energy-adjusted intakes of all phytonutrients other than ellagic acid were considerably higher among both men and women meeting dietary recommendations for fruit and vegetable intakes compared to those not meeting the recommendations; energy-adjusted intakes of ellagic acid were higher only among women meeting vs not meeting the recommendations. For five of the nine phytonutrients (α-carotene, β-cryptoxanthin, lycopene, hesperetin, and ellagic acid), a single food accounted for 64% or more of the total intake of the phytonutrient. Conclusions Energy-adjusted intakes of carotenoids and flavonoids are higher among men and women whose diets conform to dietary guidance for fruits and vegetables. A limited number of foods provide the majority of these phytonutrients. Findings from this research provide important reference information on the phytonutrient contributions of a diet rich in fruits and vegetables.

Background Botanical products are frequently used for treatment of nasal allergy. Three of these substances, Cinnamomum zeylanicum, Malpighia glabra, and Bidens pilosa, have been shown to have a number of anti-allergic properties in-vitro. The current study was conducted to determine the effects of these combined ingredients upon the nasal response to allergen challenge in patients with seasonal allergic rhinitis. Methods Twenty subjects were randomized to receive the combination botanical product, (CBP) 2 tablets three times a day, loratadine, 10 mg once a day in the morning, or placebo, using a randomized, double-blinded crossover design. Following 2 days of each treatment and during the third day of treatment, subjects underwent a nasal allergen challenge (NAC), in which nasal symptoms were assessed after each challenge dose and every 2 hours for 8 hours. Nasal lavage fluid was assessed for tryptase, prostaglandin D2, and leukotriene E4 concentrations and inflammatory cells. Results Loratadine significantly reduced the total nasal symptom score during the NAC compared with placebo (P = 0.04) while the CBP did not. During the 8 hour period following NAC, loratadine and the CBP both reduced NSS compared with placebo (P = 0.034 and P = 0.029, respectively). Analysis of nasal lavage fluid demonstrated that the CBP prevented the increase in prostaglandin D2 release following NAC, while neither loratadine nor placebo had this effect. None of the treatments significantly affected tryptase or leukotriene E4 release or inflammatory cell infiltration. Conclusion The CBP significantly reduced NSS during the 8 hours following NAC and marginally inhibited the release of prostaglandin D2 into nasal lavage fluid, suggesting potential clinical utility in patients with allergic rhinitis.

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 normal growth and differentiation of the epidermis require an adequate supply of vitamin A. The active form of vitamin A for normal epidermal homeostasis is retinoic acid (RA). Retinoic acid controls the expression of retinoid-responsive genes via interactions of the retinoic acid/nuclear receptor complexes at specific DNA sequences in their control regions. The message conveyed by RA is likely modulated by the concentration of the ligand available for binding to the receptors. Following the uptake of plasma retinol, epidermal keratinocytes synthesize retinoic acid via two sequential reactions with retinaldehyde as an intermediate. Several retinol dehydrogenase (RDH) enzymes, members of the short-chain dehydrogenase/reductase (SDR) gene superfamily, catalyze the first and rate-limiting step that generates retinaldehyde from retinol bound to cellular retinol-binding protein (holo-CRBP). However, little is known about these enzymes and their genes in the epidermal cells. Our work describes the first member of the RDH family found in epidermis. We show that this gene is expressed predominantly in the differentiating spinous layers and that it is under positive, feed-forward regulation by retinoic acid. It encodes a protein that, using NAD+ as a preferred cofactor, utilizes free and CRBP-bound all-trans-retinol and steroids as substrates.

The accessibility of plasma retinol and retinoic acid to the epidermis may be influenced by the number and metabolic capacity of fibroblasts in papillary dermis. The metabolism of retinol-binding protein-bound all-trans-retinol, and albumin-bound all-trans-retinoic acid, by fibroblasts cultured on plastic dishes or in type I collagen gels, was examined. There were no significant differences in the metabolism of either retinoid by fibroblasts as a function of culture condition. There were large differences between retinoids, however. Retinoic acid was rapidly taken up and metabolized to unidentified polar metabolites that were released to the medium. Metabolic capacity was not saturated up to a medium retinoic acid concentration of 1 microM, and was induced further by prior exposure to retinoic acid. In contrast, retinol, although readily taken up, was not metabolized, i.e., neither retinoic acid nor retinyl ester was formed. By immunohistochemistry, the average number of fibroblasts in a 100 microm thickness of papillary dermis was estimated to be 1 x 10(6) cells per cm2. Utilizing this value, the capacity of dermal fibroblasts to metabolize retinoic acid based on fibroblast abundance in the dermis was calculated. The results suggest that fibroblasts could limit delivery of plasma retinoic acid but not retinol to the epidermis on the basis of their metabolic capacity and abundance in the dermis.

