Is vitamin D3 (cholecalciferol) preferable to D2 (ergocalciferol)?

Vitamin D(3) is more potent than vitamin D(2) in humans.

BACKGROUND: Current unitage for the calciferols suggests that equimolar quantities of vitamins D(2) (D2) and D(3) (D3) are biologically equivalent. Published studies yield mixed results. OBJECTIVE: The aim of the study was to compare the potencies of D2 and D3. DESIGN: The trial used a single-blind, randomized design in 33 healthy adults. Calciferols were dosed at 50,000 IU/wk for 12 wk. Principal outcome variables were area under the curve for incremental total 25-hydroxyvitamin D [25(OH)D] and change in calciferol content of sc fat. RESULTS: Incremental mean (sd) 25(OH)D area under the curve at 12 wk was 1366 ng · d/ml (516) for the D2-treated group and 2136 (606) for the D3 (P < 0.001). Mean (sd) steady-state 25(OH)D increments showed similar differences: 24 ng/ml for D2 (10.3) and 45 ng/ml (16.2) for D3 (P <0.001). Subcutaneous fat content of D2 rose by 50 μg/kg in the D2-treated group, and D3 content rose by 104 μg/kg in the D3-treated group. Total calciferol in fat rose by only 33 ng/kg in the D2-treated, whereas it rose by 104 μg/kg in the D3-treated group. Extrapolating to total body fat D3, storage amounted to just 17% of the administered dose. CONCLUSION: D3 is approximately 87% more potent in raising and maintaining serum 25(OH)D concentrations and produces 2- to 3-fold greater storage of vitamin D than does equimolar D2. For neither was there evidence of sequestration in fat, as had been postulated for doses in this range. Given its greater potency and lower cost, D3 should be the preferred treatment option when correcting vitamin D deficiency.

Low Vitamin D Status: Definition, Prevalence, Consequences and Correction

Vitamin D is obtained from cutaneous production when 7-dehydrocholesterol is converted to vitamin D3 (cholecalciferol) by ultraviolet B radiation or by oral intake of vitamin D2 (ergocalciferol) and D3. An individual's vitamin D status is best evaluated by measuring the circulating 25-hydroxyvitamin D [25(OH)D] concentration. Though controversy surrounds the definition of low vitamin D status, there is increasing agreement that the optimal circulating 25(OH)D level should be ~30-32 ng/ml or above. Using this definition, it has been is estimated that approximately three quarters of all adults in the United States are low. Classically, low vitamin D status has skeletal consequences such as osteomalacia/rickets. More recently, associations between low vitamin D status and increased risk for various non-skeletal morbidities have been recognized; whether all of these associations are causally related to low vitamin D status remains to be determined. To achieve optimal vitamin D status, daily intakes of at least 1000 IU or more of vitamin D are required. The risk of toxicity with “high” amounts of vitamin D intake is low. Substantial between-individual variability exists in response to the same administered vitamin D dose. When to monitor 25(OH)D levels has received little attention. Supplementation with vitamin D3 may be preferable to vitamin D2.

Ergocalciferol from mushrooms or supplements consumed with a standard meal increases 25-hydroxyergocalciferol but decreases 25-hydroxycholecalcifer...

Few foods contain ergocalciferol or cholecalciferol. Treatment of mushrooms with UV light increases ergocalciferol content and could provide a dietary source of vitamin D. We evaluated the impact of consuming UV-treated white button mushrooms (Agaricus bisporus) on the vitamin D status of healthy adults. Thirty-eight volunteers were randomized to 4 treatments consumed with a standard meal for 6 wk: the control (C) group received untreated mushrooms providing 0.85 μg/d ergocalciferol (n = 10); groups M1 and M2 received UV-treated mushrooms providing 8.8 (n = 10) and 17.1 μg/d (n = 9), respectively; and the supplement (S) group received purified ergocalciferol plus untreated mushrooms, providing a total of 28.2 μg/d (n = 9). Serum total 25-hydroxyvitamin D [25(OH)D] and 25-hydroxyergocalciferol [25(OH)D2] were 83 ± 38 and 2.4 ± 2.0 nmol/L, respectively, at baseline (mean ± SD). At wk 6, 25(OH)D2 had increased and was higher in all treatment groups than in the C group, whereas 25-hydroxycholecalciferol [25(OH)D3] had decreased and was lower in the M2 and S groups than in the C group. Increases in 25(OH)D2 for groups C, M1, M2, and S were 1.2 ± 5.2, 13.8 ± 7.3, 12.7 ± 3.7, and 32.8 ± 3.3 nmol/L and decreases in 25(OH)D3 were -3.9 ± 16.3, -10.4 ± 6.4, -20.6 ± 14.6, and -29.5 ± 15.9 nmol/L, respectively. Concentrations did not change in group C. In summary, ergocalciferol was absorbed and metabolized to 25(OH)D2 but did not affect vitamin D status, because 25(OH)D3 decreased proportionally.

Vitamin D supplementation for prevention of mortality in adults.

BACKGROUND: The available evidence on vitamin D and mortality is inconclusive. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D for prevention of mortality in adults. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science (to January 2011). We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. SELECTION CRITERIA: We included randomised trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention. Vitamin D could have been administered as supplemental vitamin D (vitamin D(3) (cholecalciferol) or vitamin D(2) (ergocalciferol)) or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol) or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: Six authors extracted data independently. Random-effects and fixed-effect model meta-analyses were conducted. For dichotomous outcomes, we calculated the risk ratios (RR). To account for trials with zero events, meta-analyses of dichotomous data were repeated using risk differences (RD) and empirical continuity corrections. Risk of bias was considered in order to minimise risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. MAIN RESULTS: Fifty randomised trials with 94,148 participants provided data for the mortality analyses. Most trials included elderly women (older than 70 years). Vitamin D was administered for a median of two years. More than one half of the trials had a low risk of bias. Overall, vitamin D decreased mortality (RR 0.97, 95% confidence interval (CI) 0.94 to 1.00, I(2) = 0%). When the different forms of vitamin D were assessed separately, only vitamin D(3) decreased mortality significantly (RR 0.94, 95% CI 0.91 to 0.98, I(2) = 0%; 74,789 participants, 32 trials) whereas vitamin D(2), alfacalcidol, or calcitriol did not. Trial sequential analysis supported our finding regarding vitamin D(3), corresponding to 161 individuals treated to prevent one additional death. Vitamin D(3) combined with calcium increased the risk of nephrolithiasis (RR 1.17, 95% CI 1.02 to 1.34, I(2) = 0%). Alfacalcidol and calcitriol increased the risk of hypercalcaemia (RR 3.18, 95% CI 1.17 to 8.68, I(2) = 17%). Data on health-related quality of life and health economics were inconclusive. AUTHORS' CONCLUSIONS: Vitamin D in the form of vitamin D(3) seems to decrease mortality in predominantly elderly women who are mainly in institutions and dependent care. Vitamin D(2), alfacalcidol, and calcitriol had no statistically significant effect on mortality. Vitamin D(3) combined with calcium significantly increased nephrolithiasis. Both alfacalcidol and calcitriol significantly increased hypercalcaemia.

Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis

Background: Currently, there is a lack of clarity in the literature as to whether there is a definitive difference between the effects of vitamins D2 and D3 in the raising of serum 25-hydroxyvitamin D [25(OH)D]. Objective: The objective of this article was to report a systematic review and meta-analysis of randomized controlled trials (RCTs) that have directly compared the effects of vitamin D2 and vitamin D3 on serum 25(OH)D concentrations in humans. Design: The ISI Web of Knowledge (January 1966 to July 2011) database was searched electronically for all relevant studies in adults that directly compared vitamin D3 with vitamin D2. The Cochrane Clinical Trials Registry, International Standard Randomized Controlled Trials Number register, and clinicaltrials.gov were also searched for any unpublished trials. Results: A meta-analysis of RCTs indicated that supplementation with vitamin D3 had a significant and positive effect in the raising of serum 25(OH)D concentrations compared with the effect of vitamin D2 (P = 0.001). When the frequency of dosage administration was compared, there was a significant response for vitamin D3 when given as a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the effect was lost with daily supplementation. Conclusions: This meta-analysis indicates that vitamin D3 is more efficacious at raising serum 25(OH)D concentrations than is vitamin D2, and thus vitamin D3 could potentially become the preferred choice for supplementation. However, additional research is required to examine the metabolic pathways involved in oral and intramuscular administration of vitamin D and the effects across age, sex, and ethnicity, which this review was unable to verify.

A wholly nutritional 'multifocal angiostatic therapy' for control of disseminated cancer.

A great deal of effort is now being devoted to the development of new drugs that hopefully will control the spread of inoperable cancer by safely inhibiting tumor-evoked angiogenesis. However, there is growing evidence that certain practical nutritional measures have the potential to slow tumor angiogenesis, and it is reasonable to anticipate that, by combining several measures that work in distinct but complementary ways to impede the angiogenic process, a clinically useful 'multifocal angiostatic therapy' (MAT) might be devised. Several measures which might reasonably be included in such a protocol are discussed below, and include: a low-fat, low-glycemic index vegan diet, which may down-regulate the systemic IGF-I activity that supports angiogenesis; supplemental omega-3-rich fish oil, which has been shown to inhibit endothelial expression of Flk-1, a functionally crucial receptor for VEGF, and also can suppress tumor production of pro-angiogenic eicosanoids; high-dose selenium, which has recently been shown to inhibit tumor production of VEGF; green tea polyphenols, which can suppress endothelial responsiveness to both VEGF and fibroblast growth factor; and high-dose glycine, whose recently reported angiostatic activity may reflect inhibition of endothelial cell mitosis, possibly mediated by activation of glycine-gated chloride channels. In light of evidence that tumor-evoked angiogenesis has a high requirement for copper, copper depletion may have exceptional potential as an angiostatic measure, and is most efficiently achieved with the copper-chelating drug tetrathiomolybdate. If logistical difficulties make it difficult to acquire this experimental drug, high-dose zinc supplementation can achieve a slower depletion of the body's copper pool, and in any case can be used as maintenance therapy to maintain an adequate level of copper depletion. A provisional protocol is offered for a nutritionally based MAT entailing a vegan diet and supplemental intakes of fish oil, selenium, green tea polyphenols, glycine, and zinc. Inasmuch as cox-2 is overexpressed in many cancers, and cAMP can boost tumor production of various angiogenic factors as well as autogenous growth factors, adjunctive use of cox-2-specific NSAIDS may be warranted in some cases.

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.

OBJECTIVE: The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. PARTICIPANTS: The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D(2) or vitamin D(3) was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

Omega-3 fatty acids and antioxidants in edible wild plants.

Human beings evolved on a diet that was balanced in the omega-6 and omega-3 polyunsaturated fatty acids (PUFA), and was high in antioxidants. Edible wild plants provide alpha-linolenic acid (ALA) and higher amounts of vitamin E and vitamin C than cultivated plants. In addition to the antioxidant vitamins, edible wild plants are rich in phenols and other compounds that increase their antioxidant capacity. It is therefore important to systematically analyze the total antioxidant capacity of wild plants and promote their commercialization in both developed and developing countries. The diets of Western countries have contained increasingly larger amounts of linoleic acid (LA), which has been promoted for its cholesterol-lowering effect. It is now recognized that dietary LA favors oxidative modification of low density lipoprotein (LDL) cholesterol and increases platelet response to aggregation. In contrast, ALA intake is associated with inhibitory effects on the clotting activity of platelets, on their response to thrombin, and on the regulation of arachidonic acid (AA) metabolism. In clinical studies, ALA contributed to lowering of blood pressure, and a prospective epidemiological study showed that ALA is inversely related to the risk of coronary heart disease in men. Dietary amounts of LA as well as the ratio of LA to ALA appear to be important for the metabolism of ALA to longer-chain omega-3 PUFAs. Relatively large reserves of LA in body fat. as are found in vegans or in the diet of omnivores in Western societies, would tend to slow down the formation of long-chain omega-3 fatty acids from ALA. Therefore, the role of ALA in human nutrition becomes important in terms of long-term dietary intake. One advantage of the consumption of ALA over omega-3 fatty acids from fish is that the problem of insufficient vitamin E intake does not exist with high intake of ALA from plant sources.

Vitamin D2 Is as Effective as Vitamin D3 in Maintaining Circulating Concentrations of 25-Hydroxyvitamin D

Context: Two reports suggested that vitamin D2 is less effective than vitamin D3 in maintaining vitamin D status. Objective: Our objective was to determine whether vitamin D2 was less effective than vitamin D3 in maintaining serum 25-hydroxyvitamin D levels or increased the catabolism of 25-hydroxyvitamin D3. Subjects and Design: This was a randomized, placebo-controlled, double-blinded study of healthy adults ages 18–84 yr who received placebo, 1000 IU vitamin D3, 1000 IU vitamin D2, or 500 IU vitamin D2 plus 500 IU vitamin D3 daily for 11 wk at the end of the winter. Results: Sixty percent of the healthy adults were vitamin D deficient at the start of the study. The circulating levels of 25-hydroxyvitamin D (mean ± sd) increased to the same extent in the groups that received 1000 IU daily as vitamin D2 (baseline 16.9 ± 10.5 ng/ml; 11 wk 26.8 ± 9.6 ng/ml), vitamin D3 (baseline 19.6 ± 11.1 ng/ml; 11 wk 28.9 ± 11.0 ng/ml), or a combination of 500 IU vitamin D2 and 500 IU vitamin D3 (baseline 20.2 ± 10.4 ng/ml; 11 wk 28.4 ± 7.7 ng/ml). The 25-hydroxyvitamin D3 levels did not change in the group that received 1000 IU vitamin D2 daily. The 1000 IU dose of vitamin D2 or vitamin D3 did not raise 25-hydroxyvitamin D levels in vitamin D-deficient subjects above 30 ng/ml. Conclusion: A 1000 IU dose of vitamin D2 daily was as effective as 1000 IU vitamin D3 in maintaining serum 25-hydroxyvitamin D levels and did not negatively influence serum 25-hydroxyvitamin D3 levels. Therefore, vitamin D2 is equally as effective as vitamin D3 in maintaining 25-hydroxyvitamin D status.

Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis.

There is strong evidence indicating that elevated plasma total homocysteine (tHcy) levels are a major independent biomarker and/or a contributor to chronic conditions, such as CVD. A deficiency of vitamin B₁₂ can elevate homocysteine. Vegetarians are a group of the population who are potentially at greater risk of vitamin B₁₂ deficiency than omnivores. This is the first systematic review and meta-analysis to appraise a range of studies that compared the homocysteine and vitamin B₁₂ levels of vegetarians and omnivores. The search methods employed identified 443 entries, from which, by screening using set inclusion and exclusion criteria, six eligible cohort case studies and eleven cross-sectional studies from 1999 to 2010 were revealed, which compared concentrations of plasma tHcy and serum vitamin B₁₂ of omnivores, lactovegetarians or lacto-ovovegetarians and vegans. Of the identified seventeen studies (3230 participants), only two studies reported that vegan concentrations of plasma tHcy and serum vitamin B₁₂ did not differ from omnivores. The present study confirmed that an inverse relationship exists between plasma tHcy and serum vitamin B₁₂, from which it can be concluded that the usual dietary source of vitamin B₁₂ is animal products and those who choose to omit or restrict these products are destined to become vitamin B₁₂ deficient. At present, the available supplement, which is usually used for fortification of food, is the unreliable cyanocobalamin. A well-designed study is needed to investigate a reliable and suitable supplement to normalise the elevated plasma tHcy of a high majority of vegetarians. This would fill the gaps in the present nutritional scientific knowledge.

Bioavailability of vitamin D₂ from UV-B-irradiated button mushrooms in healthy adults deficient in serum 25-hydroxyvitamin D: a randomized controll...

BACKGROUND/OBJECTIVES: Mushrooms contain very little or any vitamin D(2) but are abundant in ergosterol, which can be converted into vitamin D(2) by ultraviolet (UV) irradiation. Our objective was to investigate the bioavailability of vitamin D(2) from vitamin D(2)-enhanced mushrooms by UV-B in humans, and comparing it with a vitamin D(2) supplement. SUBJECTS/METHODS: Fresh mushrooms were irradiated with an UV-B dose of 1.5 J/cm(2), increasing vitamin D(2) content from <1 to 491 μg/100 g and made to an experimental soup. In this 5-week, single-blinded, randomized, placebo-controlled trial, 26 young subjects with serum 25-hydroxyvitamin D (25OHD) ≤ 50 nmol/l were randomly assigned into three groups ((a) mushroom, (b) supplement and (c) placebo). They received during winter (a) 28,000 IU (700 μg) vitamin D(2) via the experimental soup, or (b) 28,000 IU vitamin D(2) via a supplement or (c) placebo, respectively. RESULTS: After 2 weeks, serum 25OHD was significantly higher in the mushroom than in the placebo group (P=0.001). The serum 25OHD concentrations in the mushroom and supplement groups rose significantly and similarly over the study period by 3.9 nmol/l (95% confidence interval (95% CI): 2.9, 4.8) and by 4.7 nmol/l per week (95% CI: 3.8, 5.7), respectively. CONCLUSIONS: We are the first to demonstrate in humans that the bioavailability of vitamin D(2) from vitamin D(2)-enhanced button mushrooms via UV-B irradiation was effective in improving vitamin D status and not different to a vitamin D(2) supplement. This trial was registered at http://germanctr.de as DRKS00000195.

Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment

Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.

Effects of tomato extract on human platelet aggregation in vitro.

Among all fruits tested in vitro for their anti-platelet property, tomato had the highest activity followed by grapefruit, melon, and strawberry, whereas pear and apple had little or no activity. Tomato extract (20-50 microl of 100% juice) inhibited both ADP- and collagen-induced aggregation by up to 70% but could not inhibit arachidonic acid-induced platelet aggregation and concomitant thromboxane synthesis under similar experimental conditions. The anti-platelet components (MW <1000 Da) in tomatoes are water soluble, heat stable and are concentrated in the yellow fluid around the seeds. The active fractions were separated using gel filtration and HPLC. The aqueous fraction (110 000 xg supernatant) of tomatoes containing anti-platelet activity was subjected to gel filtration column chromatography (Biogel P2 column). The activity was fractionated into two peaks, peak-3 and peak-4 (major peak). Subsequently, peak-4 was further purified by HPLC using a reversed-phase column. NMR and mass spectroscopy studies indicated that peak F2 (obtained from peak 4) contained adenosine and cytidine. Deamination of peak F2 with adenosine deaminase almost completely abolished its anti-platelet activity, confirming the presence of adenosine in this fraction. In comparison, deamination of peak-4 resulted in only partial loss of inhibitory activity while the activity of peak-3 remained unaffected. These results indicate that tomatoes contain anti-platelet compounds in addition to adenosine. Unlike aspirin, the tomato-derived compounds inhibit thrombin-induced platelet aggregation. All these data indicate that tomato contains very potent anti-platelet components, and consuming tomatoes might be beneficial both as a preventive and therapeutic regime for cardiovascular disease.

Selective induction of apoptosis of human oral cancer cell lines by avocado extracts via a ROS-mediated mechanism.

Avocados have a high content of phytochemicals with potential chemopreventive activity. Previously we reported that phytochemicals extracted from avocado meat into a chloroform partition (D003) selectively induced apoptosis in cancer but not normal, human oral epithelial cell lines. In the present study, we observed that treatment of human oral cancer cell lines containing high levels of reactive oxygen (ROS) with D003 increased ROS levels twofold to threefold and induced apoptosis. In contrast, ROS levels increased only 1.3-fold, and apoptosis was not induced in the normal cell lines containing much lower levels of basal ROS. When cellular ROS levels in the malignant cell lines were reduced by N-acetyl-l-cysteine (NAC), cells were resistant to D003 induced apoptosis. NAC also delayed the induction of apoptosis in dominant negative FADD-expressing malignant cell lines. D003 increased ROS levels via mitochondrial complex I in the electron transport chain to induce apoptosis. Normal human oral epithelial cell lines transformed with HPV16 E6 or E7 expressed higher basal levels of ROS and became sensitive to D003. These data suggest that perturbing the ROS levels in human oral cancer cell lines may be a key factor in selective apoptosis and molecular targeting for chemoprevention by phytochemicals.

Fostering antioxidant defences: up-regulation of antioxidant genes or antioxidant supplementation?

Vitamins have traditionally been considered as food components that are required in the normal diet to prevent deficiencies. However, a newer concept of the function of vitamins in nutrition has taken them beyond simply prevention of deficiency symptoms. This concept considers that many vitamins, when taken in relatively large doses, have important functions beyond preventing deficiencies. Linus Pauling was instrumental in putting forward this concept, particularly for vitamin C. Thus, relatively high intakes of vitamins, and in particular vitamins C and E which are antioxidants, are considered to be healthy for the human population. This may be true in some special situations such as, for instance, the prevention of Alzheimer's disease progression. However, recent epidemiological evidence has not supported the claim that antioxidant vitamins increase well-being and prolong life span. In fact, vitamin supplementation may be even detrimental and reduce life span. A new concept that we would like to put forward is that nutrients up-regulate the endogenous antioxidant defences. This is particularly true in the case of phytoestrogens for example, which bind to oestrogen receptors and eventually up-regulate the expression of antioxidant genes. In this review we discuss the pros and cons of antioxidant vitamin supplementation and also the possibility that the ingestion of some nutrients may be very effective in increasing antioxidant defences by up-regulating the activity of antioxidant enzymes which are normally present in the cell.

Bioequivalence of Docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food.

Docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, is important for eye and brain development and ongoing visual, cognitive, and cardiovascular health. Unlike fish-sourced oils, the bioavailability of DHA from vegetarian-sourced (algal) oils has not been formally assessed. We assessed bioequivalence of DHA oils in capsules from two different algal strains versus bioavailability from an algal-DHA-fortified food. Our 28-day randomized, placebo-controlled, parallel group study compared bioavailability of (a) two different algal DHA oils in capsules ("DHASCO-T" and "DHASCO-S") at doses of 200, 600, and 1,000 mg DHA per day (n = 12 per group) and of (b) an algal-DHA-fortified food (n = 12). Bioequivalence was based on changes in plasma phospholipid and erythrocyte DHA levels. Effects on arachidonic acid (ARA), docosapentaenoic acid-n-6 (DPAn-6), and eicosapentaenoic acid (EPA) were also determined. Both DHASCO-T and DHASCO-S capsules produced equivalent DHA levels in plasma phospholipids and erythrocytes. DHA response was dose-dependent and linear over the dose range, plasma phospholipid DHA increased by 1.17, 2.28 and 3.03 g per 100 g fatty acid at 200, 600, and 1,000 mg dose, respectively. Snack bars fortified with DHASCO-S oil also delivered equivalent amounts of DHA on a DHA dose basis. Adverse event monitoring revealed an excellent safety and tolerability profile. Two different algal oil capsule supplements and an algal oil-fortified food represent bioequivalent and safe sources of DHA.

Zinc and multi-mineral supplementation should mitigate the pathogenic impact of cadmium exposure.

High-level cadmium (Cd) exposure has long been known to induce nephropathy, severe osteoporosis, and fractures in humans. More recent epidemiology, however, reveals that, in populations not known to have important industrial exposure to this heavy metal, high-normal blood or urine Cd levels correlate with increased risk for vascular disorders, cancers, diabetes, and total mortality, as well as osteoporosis and nephropathy. Since these disorders appear unlikely to expedite Cd absorption, and since Cd has promoted these pathologies in rodent studies, it seems reasonable to conclude that Cd is an important mediating risk factor for these disorders in humans. Avoiding tobacco smoke or frequent ingestion of shellfish or organ meats can lessen humans exposure to Cd, but the chief dietary sources of Cd are plant-derived foods - green leafy vegetables, whole grains, tubers, and root vegetables - typically recommended for their health-supportive properties; indeed, among non-smokers, vegans tend to have the highest Cd body burden. Fortunately, iron sufficiency and ample dietary intakes of calcium, magnesium, and zinc can impede absorption of dietary Cd, both by down-regulating intestinal expression of mineral transporters, and by directly competing with Cd for access to these transporters. Correction of iron deficiency appears to be of particular importance for controlling Cd absorption. Moreover, zinc supplementation can counteract the toxicity of Cd already in the body via induction of metallothionein, which binds Cd avidly via its sulfhydryl groups; so long as it remains sequestered in this form, Cd is innocuous. Zinc supplementation may in any case be recommendable, as optimal zinc status exerts protective anti-inflammatory, antioxidant, and immunosupportive effects. Inasmuch as the toxicity of Cd appears to be mediated in large part by oxidative stress, ingestion of spirulina, lipoic acid, melatonin, and N-acetylcysteine may also have potential for mitigating the risk associated with Cd exposure, as suggested by rodent studies. Hence, although Cd may prove to be a major risk factor for morbidity and mortality in humans, practical strategies for limiting its absorption and pathogenic impact are at hand. Copyright © 2012 Elsevier Ltd. All rights reserved.

Treatment of Hypovitaminosis D in Infants and Toddlers

Context: Hypovitaminosis D appears to be on the rise in young children, with implications for skeletal and overall health. Objective: The objective of the study was to compare the safety and efficacy of vitamin D2 daily, vitamin D2 weekly, and vitamin D3 daily, combined with supplemental calcium, in raising serum 25-hydroxyvitamin D [25(OH)D] and lowering PTH concentrations. Design: This was a 6-wk randomized controlled trial. Setting: The study was conducted at an urban pediatric clinic in Boston. Subjects: Forty otherwise healthy infants and toddlers with hypovitaminosis D [25(OH)D < 20 ng/ml] participated in the study. Interventions: Participants were assigned to one of three regimens: 2,000 IU oral vitamin D2 daily, 50,000 IU vitamin D2 weekly, or 2,000 IU vitamin D3 daily. Each was also prescribed elemental calcium (50 mg/kg·d). Infants received treatment for 6 wk. Main Outcome Measures: Before and after treatment, serum measurements of 25(OH)D, PTH, calcium, and alkaline phosphatase were taken. Results: All treatments approximately tripled the 25(OH)D concentration. Preplanned comparisons were nonsignificant: daily vitamin D2 vs. weekly vitamin D2 (12% difference in effect, P = 0.66) and daily D2 vs. daily D3 (7%, P = 0.82). The mean serum calcium change was small and similar in the three groups. There was no significant difference in PTH suppression. Conclusions: Short-term vitamin D2 2,000 IU daily, vitamin D2 50,000 IU weekly, or vitamin D3 2,000 IU daily yield equivalent outcomes in the treatment of hypovitaminosis D among young children. Therefore, pediatric providers can individualize the treatment regimen for a given patient to ensure compliance, given that no difference in efficacy or safety was noted among these three common treatment regimens.

No evidence supports vitamin E indiscriminate supplementation.

For many years, the prevailing concept was that LDL oxidation plays the central role in atherogenesis. As a consequence, supplementation of antioxidants, particularly vitamin E, became very popular. Unfortunately, major randomized clinical trials yielded disappointing results and recent meta-analyses concluded that indiscriminate, high dose vitamin E supplementation results in increased mortality. This conclusion raised (quite reasonable) criticism, much of which referred to the characteristics of meta-analysis. In our recent study, we used a Markov-model approach, which is free of most of the limitations of meta-analyses. Our major finding was that the average quality-adjusted life years (QALY) of vitamin E- supplemented individuals was 0.30 QALY (95%CI 0.21 to 0.39) less than that of untreated people. In our view, this supports the view that indiscriminate supplementation of high dose vitamin E can not be recommended to the general public.In the present communication we address several recent studies that demonstrated negative effects of vitamin E and raise possible mechanisms that may be responsible for the harmful effects of vitamin E supplementation. We also review recent studies conducted with specific groups of patients that gained from vitamin E supplementation, indicating that although, on the average, indiscriminate supplementation of high dose vitamin E is not beneficial, specific populations may gain from vitamin E. The challenge is to establish selection criteria that will predict who is likely to benefit from vitamin E supplementation. Such criteria may be based either on the assumption that antioxidants are likely to be beneficial for people under oxidative stress or on knowledge regarding the benefit of sick people with certain diseases. In short, we adopt the view that vitamin E is a "double-edge sword" that should not be consumed until criteria are defined to predict who is likely to benefit from high dose supplementation of vitamin E. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

VITAMIN D: A D-LIGHTFUL SOLUTION FOR HEALTH

Throughout evolution sunlight produced vitamin D in the skin has been critically important for health. Vitamin D, known as the sunshine vitamin, is actually a hormone. Once it is produced in the skin or ingested from the diet it is converted sequentially in the liver and kidneys to its biologically active form 1,25-dihydroxyvitamin D. This hormone interacts with its receptor in the small intestine to increase the efficiency of intestinal calcium and phosphate absorption for the maintenance of the skeleton throughout life. Vitamin D deficiency during the first few years of life results in a flattened pelvis making it difficult for childbirth. Vitamin D deficiency causes osteopenia and osteoporosis increasing risk of fracture. Essentially every tissue and cell in the body has a vitamin D receptor. Therefore vitamin D deficiency has been linked to increased risk for preeclampsia, requiring a Cesarean section for birthing, multiple sclerosis, rheumatoid arthritis, type I diabetes, type II diabetes, heart disease, dementia, deadly cancers and infectious diseases. Therefore sensible sun exposure along with vitamin D supplementation of at least 2000 IU/d for adults and 1000 IU/d for children is essential to maximize their health.