Keratinocytes differentiating in vitro exhibit greater cytosolic capacity for retinoic acid synthesis from retinol or retinaldehyde as compared to nondifferentiated cells (Siegenthaler et al. 1990. Biochem. J. 268: 371-378), and increased expression of CRABP-II (Siegenthaler et al. 1988. Exp. Cell Res. 178: 114-126). Based on these observations, the content and disposition of ( 3 H)retinoic acids were deter- mined in intact, nondifferentiated and differentiating kera- tinocytes incubated with ( 3 H)retinaldehyde or ( 3 H)retinol. Differentiating keratinocytes contained higher levels of ( 3 H) retinoic acids compared to undifferentiated cells when either ( 3 H)retinaldehyde or ( 3 H)retinol was the substrate. The larg- est increases in ( 3 H)retinoic acids were achieved with ( 3 H)ret- inaldehyde. Differentiation-associated increases in ( 3 H)reti- noic acids correlated with cellular content of retinoid alcohol substrates in incubations with retinaldehyde but not in incu- bations with retinol. Consistent with previous observations, CRABP-II was significantly increased in differentiating cells. Moreover, newly synthesized ( 3 H)retinoic acids were retained within cells bound to CRABP-II. The results suggest that increasing cellular concentration of retinoic acids in in vitro differentiating keratinocytes is achieved by a combination of increased activity of the retinoic acid synthesis pathway and increased cellular content of CRABP-II.— Chatellard-Gruaz, D., R. K. Randolph, G. Hagens, J-H. Saurat, and G. Siegen- thaler. Differentiation of human epidermal keratinocytes is accompanied by increased expression of CRABP-II and in- creased cellular concentration of retinoic acids: retention of newly synthesized retinoic acids by CRABP-II. J. Lipid Res. 1998. 39: 1421-1429.

The potential for all- trans -retinoic acid to regulate the metabolism of 3 H-retinol and 3 H-3,4-didehydro-retinol was examined in cultured human epidermal keratinocytes. Confluent cultures were treated daily with medium containing 5% fetal bovine serum or the same medium supplemented with nanomolar concentrations of all- trans -retinoic acid for up to 3 d. During the last 24h of treatment, cells were incubated with 3 H-retinol or 3 H-3,4-didehydroretinol for 24h (isotopic steady state) to label the endogenous retinoids. After the labeling period, one group of cells was harvested and another group was allowed to incubate for an additional 24h in the absence of medium retinol for the determination of endogenous 3 H-retinoid utilization. The 3 H-retinoids present in cells were extracted and quantitated by reverse-phased high-pressure liquid chromatography. Keratinocytes treated with retinoic acid and labeled with 3 H-retinol exhibited time- and concentration-dependent (i) increases in retinyl ester mass, (ii) increases in the rate of retinyl ester synthesis, (iii) decreases in retinyl ester utilization and (iv) decreases in the cellular concentrations of retinoic and 3,4-didehydroretinoic acids. There was no effect of exogenous retinoic acid on its own metabolism. Cells labeled with 3 H-3,4-didehydroretinol exhibited exclusive labeling of vitamin A 2 -related retinoids suggesting that the A 1 to A 2 conversion is not reversible. Treatment of cells with low nanomolar concentrations of retinoic acid decreased the utilization of 3,4-didehydroretinyl esters, decreased the production of 3,4-didehydroretinoic acid but had no effect on the synthesis of 3,4-didehydroretinol or its esters. The results demonstrate that keratinocytes respond to extracellular retinoic acid by decreasing endogenous production of active retinoids, sequestering extracellular substrate retinol as retinyl ester, and decreasing ester utilization.