Safety considerations and potential interactions of vitamins: should vitamins be considered drugs?

OBJECTIVE: To examine adverse effects, adverse events, and potential interactions of vitamins in light of their current prevalence of use, and to discuss whether vitamins should be considered over-the-counter drugs or natural health products/dietary supplements. DATA SOURCES: We performed a MEDLINE/PubMed search, explored 4 online databases (Medline Plus, Drug Digest, Natural Medicine Comprehensive Database, and the database of the University of Maryland), and examined reference lists of included studies published from 1966 through October 2009. STUDY SELECTION AND DATA EXTRACTION: The studies were reviewed, with an emphasis on randomized controlled clinical trials. We included articles with the most clinically important information with regard to adverse events and interactions. DATA SYNTHESIS: Vitamins are used by over one third of the North American population. Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs. While some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin B(12), vitamin K) have minor and reversible adverse effects, others, such as fat-soluble vitamins (A, E, D), can cause serious adverse events. Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events. CONCLUSIONS: Our recommendation is that vitamins A, E, D, folic acid, and niacin should be categorized as over-the-counter medications. Labeling of vitamins, especially those intended for children and other vulnerable groups, should include information on possible toxicities, dosing, recommended upper intake limits, and concurrent use with other products. Vitamin A should be excluded from multivitamin supplements and food fortificants.

The effect of vegetarian diet on selected essential nutrients in children.

INTRODUCTION: Vegetarian diets are considered to promote health and reduce the risk of some chronic diseases. It is also known that restriction or exclusion of animal foods may result in low intake of essential nutrients. The aim of the presented study was to assess the intake and serum status of vitamin B12, folate, vitamins A, E and D, as well as concentrations of homocysteine, total antioxidant status and iron balance in Polish vegetarian children. MATERIAL AND METHODS: The study included 50 children, aged 5-11 who had been referred to the Institute of Mother and Child for dietary consultation. From those, 32 were vegetarians (aged 6.5±4.2 years) and 18 omnivores (aged 7.9±2.7 years). Dietary constituents were analyzed using the nutritional programme Dietetyk2®. Folate and vitamin B12 were determined with a chemiluminescence immunoassay, total homocysteine with a fluorescence polarization immunoassay and TAS (total antioxidant status) by colorimetric method. Vitamin A and E in serum were determined by the high-pressure liquid chromatography method (HPLC) and vitamin D by immunoenzymatic assay (ELISA). Concentrations of iron, ferritin, transferrin and total iron-binding capacity (TIBC) in serum were determined by commercially available kits. RESULTS: In vegetarian children daily intake of vitamin B12 (1.6 ěg) was in the recommended range, that of folate (195 ěg) and vitamin A (1245 ěg) higher, but vitamin E slightly lower (6.6 ěg) and three-fold lower vitamin D (1.1 ěg) than references allowance. Serum concentrations of vitamin B12 (548 pg/ml), folate (12.8 ng/ml), vitamin A (1.2 ěmol/L), vitamin E (15.6 ěmol/l) were within physiological range, but that of vitamin D (13.7 ěg/L) was only half of the lowest limit of the reference value. In vegetarian children in comparison to omnivorous similar levels of homocysteine (6.13 ěmol/L vs 5.45 ěmol/L) and vitamin A (1,17 ěmol/L vs 1.32 ěmol/L) were observed. Lower (p<0.05) values of vitamin E (15.6 ěmol/L vs 18.4 ěmol/L) and TAS (1.21 mmol/L vs 1.30 mmol/L; p<0.0001) were found. Concentrations of iron markers were in physiological range. CONCLUSION: Obtained results indicated that intakes of vitamin B12 and folic acid from vegetarian diets are sufficient to maintain serum concentrations of both homocysteine and iron in the range observed in omnivorous children. High consumption of vitamin A and low vitamin E only slightly affected their serum values. Significantly lower concentration of serum vitamin E in vegetarian children in comparison to nonvegetarians may be reflected with statistically significant lowering of total antioxidant status. Insufficient intake of vitamin D and its low serum concentration should be under close monitoring in vegetarian children. In order to prevent vitamin D deficiency appropriate age-dependent supplementation should be considered.

Potential efficacy of broccoli sprouts as a unique supplement for management of type 2 diabetes and its complications.

Functional foods and their nutraceutical components are now considered as supplementary treatments in type 2 diabetes and prevention of its long-term complications. Young broccoli sprouts as a functional food contain many bioactive compounds specially sulforaphane. In hyperglycemic and oxidative conditions, sulforaphane has the potential to activate the NF-E2-related factor-2 (Nrf2)-dependent antioxidant response-signaling pathway, induces phase 2 enzymes, attenuates oxidative stress, and inactivates nuclear factor kappa-B (NF-κB), a key modulator of inflammatory pathways. Interestingly, sulforaphane induces some peroxisome proliferator-activated receptors, which contribute to lipid metabolism and glucose homeostasis. In animal and in vitro models, sulforaphane also shows antihypertensive, anticancer, cardioprotective, and hypocholesterolemic capacity, and has bactericidal properties against Helicobacter pylori. Supplementation of type 2 diabetics with high sulforaphane content broccoli sprouts resulted in increased total antioxidant capacity of plasma and in decreased oxidative stress index, lipid peroxidation, serum triglycerides, oxidized low-density lipoprotein (LDL)/LDL-cholesterol ratio, serum insulin, insulin resistance, and serum high-sensitive C-reactive protein. Sulforaphane could prevent nephropathy, diabetes-induced fibrosis, and vascular complications. Potential efficacy of sulforaphane and probably other bioactive components of young broccoli sprouts makes it as an excellent choice for supplementary treatment in type 2 diabetes.

Upregulation of lymphocyte apoptosis as a strategy for preventing and treating autoimmune disorders: a role for whole-food vegan diets, fish oil an...

Induced apoptosis of autoreactive T-lymphocyte precursors in the thymus is crucial for the prevention of autoimmune disorders. IGF-I and prolactin, which are lymphocyte growth factors, may have the potential to suppress apoptosis in thymocytes and thus encourage autoimmunity; conversely, dietary fish oil rich in omega-3 fats appears to upregulate apoptosis in lymphocytes. Since whole-food vegan diets may downregulate systemic IGF-I activity, it is proposed that such a diet, in conjunction with fish oil supplementation and treatment with dopamine agonists capable of suppressing prolactin secretion, may have utility for treating and preventing autoimmune disorders. This prediction is consistent with the extreme rarity of autoimmune disorders among sub-Saharan black Africans as long as they followed their traditional quasi-vegan lifestyles, and with recent ecologic studies correlating risks for IDDM and for multiple sclerosis mortality with animal product and/or saturated fat consumption. Moreover, there is evidence that vegan or quasi-vegan diets are useful in the management of rheumatoid arthritis, multiple sclerosis, and possibly SLE. The dopamine agonist bromocryptine exerts anti-inflammatory effects in rodent models of autoimmunity, and there is preliminary evidence that this drug may be clinically useful in several human autoimmune diseases; better tolerated D2-specific agonists such as cabergoline may prove to be more practical for use in therapy. The moderate clinical utility of supplemental fish oil in rheumatoid arthritis and certain other autoimmune disorders is documented. It is not unlikely that extra-thymic anti-inflammatory effects contribute importantly to the clinical utility of vegan diets, bromocryptine, and fish oil in autoimmunity. The favorable impact of low latitude or high altitude on autoimmune risk may be mediated by superior vitamin D status, which is associated with decreased secretion of parathyroid hormone; there are theoretical grounds for suspecting that parathyroid hormone may inhibit apoptosis in thymocytes. Androgens appear to up-regulate thymocyte apoptosis, may be largely responsible for the relative protection from autoimmunity enjoyed by men, and merit further evaluation for the management of autoimmunity in women. It will probably prove more practical to prevent autoimmune disorders than to reverse them once established; a whole-food vegan diet, coupled with fish oil and vitamin D supplementation, may represent a practical strategy for achieving this prevention, while concurrently lowering risk for many other life-threatening 'Western' diseases. Copyright 2001 Harcourt Publishers Ltd.

Effect of vitamin C supplements on physical performance.

Vitamin C is an essential component of the diet and may reduce the adverse effects of exercise-induced reactive oxygen species, including muscle damage, immune dysfunction, and fatigue. However, reactive oxygen species may mediate beneficial training adaptations that vitamin C attenuates; indeed, from a total of 12 studies, vitamin C in doses >1 g·d(-1) impaired sport performance substantially in four of four studies, possibly by reducing mitochondrial biogenesis, while a further four studies demonstrated impairments that were not statistically significant. Doses of ∼0.2 g·d(-1) of vitamin C consumed through five or more servings of fruit and vegetables may be sufficient to reduce oxidative stress and provide other health benefits without impairing training adaptations.

Vegan proteins may reduce risk of cancer, obesity, and cardiovascular disease by promoting increased glucagon activity.

Amino acids modulate the secretion of both insulin and glucagon; the composition of dietary protein therefore has the potential to influence the balance of glucagon and insulin activity. Soy protein, as well as many other vegan proteins, are higher in non-essential amino acids than most animal-derived food proteins, and as a result should preferentially favor glucagon production. Acting on hepatocytes, glucagon promotes (and insulin inhibits) cAMP-dependent mechanisms that down-regulate lipogenic enzymes and cholesterol synthesis, while up-regulating hepatic LDL receptors and production of the IGF-I antagonist IGFBP-1. The insulin-sensitizing properties of many vegan diets--high in fiber, low in saturated fat--should amplify these effects by down-regulating insulin secretion. Additionally, the relatively low essential amino acid content of some vegan diets may decrease hepatic IGF-I synthesis. Thus, diets featuring vegan proteins can be expected to lower elevated serum lipid levels, promote weight loss, and decrease circulating IGF-I activity. The latter effect should impede cancer induction (as is seen in animal studies with soy protein), lessen neutrophil-mediated inflammatory damage, and slow growth and maturation in children. In fact, vegans tend to have low serum lipids, lean physiques, shorter stature, later puberty, and decreased risk for certain prominent 'Western' cancers; a vegan diet has documented clinical efficacy in rheumatoid arthritis. Low-fat vegan diets may be especially protective in regard to cancers linked to insulin resistance--namely, breast and colon cancer--as well as prostate cancer; conversely, the high IGF-I activity associated with heavy ingestion of animal products may be largely responsible for the epidemic of 'Western' cancers in wealthy societies. Increased phytochemical intake is also likely to contribute to the reduction of cancer risk in vegans. Regression of coronary stenoses has been documented during low-fat vegan diets coupled with exercise training; such regimens also tend to markedly improve diabetic control and lower elevated blood pressure. Risk of many other degenerative disorders may be decreased in vegans, although reduced growth factor activity may be responsible for an increased risk of hemorrhagic stroke. By altering the glucagon/insulin balance, it is conceivable that supplemental intakes of key non-essential amino acids could enable omnivores to enjoy some of the health advantages of a vegan diet. An unnecessarily high intake of essential amino acids--either in the absolute sense or relative to total dietary protein--may prove to be as grave a risk factor for 'Western' degenerative diseases as is excessive fat intake.

Curcumin: getting back to the roots.

The use of turmeric, derived from the root of the plant Curcuma longa, for treatment of different inflammatory diseases has been described in Ayurveda and in traditional Chinese medicine for thousands of years. The active component of turmeric responsible for this activity, curcumin, was identified almost two centuries ago. Modern science has revealed that curcumin mediates its effects by modulation of several important molecular targets, including transcription factors (e.g., NF-kappaB, AP-1, Egr-1, beta-catenin, and PPAR-gamma), enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase-1), cell cycle proteins (e.g., cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6, and chemokines), receptors (e.g., EGFR and HER2), and cell surface adhesion molecules. Because it can modulate the expression of these targets, curcumin is now being used to treat cancer, arthritis, diabetes, Crohn's disease, cardiovascular diseases, osteoporosis, Alzheimer's disease, psoriasis, and other pathologies. Interestingly, 6-gingerol, a natural analog of curcumin derived from the root of ginger (Zingiber officinalis), exhibits a biologic activity profile similar to that of curcumin. The efficacy, pharmacologic safety, and cost effectiveness of curcuminoids prompt us to "get back to our roots."

Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer.

The properties of N-nitroso compounds (NNC) and of vitamins C and E are briefly described. The author reviews the ability of vitamins C and E to inhibit NNC formation in chemical systems, in nitrite-preserved meat, in experimental animals and in humans. Dietary vitamins C and E both produced 30% to 60% inhibitions in most carcinogenesis experiments employing preformed carcinogens. Vitamin C reversed transformation in an in vitro system. Carcinogenicity tests of the vitamins are reviewed (vitamin C can promote bladder carcinogenesis). Intake of fresh fruits and vegetables (which contain vitamin C) is negatively correlated with cancer of the stomach, esophagus, larynx, mouth and cervix. For gastric and esophageal cancer, there is evidence that this association is due to an inhibition of in vivo NNC formation. Vitamin C is apparently not a useful treatment for cancer. The author supports the recommendation that fresh fruit and vegetable intake be increased to lower the risk of cancer.

Effect of the vegetarian diet on non-communicable diseases.

A vegetarian diet generally includes plenty of vegetables and fruits, which are rich in phytochemicals, antioxidants, fiber, magnesium, vitamins C and E, Fe³⁺, folic acid and n-6 polyunsaturated fatty acid (PUFA), and is low in cholesterol, total fat and saturated fatty acid, sodium, Fe²⁺, zinc, vitamin A, B₁₂ and D, and especially n-3 PUFA. Mortality from all-cause, ischemic heart disease, and circulatory and cerebrovascular diseases was significantly lower in vegetarians than in omnivorous populations. Compared with omnivores, the incidence of cancer and type 2 diabetes was also significantly lower in vegetarians. However, vegetarians have a number of increased risk factors for non-communicable diseases such as increased plasma homocysteine, mean platelet volume and platelet aggregability compared with omnivores, which are associated with low intake of vitamin B₁₂ and n-3 PUFA. Based on the present data, it would seem appropriate for vegetarians to carefully design their diet, specifically focusing on increasing their intake of vitamin B₁₂ and n-3 PUFA to further reduce already low mortality and morbidity from non-communicable diseases. © 2013 Society of Chemical Industry.

Vitamin D and sterol composition of 10 types of mushrooms from retail suppliers in the United States.

Vitamin D(2) (ergocalciferol) and sterols were analyzed in mushrooms sampled nationwide in the United States to update the USDA Nutrient Database for Standard Reference. Vitamin D(2) was assayed using HPLC with [(3)H]-vitamin D(3) internal standard and sterols by GC-FID mass spectrometric (MS) confirmation. Vitamin D(2) was low (0.1-0.3 μg/100 g) in Agaricus bisporus (white button, crimini, portabella) and enoki, moderate in shiitake and oyster (0.4-0.7 μg/100 g), and high in morel, chanterelle, maitake (5.2-28.1 μg/100 g) and UV-treated portabella (3.4-20.9 μg/100 g), with significant variability among composites for some types. Ergosterol (mg/100 g) was highest in maitake and shiitake (79.2, 84.9) and lowest in morel and enoki (26.3, 35.5); the range was <10 mg/100 g among white button composites but 12-50 mg/100 g among samples of other types. All mushrooms contained ergosta-5,7-dienol (22,23-dihydroergosterol) (3.53-18.0 mg/100 g) and (except morel) ergosta-7-enol. Only morel contained brassicasterol (28.6 mg/100 g) and campesterol (1.23-4.54 mg/100 g) and no ergosta-7,22-dienol. MS was critical in distinguishing campesterol from ergosta-7,22-dienol.

Lowered methionine ingestion as responsible for the decrease in rodent mitochondrial oxidative stress in protein and dietary restriction possible i...

Available information indicates that long-lived mammals have low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, many studies have consistently shown that dietary restriction (DR) in rodents also decreases mitochondrial ROS (mtROS) production and oxidative damage to mitochondrial DNA and proteins. It has been observed that protein restriction also decreases mtROS generation and oxidative stress in rat liver, whereas neither carbohydrate nor lipid restriction change these parameters. This is interesting because protein restriction also increases maximum longevity in rodents (although to a lower extent than DR) and is a much more practicable intervention for humans than DR, whereas neither carbohydrate nor lipid restriction seem to change rodent longevity. Moreover, it has been found that isocaloric methionine restriction also decreases mtROS generation and oxidative stress in rodent tissues, and this manipulation also increases maximum longevity in rats and mice. In addition, excessive dietary methionine also increases mtROS generation in rat liver. These studies suggest that the reduced intake of dietary methionine can be responsible for the decrease in mitochondrial ROS generation and the ensuing oxidative damage that occurs during DR, as well as for part of the increase in maximum longevity induced by this dietary manipulation. In addition, the mean intake of proteins (and thus methionine) of Western human populations is much higher than needed. Therefore, decreasing such levels to the recommended ones has a great potential to lower tissue oxidative stress and to increase healthy life span in humans while avoiding the possible undesirable effects of DR diets.

Vitamin D: extraskeletal health.

Vitamin D deficiency is the most common nutritional deficiency and likely the most common medical condition in the world. The major cause of vitamin D deficiency has been the lack of appreciation that the body requires 5- to 10-fold higher intakes than is currently recommended by health agencies. There is now overwhelming and compelling scientific and epidemiologic data suggesting that the human body requires a blood level of 25(OH)D above 30 ng/mL for maximum health. To increase the blood level to the minimum 30 ng/mL requires the ingestion of at least 1000 IU of vitamin D per day for adults. In general, there is no downside to increasing either a child's or adult's vitamin D intake. Copyright 2010 Elsevier Inc. All rights reserved.

Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D.

Many patients treated for vitamin D deficiency fail to achieve an adequate serum level of 25-hydroxyvitamin D [25(OH)D] despite high doses of ergo- or cholecalciferol. The objective of this study was to determine whether administration of vitamin D supplement with the largest meal of the day would improve absorption and increase serum levels of 25(OH)D. This was a prospective cohort study in an ambulatory tertiary-care referral center. Patients seen at the Cleveland Clinic Foundation Bone Clinic for the treatment of vitamin D deficiency who were not responding to treatment make up the study group. Subjects were instructed to take their usual vitamin D supplement with the largest meal of the day. The main outcome measure was the serum 259(OH)D level after 2 to 3 months. Seventeen patients were analyzed. The mean age (+/-SD) and sex (F/M) ratio were 64.5 +/- 11.0 years and 13 females and 4 males, respectively. The dose of 25(OH)D ranged from 1000 to 50,000 IU daily. The mean baseline serum 25(OH)D level (+/-SD) was 30.5 +/- 4.7 ng/mL (range 21.6 to 38.8 ng/mL). The mean serum 25(OH)D level after diet modification (+/-SD) was 47.2 +/- 10.9 ng/mL (range 34.7 to 74.0 ng/mL, p < .01). Overall, the average serum 25(OH)D level increased by 56.7% +/- 36.7%. A subgroup analysis based on the weekly dose of vitamin D was performed, and a similar trend was observed.Thus it is concluded that taking vitamin D with the largest meal improves absorption and results in about a 50% increase in serum levels of 25(OH)D levels achieved. Similar increases were observed in a wide range of vitamin D doses taken for a variety of medical conditions. Copyright 2010 American Society for Bone and Mineral Research.

Radioprotective effects of Zingiber officinale Roscoe (ginger): past, present and future.

Radiation is an important modality in treating people with cancer especially when surgical intervention is impracticable or might debilitate the patient. However, effective use of ionizing radiation is compromised by the side effects that result from radiation-induced damage to normal tissue. The use of radioprotective compounds, which can selectively protect normal tissues against radiation injury is of immense use because in addition to association with protecting the normal tissue, it will also permits use of higher doses of radiation to obtain better cancer control and possible cure. However, till date no ideal radioprotectors are available as most synthetic compounds are toxic at their optimal concentrations. Plants commonly used as dietary and or therapeutic agents have recently been the focus of attention since in most cases they are non-toxic and are easily accepted for human use. Ginger, the rhizomes of Zingiber officinale Roscoe (Zingiberaceae), has widely been used as both culinary and medicinal agent. Preclinical studies carried out in the last decade has shown that ginger and its phytochemicals dehydrozingerone, zingerone possess radioprotective effects in laboratory animals and in cultured cells in vitro. The hydroalcoholic extract of ginger rhizome when administered either through intraperitoneal or oral route was effective in protecting against gamma radiation-induced sickness and mortality. The phytochemicals dehydrogingerone and zingerone present in ginger are also shown to protect mice against radiation-induced sickness and mortality. Mechanistic studies have indicated that the free radical scavenging, antioxidant affects, anti-inflammatory and anti-clastogenic effects may contribute towards the observed protection. Additionally, studies with tumor bearing mice have also shown that zingerone selectively protects the normal tissues against the tumoricidal effects of radiation. This review for the first time summarizes the results related to the radioprotective properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a radioprotective agent.

Evidence for a human-specific mechanism for diet and antibody-mediated inflammation in carcinoma progression

Patients with cancer have circulating heterophile antibodies that agglutinate animal red cells via recognition of the mammalian cell surface sialic acid N-glycolylneuraminic acid (Neu5Gc), which was long considered an oncofetal antigen in humans. However, humans are genetically deficient in Neu5Gc production and instead metabolically accumulate Neu5Gc from dietary sources, particularly red meats and milk products. Moreover, mice with a human-like defect showed no alternate pathway for Neu5Gc synthesis and even normal humans express anti-Neu5Gc antibodies. We show here that human tumors accumulate Neu5Gc that is covalently attached to multiple classes of glycans. The paradox of human tumor Neu5Gc accumulation in the face of circulating anti-Neu5Gc antibodies was hypothesized to be due to facilitation of tumor progression by the resulting low-grade chronic inflammation. Indeed, murine tumors expressing human-like levels of Neu5Gc show accelerated growth in syngeneic mice with a human-like Neu5Gc deficiency, coincident with the induction of anti-Neu5Gc antibodies and increased infiltration of inflammatory cells. Transfer of polyclonal monospecific syngeneic mouse anti-Neu5Gc serum also enhanced growth of transplanted syngeneic tumors bearing human-like levels of Neu5Gc, with tumors showing evidence for antibody deposition, enhanced angiogenesis and chronic inflammation. These effects were suppressed by a cyclooxygenase-2 inhibitor, a drug type known to reduce human carcinoma risk. Finally, affinity-purified human anti-Neu5Gc antibodies also accelerate growth of Neu5Gc-containing tumors in Neu5Gc-deficient mice. Taken together, the data suggest that the human propensity to develop diet-related carcinomas is contributed to by local chronic inflammation, resulting from interaction of metabolically-accumulated dietary Neu5Gc with circulating anti-Neu5Gc antibodies.

A possible role for lutein and zeaxanthin in cognitive function in the elderly.

Epidemiologic studies suggest that dietary lutein and zeaxanthin may be of benefit in maintaining cognitive health. Among the carotenoids, lutein and zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment (MP) in the eye. They also preferentially accumulate in the human brain. Lutein and zeaxanthin in macula from nonhuman primates were found to be significantly correlated with their concentrations in matched brain tissue. Therefore, MP can be used as a biomarker of lutein and zeaxanthin in primate brain tissue. This is of interest given that a significant correlation was found between MP density and global cognitive function in healthy older adults. An examination of a relation between cognition and lutein and zeaxanthin concentrations in the brain tissue of decedents from a population-based study in centenarians found that zeaxanthin concentrations in brain tissue were significantly related to antemortem measures of global cognitive function, memory retention, verbal fluency, and dementia severity after adjustment for age, sex, education, hypertension, and diabetes. In univariate analyses, lutein was related to recall and verbal fluency, but the strength of the associations was attenuated with adjustment for covariates. However, lutein concentrations in the brain were significantly lower in individuals with mild cognitive impairment than in those with normal cognitive function. Last, in a 4-mo, double-blinded, placebo-controlled trial in older women that involved lutein supplementation (12 mg/d), alone or in combination with DHA (800 mg/d), verbal fluency scores improved significantly in the DHA, lutein, and combined-treatment groups. Memory scores and rate of learning improved significantly in the combined-treatment group, who also showed a trend toward more efficient learning. When all of these observations are taken into consideration, the idea that lutein and zeaxanthin can influence cognitive function in older adults warrants further study.

Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10–100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at −50°C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.

Plant-derived health: the effects of turmeric and curcuminoids.

Plants contain numerous polyphenols, which have been shown to reduce inflammation and hereby to increase resistance to disease. Examples of such polyphenols are isothiocyanates in cabbage and broccoli, epigallocatechin in green tee, capsaicin in chili peppers, chalones, rutin and naringenin in apples, resveratrol in red wine and fresh peanuts and curcumin/curcuminoids in turmeric. Most diseases are maintained by a sustained discreet but obvious increased systemic inflammation. Many studies suggest that the effect of treatment can be improved by a combination of restriction in intake of proinflammatory molecules such as advanced glycation end products (AGE), advanced lipoperoxidation end products (ALE), and rich supply of antiinflammatory molecules such as plant polyphenols. To the polyphenols with a bulk of experimental documentation belong the curcuminoid family and especially its main ingredient, curcumin. This review summarizes the present knowledge about these turmericderived ingredients, which have proven to be strong antioxidants and inhibitors of cyclooxigenase-2 (COX-2), lipoxygenase (LOX) and nuclear factor kappa B (NF-kappaB) but also AGE. A plethora of clinical effects are reported in various experimental diseases, but clinical studies in humans are few. It is suggested that supply of polyphenols and particularly curcuminoids might be value as complement to pharmaceutical treatment, but also prebiotic treatment, in conditions proven to be rather therapy-resistant such as Crohn's, long-stayed patients in intensive care units, but also in conditions such as cancer, liver cirrhosis, chronic renal disease, chronic obstructive lung disease, diabetes and Alzheimer's disease.

Supplementation with vitamin C and N-acetyl-cysteine increases oxidative stress in humans after an acute muscle injury induced by eccentric exercise.

There has been no investigation to determine if the widely used over-the-counter, water-soluble antioxidants vitamin C and N-acetyl-cysteine (NAC) could act as pro-oxidants in humans during inflammatory conditions. We induced an acute-phase inflammatory response by an eccentric arm muscle injury. The inflammation was characterized by edema, swelling, pain, and increases in plasma inflammatory indicators, myeloperoxidase and interleukin-6. Immediately following the injury, subjects consumed a placebo or vitamin C (12.5 mg/kg body weight) and NAC (10 mg/kg body weight) for 7 d. The resulting muscle injury caused increased levels of serum bleomycin-detectable iron and the amount of iron was higher in the vitamin C and NAC group. The concentrations of lactate dehydrogenase (LDH), creatine kinase (CK), and myoglobin were significantly elevated 2, 3, and 4 d postinjury and returned to baseline levels by day 7. In addition, LDH and CK activities were elevated to a greater extent in the vitamin C and NAC group. Levels of markers for oxidative stress (lipid hydroperoxides and 8-iso prostaglandin F2alpha; 8-Iso-PGF2alpha) and antioxidant enzyme activities were also elevated post-injury. The subjects receiving vitamin C and NAC had higher levels of lipid hydroperoxides and 8-Iso-PGF2alpha 2 d after the exercise. This acute human inflammatory model strongly suggests that vitamin C and NAC supplementation immediately post-injury, transiently increases tissue damage and oxidative stress.

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells.

The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.

Immunity: plants as effective mediators.

In the domain of nutrition, exploring the diet-health linkages is major area of research. The outcomes of such interventions led to widespread acceptance of functional and nutraceutical foods; however, augmenting immunity is a major concern of dietary regimens. Indeed, the immune system is incredible arrangement of specific organs and cells that enabled humans to carry out defense against undesired responses. Its proper functionality is essential to maintain the body homeostasis. Array of plants and their components hold immunomodulating properties. Their possible inclusion in diets could explore new therapeutic avenues to enhanced immunity against diseases. The review intended to highlight the importance of garlic (Allium sativum), green tea (Camellia sinensis), ginger (Zingiber officinale), purple coneflower (Echinacea), black cumin (Nigella sativa), licorice (Glycyrrhiza glabra), Astragalus and St. John's wort (Hypericum perforatum) as natural immune boosters. These plants are bestowed with functional ingredients that may provide protection against various menaces. Modes of their actions include boosting and functioning of immune system, activation and suppression of immune specialized cells, interfering in several pathways that eventually led to improvement in immune responses and defense system. In addition, some of these plants carry free radical scavenging and anti-inflammatory activities that are helpful against cancer insurgence. Nevertheless, interaction between drugs and herbs/botanicals should be well investigated before recommended for their safe use, and such information must be disseminated to the allied stakeholders.

Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants.

The need for a dietary supply of docosahexaenoic acid (DHA) and arachidonic aid (AA) in term infants was evaluated in a double-masked randomized clinical trial of the effects of supplementation of term infant formula with DHA (0.35% of total fatty acids) or with DHA (0.36%) and AA (0.72%) on visual acuity development. One hundred and eight healthy term infants were enrolled in the study; 79 were exclusively formula-fed from birth (randomized group) and 29 were exclusively breast-fed (gold standard group). Infants were evaluated at four time points during the first 12 mo of life for blood fatty acid composition, growth, sweep visual evoked potential (VEP) acuity, and forced choice preferential looking acuity. Supplementation of term infant formula with DHA or with DHA and AA during the first 4 mo of life yields clear differences in total red blood cell (RBC) lipid composition. Supplementation of term infant formula with DHA or with DHA and AA also yields better sweep VEP acuity at 6, 17, and 52 wk of age but not at 26 wk of age, when acuity development reaches a plateau. The RBC lipid composition and sweep VEP acuity of supplemented infants was similar to that of human milk-fed infants, whereas the RBC lipid composition and sweep VEP acuity of unsupplemented infants was significantly different from human milk-fed infants. Differences in acuity among diet groups were too subtle to be detected by the forced choice preferential looking protocol. Infants in all diet groups had similar rates of growth and tolerated all diets well. Thus, early dietary intake of preformed DHA and AA appears necessary for optimal development of the brain and eye of the human infant.

Curcumin, an active component of turmeric in the prevention and treatment of ulcerative colitis: preclinical and clinical observations.

Inflammatory bowel disease (IBD) comprising of ulcerative colitis (UC) and Crohn's disease (CD) is a major ailment affecting the small and large bowel. In clinics, IBD is treated using 5-amninosalicylates, antibiotics, the steroids and immunomodulators. Unfortunately, the long term usages of these agents are associated with undue side effects and compromise the therapeutic advantage. Accordingly, there is a need for novel agents that are effective, acceptable and non toxic to humans. Preclinical studies in experimental animals have shown that curcumin, an active principle of the Indian spice turmeric (Curcuma longa Linn) is effective in preventing or ameliorating UC and inflammation. Over the last few decades there has been increasing interest in the possible role of curcumin in IBD and several studies with various experimental models of IBD have shown it to be effective in mediating the inhibitory effects by scavenging free radicals, increasing antioxidants, influencing multiple signaling pathways, especially the kinases (MAPK, ERK), inhibiting myeloperoxidase, COX-1, COX-2, LOX, TNF-α, IFN-γ, iNOS; inhibiting the transcription factor NF-κB. Clinical studies have also shown that co-administration of curcumin with conventional drugs was effective, to be well-tolerated and treated as a safe medication for maintaining remission, to prevent relapse and improve clinical activity index. Large randomized controlled clinical investigations are required to fully understand the potential of oral curcumin for treating IBD.

The Garden of Eden--plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century.

It is likely that plant food consumption throughout much of human evolution shaped the dietary requirements of contemporary humans. Diets would have been high in dietary fiber, vegetable protein, plant sterols and associated phytochemicals, and low in saturated and trans-fatty acids and other substrates for cholesterol biosynthesis. To meet the body's needs for cholesterol, we believe genetic differences and polymorphisms were conserved by evolution, which tended to raise serum cholesterol levels. As a result modern man, with a radically different diet and lifestyle, especially in middle age, is now recommended to take medications to lower cholesterol and reduce the risk of cardiovascular disease. Experimental introduction of high intakes of viscous fibers, vegetable proteins and plant sterols in the form of a possible Myocene diet of leafy vegetables, fruit and nuts, lowered serum LDL-cholesterol in healthy volunteers by over 30%, equivalent to first generation statins, the standard cholesterol-lowering medications. Furthermore, supplementation of a modern therapeutic diet in hyperlipidemic subjects with the same components taken as oat, barley and psyllium for viscous fibers, soy and almonds for vegetable proteins and plant sterol-enriched margarine produced similar reductions in LDL-cholesterol as the Myocene-like diet and reduced the majority of subjects' blood lipids concentrations into the normal range. We conclude that reintroduction of plant food components, which would have been present in large quantities in the plant based diets eaten throughout most of human evolution into modern diets can correct the lipid abnormalities associated with contemporary eating patterns and reduce the need for pharmacological interventions.

Chocolate--guilty pleasure or healthy supplement?

Dark chocolate and other cocoa products are popular in the population as a whole, but their overall health benefit remains controversial. Observations from the Kuna Indian population have shown an impressive cardiovascular health benefit from cocoa. For various reasons, this benefit has not been as robust as in other populations. Additionally, several mechanisms have been proposed that might confer cocoa's possible health benefit, but no consensus has been reached on cocoa's physiologic role in promoting cardiovascular health. Flavanols, as well as theobromine, may contribute to enhancements in endothelial function and subsequent improvements in various contributors to cardiovascular disease (CVD) including hypertension, platelet aggregation and adhesion, insulin resistance, and hypercholesterolemia. While the benefits of cocoa may be altered at the various stages of growth, development, and production, it appears that for many people "healthy" dark chocolate may, indeed, provide a pleasurable role in CVD risk reduction. The objectives of this review are to discuss the associations of cocoa with decreased blood pressure and improved CVD risk, to describe the possible mechanisms for these potential benefits, and to highlight considerations for the use of cocoa as a dietary supplement.

Plant phenolics as drug leads -- what is missing?

Low molecular weight phenols of plant origin are undoubtedly semiochemicals although not all of them can be easily classified as typical allelochemicals, which straightforwardly benefit the releaser. We have selected and surveyed this particular class of secondary metabolites, which shares high chemical reactivity with intrinsic biocompatibility and affinity for variety of molecular targets gained through evolution, because their suitability as prospective lead compounds for medicinal chemistry seems high but relatively unexplored. In particular, plant phenolics could be perceived as a natural product library, which contains privileged scaffolds, as evidenced by examples of endogenous phenols, phytochemicals containing aryl hydroxyl groups and phenolic synthetic drugs. It is postulated that application of bio-chemo-informatic tools to such library can be helpful in pulling out new drug candidates as well as in validating ADMET compatibility and suitability of the old ones. After short survey of structural diversity represented by plant phenolics, we focus on the compounds which either have obvious dietary significance or rich record of pharmacological studies, or both. It can be seen that apart from growing use of phytochemicals in dietary supplements, slow progress through clinical trials towards new drug registration is observed in that category of natural products. Such waste of resources on the way of transformation from renewable materials to high tech/high value products aimed for improved human healthcare is deplorable and should be reformed in name of sustainability. We attempt to answer the question why popular plant phenolics with well established health benefits and reasonably well recognized molecular pharmacology (such as: catechins, curcumin, resveratrol, quercetin and its glycosides, genistein, silymarin) have difficulties in attaining registered drug or even IND level.

Steam cooking significantly improves in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage.

Bile acid binding capacity has been related to the cholesterol-lowering potential of foods and food fractions. Lowered recirculation of bile acids results in utilization of cholesterol to synthesize bile acid and reduced fat absorption. Secondary bile acids have been associated with increased risk of cancer. Bile acid binding potential has been related to lowering the risk of heart disease and that of cancer. Previously, we have reported bile acid binding by several uncooked vegetables. However, most vegetables are consumed after cooking. How cooking would influence in vitro bile acid binding of various vegetables was investigated using a mixture of bile acids secreted in human bile under physiological conditions. Eight replicate incubations were conducted for each treatment simulating gastric and intestinal digestion, which included a substrate only, a bile acid mixture only, and 6 with substrate and bile acid mixture. Cholestyramine (a cholesterol-lowering, bile acid binding drug) was the positive control treatment and cellulose was the negative control. Relative to cholestyramine, in vitro bile acid binding on dry matter basis was for the collard greens, kale, and mustard greens, 13%; broccoli, 10%; Brussels sprouts and spinach, 8%; green bell pepper, 7%; and cabbage, 5%. These results point to the significantly different (P < or = .05) health-promoting potential of collard greens = kale = mustard greens > broccoli > Brussels sprouts = spinach = green bell pepper > cabbage as indicated by their bile acid binding on dry matter basis. Steam cooking significantly improved the in vitro bile acid binding of collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage compared with previously observed bile acid binding values for these vegetables raw (uncooked). Inclusion of steam-cooked collard greens, kale, mustard greens, broccoli, green bell pepper, and cabbage in our daily diet as health-promoting vegetables should be emphasized. These green/leafy vegetables, when consumed regularly after steam cooking, would lower the risk of cardiovascular disease and cancer, advance human nutrition research, and improve public health.

Effect of freezing and storage on the phenolics, ellagitannins, flavonoids, and antioxidant capacity of red raspberries.

Scottish-grown red raspberries are a rich source of vitamin C and phenolics, most notably, the anthocyanins cyanidin-3-sophoroside, cyanidin-3-(2(G)-glucosylrutinoside), and cyanidin-3-glucoside, and two ellagitannins, sanguiin H-6 and lambertianin C, which are present together with trace levels of flavonols, ellagic acid, and hydroxycinnamates. The antioxidant capacity of the fresh fruit and the levels of vitamin C and phenolics were not affected by freezing. When fruit were stored at 4 degrees C for 3 days and then at 18 degrees C for 24 h, mimicking the route fresh fruit takes after harvest to the supermarket and onto the consumer's table, anthocyanin levels were unaffected while vitamin C levels declined and those of elligitannins increased, and overall, there was no effect on the antioxidant capacity of the fruit. It is concluded, therefore, that freshly picked, fresh commercial, and frozen raspberries all contain similar levels of phytochemicals and antioxidants per serving.

Strawberry fields forever?

On the basis of copious preclinical data supporting the preventive efficacy of small fruits such as berries and grapes, Chen and colleagues conducted a randomized (noncomparative) phase II trial evaluating two doses of strawberry powder (60 g/d or 30 g/d for six months) to prevent esophageal cancer in China (reported in this issue of the journal, beginning on page 41); 60 g/d reduced the histologic grade of dysplastic lesions and reduced localized biomarkers, whereas 30 g/d was not effective. Fundamental questions remain such as the best formulation of strawberry powder, the active components associated with powder, and the actual mechanism of action, and standardized preparations will be required to permit the widespread use of strawberry powder with a predicable outcome. Clearly, however, this work is a good example of proof-of-principle and highlights the important role of diet, nutrition, and natural products in cancer prevention. ©2012 AACR.

Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively?

Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail.

Effect of tomato industrial processing on phenolic profile and antiplatelet activity.

BACKGROUND: Regular consumption of fruits and vegetables (e.g., tomatoes) has been shown to be beneficial in terms of reducing the incidence of cardiovascular diseases. The industrial processing of tomatoes into tomato-based products includes several thermal treatments. Very little is known on the effect of tomato industrial processing on antiaggregatory activity and phenolic profile. METHODS: It was assessed the effect of tomato and by-products extracts on platelet aggregation induced by ADP, collagen, TRAP-6 and arachidonic acid. These in vitro antithrombotic properties were further supported in an in vivo model of thrombosis. A set of antiplatelet compounds has been selected for HPLC analysis in the different extracts. RESULTS: Some natural compounds such as chlorogenic, caffeic, ferulic and p-coumaric acids were identified by HPLC in tomatoes and its products may inhibit platelet activation. Red tomatoes, tomato products (sauce, ketchup and juice) and by-products extracts inhibited platelet aggregation induced adenosine 5'-diphosphate, collagen, thrombin receptor activator peptide-6 and arachidonic acid, but to a different extent. Also, pomace extract presents antithrombotic activity. CONCLUSIONS: Processed tomatoes may have a higher content of health-benefiting compounds than fresh ones. Pomace even presents the best antiplatelet activity. Finally, tomato products may be used as a functional ingredient adding antiplatelet activities to processed foods.

Dietary cholesterol from eggs increases the ratio of total cholesterol to high-density lipoprotein cholesterol in humans: a meta-analysis.

BACKGROUND: Several epidemiologic studies found no effect of egg consumption on the risk of coronary heart disease. It is possible that the adverse effect of eggs on LDL-cholesterol is offset by their favorable effect on HDL cholesterol. OBJECTIVE: The objective was to review the effect of dietary cholesterol on the ratio of total to HDL cholesterol. DESIGN: Studies were identified by MEDLINE and Biological s searches (from 1974 to June 1999) and by reviewing reference lists. In addition, we included data from a more recently published study. Studies were included if they had a crossover or parallel design with a control group, if the experimental diets differed only in the amount of dietary cholesterol or number of eggs and were fed for > or =14 d, and if HDL-cholesterol concentrations were reported. Of the 222 studies identified, 17 studies involving 556 subjects met these criteria. RESULTS: The addition of 100 mg dietary cholesterol/d increased the ratio of total to HDL cholesterol by 0.020 units (95% CI: 0.010, 0.030), total cholesterol concentrations by 0.056 mmol/L (2.2 mg/dL) (95% CI: 0.046, 0.065 mmol/L; 1.8, 2.5 mg/dL), and HDL-cholesterol concentrations by 0.008 mmol/L (0.3 mg/dL) (95% CI: 0.005, 0.010 mmol/L; 0.2, 0.4 mg/dL). CONCLUSIONS: Dietary cholesterol raises the ratio of total to HDL cholesterol and, therefore, adversely affects the cholesterol profile. The advice to limit cholesterol intake by reducing consumption of eggs and other cholesterol-rich foods may therefore still be valid.

Therapeutic Roles of Curcumin: Lessons Learned from Clinical Trials

Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn’s disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin’s pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF–κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.

Management of diabetic retinopathy: a systematic review.

CONTEXT: Diabetic retinopathy (DR) is the leading cause of blindness in the working-aged population in the United States. There are many new interventions for DR, but evidence to support their use is uncertain. OBJECTIVE: To review the best evidence for primary and secondary intervention in the management of DR, including diabetic macular edema. EVIDENCE ACQUISITION: Systematic review of all English-language articles, retrieved using a keyword search of MEDLINE (1966 through May 2007), EMBASE, Cochrane Collaboration, the Association for Research in Vision and Ophthalmology database, and the National Institutes of Health Clinical Trials Database, and followed by manual searches of reference lists of selected major review articles. All English-language randomized controlled trials (RCTs) with more than 12 months of follow-up and meta-analyses were included. Delphi consensus criteria were used to identify well-conducted studies. EVIDENCE SYNTHESIS: Forty-four studies (including 3 meta-analyses) met the inclusion criteria. Tight glycemic and blood pressure control reduces the incidence and progression of DR. Pan-retinal laser photocoagulation reduces the risk of moderate and severe visual loss by 50% in patients with severe nonproliferative and proliferative retinopathy. Focal laser photocoagulation reduces the risk of moderate visual loss by 50% to 70% in eyes with macular edema. Early vitrectomy improves visual recovery in patients with proliferative retinopathy and severe vitreous hemorrhage. Intravitreal injections of steroids may be considered in eyes with persistent loss of vision when conventional treatment has failed. There is insufficient evidence for the efficacy or safety of lipid-lowering therapy, medical interventions, or antivascular endothelial growth factors on the incidence or progression of DR. CONCLUSIONS: Tight glycemic and blood pressure control remains the cornerstone in the primary prevention of DR. Pan-retinal and focal retinal laser photocoagulation reduces the risk of visual loss in patients with severe DR and macular edema, respectively. There is currently insufficient evidence to recommend routine use of other treatments.

Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries.

Black raspberries are a rich natural source of chemopreventive phytochemicals. Recent studies have shown that freeze-dried black raspberries inhibit the development of oral, esophageal, and colon cancer in rodents, and extracts of black raspberries inhibit benzo(a)pyrene-induced cell transformation of hamster embryo fibroblasts. However, the molecular mechanisms and the active components responsible for black raspberry chemoprevention are unclear. In this study, we found that 2 major chemopreventive components of black raspberries, ferulic acid and beta-sitosterol, and a fraction eluted with ethanol (RO-ET) during silica column chromatography of the organic extract of freeze-dried black raspberries inhibit the growth of premalignant and malignant but not normal human oral epithelial cell lines. Another fraction eluted with CH2Cl2/ethanol (DM:ET) and ellagic acid inhibited the growth of normal as well as premalignant and malignant human oral cell lines. We investigated the molecular mechanisms by which ferulic acid and beta-sitosterol and the RO-ET fraction selectively inhibited the growth of premalignant and malignant oral cells using flow cytometry and Western blotting of cell cycle regulatory proteins. There was no discernable change in the cell cycle distribution following treatment of cells with the RO-ET fraction. Premalignant and malignant cells redistributed to the G2/M phase of the cell cycle following incubation with ferulic acid. beta-sitosterol treated premalignant and malignant cells accumulated in the G0/G1 and G2/M phases, respectively. The RO-ET fraction reduced the levels of cyclin A and cell division cycle gene 2 (cdc2) in premalignant cells and cyclin B1, cyclin D1, and cdc2 in the malignant cell lines. This fraction also elevated the levels of p21waf1/cip1 in the malignant cell line. Ferulic acid treatment led to increased levels of cyclin B1 and cdc2 in both cell lines, and p21waf1/cip1 was induced in the malignant cell line. beta-sitosterol reduced the levels of cyclin B1 and cdc2 while increasing p21waf1/cip1 in both the premalignant and malignant cell lines. These results show for the first time that the growth inhibitory effects of black raspberries on premalignant and malignant human oral cells may reside in specific components that target aberrant signaling pathways regulating cell cycle progression.

Marked variability of monacolin levels in commercial red yeast rice products: buyer beware!

BACKGROUND: Red yeast rice (RYR) is a widely available dietary supplement used by millions of patients as an alternative therapy for hyperlipidemia. It contains 14 active compounds called monacolins that inhibit hepatic cholesterol synthesis. Although studies have suggested that some formulations of RYR may be effective and safe for lipid lowering, monacolin levels are not standardized among marketed products and are generally not published on labels. We evaluated monacolin levels in 12 commercial RYR formulations and tested for citrinin, a mycotoxin that is nephrotoxic in animals. METHODS: Each formulation of RYR was labeled "600 mg/capsule" of active product. Analyses for monacolins and citrinin were performed between August 2006 and June 2008 using high-performance liquid chromatography with mass spectroscopy-mass spectroscopy detection. Laboratory analyses of RYR products were conducted by ConsumerLab.com, White Plains, New York. RESULTS: There was marked variability in the 12 RYR products in total monacolins (0.31-11.15 mg/capsule), monacolin K (lovastatin) (0.10-10.09 mg/capsule), and monacolin KA (0.00-2.30 mg/capsule). Four products had elevated levels of citrinin. CONCLUSIONS: We found striking variability in monacolin content in 12 proprietary RYR products and the presence of citrinin in one-third of the formulations tested. Although RYR may have potential as an alternative lipid-lowering agent, our findings suggest the need for improved standardization of RYR products and product labeling. Until this occurs, physicians should be cautious in recommending RYR to their patients for the treatment of hyperlipidemia and primary and secondary prevention of cardiovascular disease.

Towards prevention of vitamin D deficiency and beyond: knowledge gaps and research needs in vitamin D nutrition and public health.

The North American Institute of Medicine (IOM) recently published their report on dietary reference intakes (DRI) for Ca and vitamin D. The DRI committee's deliberations underpinning this most comprehensive report on vitamin D nutrition to date benefited hugely from a much expanded knowledge base in vitamin D over the last decade or more. However, since their release, the vitamin D DRI have been the subject of intense controversy, which is largely due to the persistence of fundamental knowledge gaps in vitamin D. These can be identified at the levels of exposure, metabolism, storage, status, dose-response, function and beneficial or adverse health effects, as well as safe and effective application of intake recommendations at the population level through sustainable food-based approaches. The present review provides a brief overview of the approach used by the IOM committee to revise the DRI for vitamin D and to collate from a number of authoritative sources key knowledge gaps in vitamin D nutrition from the public health perspective. A number of research topics are outlined and data requirements within these are identified and mapped to the risk assessment framework used by the DRI committee. While not intended as an exhaustive list, it provides a basis for organising and prioritising research efforts in the area of vitamin D, which may offer a perspective on the major areas in need of attention. It is intended to be of use to researchers, national policy makers, the public health community, industry groups and other relevant stakeholders including funding institutions.

Bioavailability of curcumin: problems and promises.

Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

A systematic review and meta-analysis of the effects of pasteurization on milk vitamins, and evidence for raw milk consumption and other health-rel...

Pasteurization of milk ensures safety for human consumption by reducing the number of viable pathogenic bacteria. Although the public health benefits of pasteurization are well established, pro-raw milk advocate organizations continue to promote raw milk as "nature's perfect food." Advocacy groups' claims include statements that pasteurization destroys important vitamins and that raw milk consumption can prevent and treat allergies, cancer, and lactose intolerance. A systematic review and meta-analysis was completed to summarize available evidence for these selected claims. Forty studies assessing the effects of pasteurization on vitamin levels were found. Qualitatively, vitamins B12 and E decreased following pasteurization, and vitamin A increased. Random effects meta-analysis revealed no significant effect of pasteurization on vitamin B6 concentrations (standardized mean difference [SMD], -2.66; 95% confidence interval [CI], -5.40, 0.8; P = 0.06) but a decrease in concentrations of vitamins B1 (SMD, -1.77; 95% CI, -2.57, -0.96; P < 0.001), B2 (SMD, -0.41; 95% CI, -0.81, -0.01; P < 0.05), C (SMD, -2.13; 95% CI, -3.52, -0.74; P < 0.01), and folate (SMD, -11.99; 95% CI, -20.95, -3.03; P < 0.01). The effect of pasteurization on milk's nutritive value was minimal because many of these vitamins are naturally found in relatively low levels. However, milk is an important dietary source of vitamin B2, and the impact of heat treatment should be further considered. Raw milk consumption may have a protective association with allergy development (six studies), although this relationship may be potentially confounded by other farming-related factors. Raw milk consumption was not associated with cancer (two studies) or lactose intolerance (one study). Overall, these findings should be interpreted with caution given the poor quality of reported methodology in many of the included studies.

Curcumin and cancer: an "old-age" disease with an "age-old" solution.

Cancer is primarily a disease of old age, and that life style plays a major role in the development of most cancers is now well recognized. While plant-based formulations have been used to treat cancer for centuries, current treatments usually involve poisonous mustard gas, chemotherapy, radiation, and targeted therapies. While traditional plant-derived medicines are safe, what are the active principles in them and how do they mediate their effects against cancer is perhaps best illustrated by curcumin, a derivative of turmeric used for centuries to treat a wide variety of inflammatory conditions. Curcumin is a diferuloylmethane derived from the Indian spice, turmeric (popularly called "curry powder") that has been shown to interfere with multiple cell signaling pathways, including cell cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of antiapoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF-kappaB, TNF, IL-6, IL-1, COX-2, and 5-LOX). The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets. Thus an "old-age" disease such as cancer requires an "age-old" treatment.

Chemopreventive properties and molecular mechanisms of the bioactive compounds in Hibiscus sabdariffa Linne.

Hibiscus sabdariffa Linne is a traditional Chinese rose tea and has been effectively used in folk medicines for treatment of hypertension, inflammatory conditions. H. sabdariffa aqueous extracts (HSE) were prepared from the dried flowers of H. sabdariffa L., which are rich in phenolic acids, flavonoids and anthocyanins. In this review, we discuss the chemopreventive properties and possible mechanisms of various H. sabdariffa extracts. It has been demonstrated that HSE, H. sabdariffa polyphenol-rich extracts (HPE), H. sabdariffa anthocyanins (HAs), and H. sabdariffa protocatechuic acid (PCA) exert many biologic effects. PCA and HAs protected against oxidative damage induced by tert-butyl droperoxide (t-BHP) in rat primary hepatocytes. In rabbits fed cholesterol and human experimental studies, these studies imply HSE could be pursued as atherosclerosis chemopreventive agents as they inhibit LDL oxidation, foam cell formation, as well as smooth muscle cell migration and proliferation. The extracts also offer hepatoprotection by influencing the levels of lipid peroxidation products and liver marker enzymes in experimental hyperammonemia. PCA has also been shown to inhibit the carcinogenic action of various chemicals in different tissues of the rat. HAs and HPE were demonstrated to cause cancer cell apoptosis, especially in leukemia and gastric cancer. More recent studies investigated the protective effect of HSE and HPE in streptozotocin induced diabetic nephropathy. From all these studies, it is clear that various H. sabdariffa extracts exhibit activities against atherosclerosis, liver disease, cancer, diabetes and other metabolic syndromes. These results indicate that naturally occurring agents such as the bioactive compounds in H. sabdariffa could be developed as potent chemopreventive agents and natural healthy foods.

Titanium Dioxide Nanoparticles in Food and Personal Care Products

Titanium dioxide is a common additive in many food, personal care, and other consumer products used by people, which after use can enter the sewage system, and subsequently enter the environment as treated effluent discharged to surface waters or biosolids applied to agricultural land, incinerated wastes, or landfill solids. This study quantifies the amount of titanium in common food products, derives estimates of human exposure to dietary (nano-) TiO2, and discusses the impact of the nanoscale fraction of TiO2 entering the environment. The foods with the highest content of TiO2 included candies, sweets and chewing gums. Among personal care products, toothpastes and select sunscreens contained 1% to >10% titanium by weight. While some other crèmes contained titanium, despite being colored white, most shampoos, deodorants, and shaving creams contained the lowest levels of titanium (<0.01 μg/mg). For several high-consumption pharmaceuticals, the titanium content ranged from below the instrument detection limit (0.0001 μg Ti/mg) to a high of 0.014 μg Ti/mg. Electron microscopy and stability testing of food-grade TiO2 (E171) suggests that approximately 36% of the particles are less than 100 nm in at least one dimension and that it readily disperses in water as fairly stable colloids. However, filtration of water solubilized consumer products and personal care products indicated that less than 5% of the titanium was able to pass through 0.45 or 0.7 μm pores. Two white paints contained 110 μg Ti/mg while three sealants (i.e., prime coat paint) contained less titanium (25 to 40 μg Ti/mg). This research showed that while many white-colored products contained titanium, it was not a prerequisite. Although several of these product classes contained low amounts of titanium, their widespread use and disposal down the drain and eventually to WWTPs deserves attention. A Monte Carlo human exposure analysis to TiO2 through foods identified children as having the highest exposures because TiO2 content of sweets is higher than other food products, and that a typical exposure for a US adult may be on the order of 1 mg Ti per kilogram body weight per day. Thus, because of the millions of tons of titanium based white pigment used annually, testing should focus on food-grade TiO2 (E171) rather than that adopted in many environmental health and safety tests (i.e., P25), which is used in much lower amounts in products less likely to enter the environment (e.g., catalyst supports, photocatalytic coatings).

Fish oil supplementation in type 2 diabetes: a quantitative systematic review.

OBJECTIVE: To determine the effects of fish oil supplementation on lipid levels and glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A comprehensive search of Medline, Embase, Lilacs, the Cochrane Clinical Trials Registry bibliographies of relevant papers, and expert input updated through September 1998 was undertaken. All randomized placebo-controlled trials were included in which fish oil supplementation was the only intervention in subjects with type 2 diabetes. Three investigators performed data extraction and quality scoring independently with discrepancies resolved by consensus. Eighteen trials including 823 subjects followed for a mean of 12 weeks were included. Doses of fish oil used ranged from 3 to 18 g/day The outcomes studied were glycemic control and lipid levels. RESULTS: Meta-analysis of pooled data demonstrated a statistically significant effect of fish oil on lowering triglycerides (-0.56 mmol/l [95% CI -0.71 to -0.41]) and raising LDL cholesterol (0.21 mmol/l [0.02 to 0.41]). No statistically significant effect was observed for fasting glucose. HbA1c total cholesterol, or HDL cholesterol. The triglyceride-lowering effect and the elevation in LDL cholesterol were most marked in those trials that recruited hypertriglyceridemic subjects and used higher doses of fish oil. Heterogeneity was observed and explained by the recruitment of subjects with baseline hypertriglyceridemia in some studies. CONCLUSIONS: Fish oil supplementation in type 2 diabetes lowers triglycerides, raises LDL cholesterol, and has no statistically significant effect on glycemic control. Trials with hard clinical end points are needed.

High alpha-linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans.

Although high alpha-linolenic acid flaxseed (Linum usitatissimum) is one of the richest dietary sources of alpha-linolenic acid and is also a good source of soluble fibre mucilage, it is relatively unstudied in human nutrition. Healthy female volunteers consumed 50 g ground, raw flaxseed/d for 4 weeks which provided 12-13% of energy intake (24-25 g/100 g total fat). Flaxseed raised alpha-linolenic acid and long-chain n-3 fatty acids in both plasma and erythrocyte lipids, as well as raising urinary thiocyanate excretion 2.2-fold. Flaxseed also lowered serum total cholesterol by 9% and low-density-lipoprotein-cholesterol by 18%. Changes in plasma alpha-linolenic acid were equivalent when 12 g alpha-linolenic acid/d was provided as raw flaxseed flour (50 g/d) or flaxseed oil (20 g/d) suggesting high bioavailability of alpha-linolenic acid from ground flaxseed. Test meals containing 50 g carbohydrate from flaxseed or 25 g flaxseed mucilage each significantly decreased postprandial blood glucose responses by 27%. Malondialdehyde levels in muffins containing 15 g flaxseed oil or flour/kg were similar to those in wheat-flour muffins. Cyanogenic glycosides (linamarin, linustatin, neolinustatin) were highest in extracted flaxseed mucilage but were not detected in baked muffins containing 150 g flaxseed/kg. We conclude that up to 50 g high-alpha-linolenic acid flaxseed/d is palatable, safe and may be nutritionally beneficial in humans by raising n-3 fatty acids in plasma and erythrocytes and by decreasing postprandial glucose responses.

Flavanols, the Kuna, Cocoa Consumption, and Nitric Oxide

The Kuna Indians who reside in an archipelago on the Caribbean Coast of Panama have very low blood pressure levels, live longer than other Panamanians, and have a reduced frequency of myocardial infarction, stroke, diabetes mellitus, and cancer -- at least on their death certificates. One outstanding feature of their diet includes a very high intake of flavanol-rich cocoa. Flavonoids in cocoa activate nitric oxide synthesis in healthy humans. The possibility that the high flavanol intake protects the Kuna against high blood pressure, ischemic heart disease, stroke, diabetes mellitus, and cancer is sufficiently intriguing and sufficiently important that large, randomized controlled clinical trials should be pursued.

Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials.

Elevated total plasma homocysteine has been linked to the development of cognitive impairment and dementia in later life and this can be reliably lowered by the daily supplementation of vitamin B6, B12, and folic acid. We performed a systematic review and meta-analysis of 19 English language randomized, placebo-controlled trials of homocysteine lowering B-vitamin supplementation of individuals with and without cognitive impairment at the time of study entry. We standardized scores to facilitate comparison between studies and to enable us to complete a meta-analysis of randomized trials. In addition, we stratified our analyses according to the folate status of the country of origin. B-vitamin supplementation did not show an improvement in cognitive function for individuals with (SMD = 0.10, 95%CI -0.08 to 0.28) or without (SMD = -0.03, 95%CI -0.1 to 0.04) significant cognitive impairment. This was irrespective of study duration (SMD = 0.05, 95%CI -0.10 to 0.20 and SMD = 0, 95%CI -0.08 to 0.08), study size (SMD = 0.05, 95%CI -0.09 to 0.19 and SMD = -0.02, 95%CI -0.10 to 0.05), and whether participants came from countries with low folate status (SMD = 0.14, 95%CI -0.12 to 0.40 and SMD = -0.10, 95%CI -0.23 to 0.04). Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment. It remains to be established if prolonged treatment with B-vitamins can reduce the risk of dementia in later life.

Curcumin as "Curecumin": from kitchen to clinic.

Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curcumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

Chronic effects of a high-fat diet enriched with virgin olive oil and a low-fat diet enriched with alpha-linolenic acid on postprandial endothelial...

Traditional cardiovascular risk factors are associated with endothelial dysfunction. The vascular endothelium plays a key role in local vascular tone regulation and can be modulated by dietary fat. We propose to determine the chronic effect of three diets with different fat compositions on postprandial endothelial function and inflammatory biomarkers. Twenty healthy men followed three 4-week diets in a randomised cross-over design: a Western diet, rich in saturated fat (22% SFA, 12% MUFA and 0.4% alpha-linolenic acid (ALA), all fractions are % of energy); a Mediterranean diet, rich in MUFA ( < 10 % SFA, 24 % MUFA and 0.4% ALA); a low-fat diet enriched in ALA ( < 10% SFA, 12% MUFA and 2% ALA). At the end of each dietary period all subjects underwent a postprandial study. Plasma concentrations of lipid parameters, soluble intercellular cell-adhesion molecule-1, soluble vascular cell-adhesion molecule-1 (sVCAM-1), nitrates and nitrites (NOx) and endothelial function studied by laser Doppler were examined at 0, 2, 4, 6 and 8 h. The endothelium-dependent vasodilatory response was greater 4 h after the ingestion of the MUFA-rich diet than after the SFA or ALA low-fat diets (P = 0.031). The 4 h postprandial plasma sVCAM-1 levels were lower after the MUFA meals than after the ALA low-fat diet (P = 0.043). The bioavailability of NOx was higher following the MUFA diet than after the SFA and ALA low-fat diets (P = 0.027). We found no differences in the other parameters measured. Chronic ingestion of a Mediterranean diet avoids the postprandial deterioration of endothelial function associated with Westernised diets in healthy individuals.

Fasting plasma zeaxanthin response to Fructus barbarum L. (wolfberry; Kei Tze) in a food-based human supplementation trial.

Age-related macular degeneration (AMD) is a common disorder that causes irreversible loss of central vision. Increased intake of foods containing zeaxanthin may be effective in preventing AMD because the macula accumulates zeaxanthin and lutein, oxygenated carotenoids with antioxidant and blue light-absorbing properties. Lycium barbarum L. is a small red berry known as Fructus lycii and wolfberry in the West, and Kei Tze and Gou Qi Zi in Asia. Wolfberry is rich in zeaxanthin dipalmitate, and is valued in Chinese culture for being good for vision. The aim of this study, which was a single-blinded, placebo-controlled, human intervention trial of parallel design, was to provide data on how fasting plasma zeaxanthin concentration changes as a result of dietary supplementation with whole wolfberries. Fasting blood was collected from healthy, consenting subjects; fourteen subjects took 15 g/d wolfberry (estimated to contain almost 3 mg zeaxanthin) for 28 d. Repeat fasting blood was collected on day 29. Age- and sex-matched controls (n 13) took no wolfberry. Responses in the two groups were compared using the Mann-Whitney test. After supplementation, plasma zeaxanthin increased 2.5-fold: mean values on day 1 and 29 were 0.038 (sem 0.003) and 0.096 (sem 0.009) micromol/l (P<0.01), respectively, for the supplementation group; and 0.038 (sem 0.003) and 0.043 (sem 0.003) micromol/l (P>0.05), respectively, for the control group. This human supplementation trial shows that zeaxanthin in whole wolfberries is bioavailable and that intake of a modest daily amount markedly increases fasting plasma zeaxanthin levels. These new data will support further study of dietary strategies to maintain macular pigment density.

Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the U.S. ...

BACKGROUND: Vitamin and mineral supplements are commonly used to prevent chronic diseases. PURPOSE: To systematically review evidence for the benefit and harms of vitamin and mineral supplements in community-dwelling, nutrient-sufficient adults for the primary prevention of cardiovascular disease (CVD) and cancer. DATA SOURCES: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of s of Reviews of Effects were searched from January 2005 to 29 January 2013, with manual searches of reference lists and gray literature. STUDY SELECTION: Two investigators independently selected and reviewed fair- and good-quality trials for benefit and fair- and good-quality trials and observational studies for harms. DATA EXTRACTION: Dual quality assessments and data abstraction. DATA SYNTHESIS: Two large trials (n = 27 658) reported lower cancer incidence in men taking a multivitamin for more than 10 years (pooled unadjusted relative risk, 0.93 [95% CI, 0.87 to 0.99]). The study that included women showed no effect in that group. High-quality studies (k = 24; n = 324 653) of single and paired nutrients (such as vitamins A, C, or D; folic acid; selenium; or calcium) were scant and heterogeneous and showed no clear evidence of benefit or harm. Neither vitamin E nor β-carotene prevented CVD or cancer, and β-carotene increased lung cancer risk in smokers. LIMITATIONS: The analysis included only primary prevention studies in adults without known nutritional deficiencies. Studies were conducted in older individuals and included various supplements and doses under the set upper tolerable limits. Duration of most studies was less than 10 years. CONCLUSION: Limited evidence supports any benefit from vitamin and mineral supplementation for the prevention of cancer or CVD. Two trials found a small, borderline-significant benefit from multivitamin supplements on cancer in men only and no effect on CVD. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Prevalence and correlates of vitamin D deficiency in US adults.

Mounting evidence suggests that vitamin D deficiency could be linked to several chronic diseases, including cardiovascular disease and cancer. The purpose of this study was to examine the prevalence of vitamin D deficiency and its correlates to test the hypothesis that vitamin D deficiency was common in the US population, especially in certain minority groups. The National Health and Nutrition Examination Survey 2005 to 2006 data were analyzed for vitamin D levels in adult participants (N = 4495). Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D concentrations ≤20 ng/mL (50 nmol/L). The overall prevalence rate of vitamin D deficiency was 41.6%, with the highest rate seen in blacks (82.1%), followed by Hispanics (69.2%). Vitamin D deficiency was significantly more common among those who had no college education, were obese, with a poor health status, hypertension, low high-density lipoprotein cholesterol level, or not consuming milk daily (all P < .001). Multivariate analyses showed that being from a non-white race, not college educated, obese, having low high-density lipoprotein cholesterol, poor health, and no daily milk consumption were all significantly, independently associated with vitamin D deficiency (all P < .05). In summary, vitamin D deficiency was common in the US population, especially among blacks and Hispanics. Given that vitamin D deficiency is linked to some of the important risk factors of leading causes of death in the United States, it is important that health professionals are aware of this connection and offer dietary and other intervention strategies to correct vitamin D deficiency, especially in minority groups. Copyright © 2011 Elsevier Inc. All rights reserved.

Consumption of blueberries with a high-carbohydrate, low-fat breakfast decreases postprandial serum markers of oxidation.

We sought to determine whether consumption of blueberries could reduce postprandial oxidation when consumed with a typical high-carbohydrate, low-fat breakfast. Participants (n 14) received each of the three treatments over 3 weeks in a cross-over design. Treatments consisted of a high blueberry dose (75 g), a low blueberry dose (35 g) and a control (ascorbic acid and sugar content matching that of the high blueberry dose). Serum oxygen radical absorbance capacity (ORAC), serum lipoprotein oxidation (LO) and serum ascorbate, urate and glucose were measured at fasting, and at 1, 2 and 3 h after sample consumption. The mean serum ORAC was significantly higher in the 75 g group than in the control group during the first 2 h postprandially, while serum LO lag time showed a significant trend over the 3 h for both blueberry doses. Changes in serum ascorbate, urate and glucose were not significantly different among the groups. To our knowledge, this is the first report that has demonstrated that increased serum antioxidant capacity is not attributable to the fructose or ascorbate content of blueberries. In summary, a practically consumable quantity of blueberries (75 g) can provide statistically significant oxidative protection in vivo after a high-carbohydrate, low-fat breakfast. Though not tested directly, it is likely that the effects are due to phenolic compounds, either directly or indirectly, as they are a major family of compounds in blueberries with potential bioactive activity.

Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal.

Physiological and pharmacological blood concentrations of melatonin inhibit tumorigenesis in a variety of in vivo and in vitro experimental models of neoplasia. Evidence indicates that melatonin's anticancer effects are exerted via inhibition of cell proliferation and a stimulation of differentiation and apoptosis. A new mechanism by which physiological and pharmacological blood levels of melatonin inhibit cancer growth in vivois via a melatonin-induced suppression of tumor linoleic acid (LA) uptake and its metabolism to the important mitogenic signaling molecule 13-hydroxyoctadecadienoic acid (13-HODE). Melatonin suppresses cAMP formation and inhibits tumor uptake of LA and its metabolism to 13-HODE via a melatonin receptor-mediated mechanism in both tissue-isolated rat hepatoma 7288 CTC and human breast cancer xenografts. It has been postulated that in industrialized societies, light at night, by suppressing melatonin production, poses a new risk for the development of breast cancer and, perhaps, other cancers as well. In support of this hypothesis, light during darkness suppresses nocturnal melatonin production and stimulates the LA metabolism and growth of rat hepatoma and human breast cancer xenografts. Nocturnal dietary supplementation with melatonin, at levels contained in a melatonin-rich diet, inhibits rat hepatoma growth via the mechanisms described above. The nocturnal melatonin signal organizes tumor metabolism and growth within circadian time structure that can be further reinforced by appropriately timed melatonin supplementation. Dietary melatonin supplementation working in concert with the endogenous melatonin signal has the potential to be a new preventive/therapeutic strategy to optimize the host/cancer balance in favor of host survival and quality of life.

Protection against cancer by dietary IP6 and inositol.

Inositol hexaphosphate (IP(6)) is a naturally occurring polyphosphorylated carbohydrate, abundantly present in many plant sources and in certain high-fiber diets, such as cereals and legumes. In addition to being found in plants, IP(6) is contained in almost all mammalian cells, although in much smaller amounts, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation, and differentiation. For a long time IP(6) has been recognized as a natural antioxidant. Recently IP(6) has received much attention for its role in cancer prevention and control of experimental tumor growth, progression, and metastasis. In addition, IP(6) possesses other significant benefits for human health, such as the ability to enhance immune system, prevent pathological calcification and kidney stone formation, lower elevated serum cholesterol, and reduce pathological platelet activity. In this review we show the efficacy and discuss some of the molecular mechanisms that govern the action of this dietary agent. Exogenously administered IP(6) is rapidly taken up into cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. A striking anticancer action of IP(6) was demonstrated in different experimental models. In addition to reducing cell proliferation, IP(6) also induces differentiation of malignant cells. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Preliminary studies in humans show that IP(6) and inositol, the precursor molecule of IP(6), appear to enhance the anticancer effect of conventional chemotherapy, control cancer metastases, and improve quality of life. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP(6) + inositol holds great promise in our strategies for cancer prevention and therapy. There is clearly enough evidence to justify the initiation of full-scale clinical trials in humans.

Turmeric (Curcuma longa) inhibits inflammatory nuclear factor (NF)-κB and NF-κB-regulated gene products and induces death receptors leading to suppressed proliferation, induced chemosensitization, and suppressed osteoclastogenesis

Scope The incidence of cancer is significantly lower in regions where turmeric is heavily consumed. Whether lower cancer incidence is due to turmeric was investigated by examining its effects on tumor cell proliferation, on pro-inflammatory transcription factors NF-κB and STAT3, and on associated gene products. Methods and results Cell proliferation and cell cytotoxicity were measured by the MTT method, NF-κB activity by EMSA, protein expression by Western blot analysis, ROS generation by FACS analysis, and osteoclastogenesis by TRAP assay. Turmeric inhibited NF-κB activation and down-regulated NF-κB-regulated gene products linked to survival (Bcl-2, cFLIP, XIAP, and cIAP1), proliferation (cyclin D1 and c-Myc), and metastasis (CXCR4) of cancer cells. The spice suppressed the activation of STAT3, and induced the death receptors (DR)4 and DR5. Turmeric enhanced the production of ROS, and suppressed the growth of tumor cell lines. Furthermore, turmeric sensitized the tumor cells to chemotherapeutic agents capecitabine and taxol. Turmeric was found to be more potent than pure curcumin for cell growth inhibition. Turmeric also inhibited NF-κB activation induced by RANKL that correlated with the suppression of osteoclastogenesis. Conclusion Our results indicate that turmeric can effectively block the proliferation of tumor cells through the suppression of NF-κB and STAT3 pathways.

Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians, and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study

Background/Objectives Vegans and to a lesser extent vegetarians have low average circulating concentrations of vitamin B12; however, the relation between factors such as age or time on these diets and vitamin B12 concentrations is not clear. The objectives were to investigate differences in serum vitamin B12 and folate concentrations between omnivores, vegetarians and vegans and to ascertain whether vitamin B12 concentrations differed by age and time on the diet. Subjects/Methods A cross-sectional analysis involving 689 men (226 omnivores, 231 vegetarians and 232 vegans) from the European Prospective Investigation into Cancer and Nutrition Oxford cohort. Results Mean serum vitamin B12 was highest among omnivores (281, 95% CI: 270-292 pmol/l), intermediate in vegetarians (182, 95% CI: 175-189 pmol/l), and lowest in vegans (122, 95% CI: 117-127 pmol/l). Fifty-two percent of vegans, 7% of vegetarians and one omnivore were classified as vitamin B12 deficient (defined as serum vitamin B12 < 118 pmol/l). There was no significant association between age or duration of adherence to a vegetarian or a vegan diet and serum vitamin B12. In contrast, folate concentrations were highest among vegans, intermediate in vegetarians, and lowest in omnivores, but only two men (both omnivores) were categorised as folate deficient (defined as serum folate < 6.3 nmol/l). Conclusion Vegans have lower vitamin B12 concentrations, but higher folate concentrations, than vegetarians and omnivores. Half of the vegans were categorised as vitamin B12 deficient and would be expected to have a higher risk of developing clinical symptoms related to vitamin B12 deficiency.

Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress.

Elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and thrombosis, as well as a variety of other pathologies such as birth defects, Alzheimer's disease and other dementias, osteoporosis, diabetes and renal disease. Homocysteine metabolism is catalyzed by a number of enzymes that require B-vitamins as cofactors, and homocysteine levels are particularly responsive to folate status. The predictive power of plasma homocysteine level as a risk factor for atherothrombotic orders raised the appealing hypothesis that reduction of homocysteine levels by vitamin supplementation might result in a commensurate reduction is the risk of atherothrombotic events. Unfortunately, most clinical trials failed to show a significant benefit of vitamin supplementation on cardiovascular events, in spite of significant lowering of plasma homocysteine levels. Thus, it is not clear whether homocysteine actually plays a causal role in many pathologies with which it is associated, or whether it is instead a marker for some other underlying mechanism. A large body of data links hyperhomocysteinemia and folate status with oxidant stress. In this article I review data that suggests that homocysteine not only promotes cellular and protein injury via oxidant mechanisms, but is also a marker for the presence of pathological oxidant stress. Thus, it is possible that hyperhomocysteinemia is not a common primary cause of atherothrombotic disorders in the general population, but rather a marker of systemic or endothelial oxidant stress that is a major mediator of these disorders. Published by Elsevier Ltd.

Atherosclerosis and oxidant stress: the end of the road for antioxidant vitamin treatment?

Extensive experimental data have revealed a central role for oxidative stress in atherogenesis and suggested a potential role for 'antioxidant' treatment in cardiovascular disease (CVD) [1-11]. Experimental data, however, have not translated into clinical benefit: most antioxidant vitamin trials have failed to reduce cardiovascular morbidity and mortality [12]. Moreover, recent clinical trials have suggested that mono-therapy with certain antioxidant vitamins like vitamin E may, in fact, be detrimental [13]. As a result of the disappointing outcome of 'antioxidant' vitamin trials, some authors have questioned both the utility of 'antioxidant' treatment in CVD and the supposedly central role of oxidative stress in atherogenesis [14-19]. Other investigators, however, sustain that the beneficial effects of lipid lowering and anti-hypertensive treatment are at least, in part, due to their 'antioxidant' properties, in addition to their specific pharmacological properties [20, 21]. Oxidant stress plays a pivotal role in atherogenesis, however, the clinical promise of antioxidant vitamins has failed to translate into clinical benefit. Increasing evidence suggests that more rigorous clinical trial designs are necessary to effectively divulge antioxidant utility and that a multifaceted antioxidant approach to atherosclerosis may yield the most clinical reward. This article reviews currently available evidence on the role of oxidant stress in atherosclerosis, analyzes the results of large anti-oxidant trials, and suggests ways to investigate the true role of antioxidant treatment in the clinical setting.

Beans and diabetes: Phaseolus vulgaris preparations as antihyperglycemic agents.

Bean pods (Phaseolus vulgaris) are among the most widely used traditional remedies against diabetes mellitus. Historical knowledge is summarized and compared to recent study results. Reports dating from the first half of the 20(th) century as well as recent publications show contradictory results. It seems that Phaseolus preparations should not be considered the first choice in phytopharmaceutical treatment of diabetes or lead structure research. To be effective, fairly high doses of aqueous extracts need to be given. Because of their fiber content and an alpha-amylase inhibitory effect, beans might be more useful as food components in preventing or ameliorating type 2 diabetes.

HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia.

BACKGROUND: Orange juice-a rich source of vitamin C, folate, and flavonoids such as hesperidin-induces hypocholesterolemic responses in animals. OBJECTIVE: We determined whether orange juice beneficially altered blood lipids in subjects with moderate hypercholesterolemia. DESIGN: The sample consisted of 16 healthy men and 9 healthy women with elevated plasma total and LDL-cholesterol and normal plasma triacylglycerol concentrations. Participants incorporated 1, 2, or 3 cups (250 mL each) of orange juice sequentially into their diets, each dose over a period of 4 wk. This was followed by a 5-wk washout period. Plasma lipid, folate, homocyst(e)ine, and vitamin C (a compliance marker) concentrations were measured at baseline, after each treatment, and after the washout period. RESULTS: Consumption of 750 mL but not of 250 or 500 mL orange juice daily increased HDL-cholesterol concentrations by 21% (P: < 0.001), triacylglycerol concentrations by 30% (from 1.56 +/- 0.72 to 2.03 +/- 0.91 mmol/L; P: < 0.02), and folate concentrations by 18% (P: < 0.01); decreased the LDL-HDL cholesterol ratio by 16% (P: < 0.005); and did not affect homocyst(e)ine concentrations. Plasma vitamin C concentrations increased significantly during each dietary period (2.1, 3.1, and 3.8 times, respectively). CONCLUSIONS: Orange juice (750 mL/d) improved blood lipid profiles in hypercholesterolemic subjects, confirming recommendations to consume >/=5-10 servings of fruit and vegetables daily.

Controlling for sugar and ascorbic acid, a mixture of flavonoids matching navel oranges significantly increases human postprandial serum antioxidan...

Fruit and vegetable consumption reduces the risk for cardiovascular disease development. The postprandial state is an important contributor to chronic disease development. Orange flavonoids may reduce postprandial oxidation. It was hypothesized that a mixture of orange flavonoids would reduce postprandial oxidation better than a single orange flavonoid or orange sugar and ascorbic acid, but not as well as orange juice, when consumed with a typical breakfast. A placebo-controlled crossover trial (16 male and female participants, 4 treatments, 4 visits) was carried out. Treatments were placebo (ascorbic acid and sugar equivalent to orange juice); placebo plus hesperidin; placebo plus hesperidin, luteolin, and naringenin (mixture; found to have synergistic antioxidant properties in vitro in previous work); and orange juice (positive control). Serum oxygen radical absorbance capacity (ORAC), total plasma phenolics (TP), and serum lipoprotein oxidation (LO) were measured after a 12-hour baseline fast and at 1, 2, and 3 hours after sample consumption. The placebo plus mixture and orange juice groups were significantly increased in ORAC and LO lag time. Data for TP were inconsistent with ORAC and LO. Contrary to previous studies attributing the protective postprandial effect to fructose and ascorbate in other fruit trials, orange phenolic compounds contribute directly to the postprandial oxidative protection of serum, despite an inconsistent change in serum TP. Copyright © 2011 Elsevier Inc. All rights reserved.

Potent antimutagenic activity of white tea in comparison with green tea in the Salmonella assay.

There is growing interest in the potential health benefits of tea, including the antimutagenic properties. Four varieties of white tea, which represent the least processed form of tea, were shown to have marked antimutagenic activity in the Salmonella assay, particularly in the presence of S9. The most active of these teas, Exotica China white tea, was significantly more effective than Premium green tea (Dragonwell special grade) against 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and four other heterocyclic amine mutagens, namely 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]quinoxaline (4,8-DiMeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). Mechanism studies were performed using rat liver S9 in assays for methoxyresorufin O-demethylase (MROD), a marker for the enzyme cytochrome P4501A2 that activates heterocyclic amines, as well as Salmonella assays with the direct-acting mutagen 2-hydroxyamino-3-methylimidazo[4,5-f]quinoline (N-hydroxy-IQ). White tea at low concentrations in the assay inhibited MROD activity, and attenuated the mutagenic activity of N-hydroxy-IQ in the absence of S9. Nine of the major constituents found in green tea also were detected in white tea, including high levels of epigallocatechin-3-gallate (EGCG) and several other polyphenols. When these major constituents were mixed to produce "artificial" teas, according to their relative levels in white and green teas, the complete tea exhibited higher antimutagenic potency compared with the corresponding artificial tea. The results suggest that the greater inhibitory potency of white versus green tea in the Salmonella assay might be related to the relative levels of the nine major constituents, perhaps acting synergistically with other (minor) constituents, to inhibit mutagen activation as well as "scavenging" the reactive intermediate(s).

Protein intake, calcium balance and health consequences.

High-protein (HP) diets exert a hypercalciuric effect at constant levels of calcium intake, even though the effect may depend on the nature of the dietary protein. Lower urinary pH is also consistently observed for subjects consuming HP diets. The combination of these two effects was suspected to be associated with a dietary environment favorable for demineralization of the skeleton. However, increased calcium excretion due to HP diet does not seem to be linked to impaired calcium balance. In contrast, some data indicate that HP intakes induce an increase of intestinal calcium absorption. Moreover, no clinical data support the hypothesis of a detrimental effect of HP diet on bone health, except in a context of inadequate calcium supply. In addition, HP intake promotes bone growth and retards bone loss and low-protein diet is associated with higher risk of hip fractures. The increase of acid and calcium excretion due to HP diet is also accused of constituting a favorable environment for kidney stones and renal diseases. However, in healthy subjects, no damaging effect of HP diets on kidney has been found in either observational or interventional studies and it seems that HP diets might be deleterious only in patients with preexisting metabolic renal dysfunction. Thus, HP diet does not seem to lead to calcium bone loss, and the role of protein seems to be complex and probably dependent on other dietary factors and the presence of other nutrients in the diet.

Amla (Emblica officinalis Gaertn), a wonder berry in the treatment and prevention of cancer.

Emblica officinalis Gaertn. or Phyllanthus emblica Linn, commonly known as Indian gooseberry or amla, is arguably the most important medicinal plant in the Indian traditional system of medicine, the Ayurveda. Various parts of the plant are used to treat a range of diseases, but the most important is the fruit. The fruit is used either alone or in combination with other plants to treat many ailments such as common cold and fever; as a diuretic, laxative, liver tonic, refrigerant, stomachic, restorative, alterative, antipyretic, anti-inflammatory, hair tonic; to prevent peptic ulcer and dyspepsia, and as a digestive. Preclinical studies have shown that amla possesses antipyretic, analgesic, antitussive, antiatherogenic, adaptogenic, cardioprotective, gastroprotective, antianemia, antihypercholesterolemia, wound healing, antidiarrheal, antiatherosclerotic, hepatoprotective, nephroprotective, and neuroprotective properties. In addition, experimental studies have shown that amla and some of its phytochemicals such as gallic acid, ellagic acid, pyrogallol, some norsesquiterpenoids, corilagin, geraniin, elaeocarpusin, and prodelphinidins B1 and B2 also possess antineoplastic effects. Amla is also reported to possess radiomodulatory, chemomodulatory, chemopreventive effects, free radical scavenging, antioxidant, anti-inflammatory, antimutagenic and immunomodulatory activities, properties that are efficacious in the treatment and prevention of cancer. This review for the first time summarizes the results related to these properties and also emphasizes the aspects that warrant future research to establish its activity and utility as a cancer preventive and therapeutic drug in humans.

Major Pesticides Are More Toxic to Human Cells Than Their Declared Active Principles

Pesticides are used throughout the world as mixtures called formulations. They contain adjuvants, which are often kept confidential and are called inerts by the manufacturing companies, plus a declared active principle, which is usually tested alone. We tested the toxicity of 9 pesticides, comparing active principles and their formulations, on three human cell lines (HepG2, HEK293, and JEG3). Glyphosate, isoproturon, fluroxypyr, pirimicarb, imidacloprid, acetamiprid, tebuconazole, epoxiconazole, and prochloraz constitute, respectively, the active principles of 3 major herbicides, 3 insecticides, and 3 fungicides. We measured mitochondrial activities, membrane degradations, and caspases 3/7 activities. Fungicides were the most toxic from concentrations 300–600 times lower than agricultural dilutions, followed by herbicides and then insecticides, with very similar profiles in all cell types. Despite its relatively benign reputation, Roundup was among the most toxic herbicides and insecticides tested. Most importantly, 8 formulations out of 9 were up to one thousand times more toxic than their active principles. Our results challenge the relevance of the acceptable daily intake for pesticides because this norm is calculated from the toxicity of the active principle alone. Chronic tests on pesticides may not reflect relevant environmental exposures if only one ingredient of these mixtures is tested alone.

Dangerous nutrition? Calcium, vitamin D, and shark cartilage nutritional supplements and cancer-related hypercalcemia.

The use of nutritional supplements in the general population and in cancer patients has become very popular. These supplements are not perceived as medications and are presumed to be safe by cancer patients, who may however be at risk for hypercalcemia. We note that many of our patients who have developed symptomatic hypercalcemia were taking vitamin D, calcium, or shark cartilage supplements. We report eight cases of hypercalcemia in cancer patients seen at the Cleveland Clinic Foundation in whom these nutritional supplements may have contributed to the prevalence or severity of hypercalcemia.

Omega-3 fatty acids for nutrition and medicine: considering microalgae oil as a vegetarian source of EPA and DHA.

Long-chain EPA/DHA omega-3 fatty acid supplementation can be co-preventative and co-therapeutic. Current research suggests increasing accumulated long chain omega-3s for health benefits and as natural medicine in several major diseases. But many believe plant omega-3 sources are nutritionally and therapeutically equivalent to the EPA/DHA omega-3 in fish oil. Although healthy, precursor ALA bio-conversion to EPA is inefficient and production of DHA is nearly absent, limiting the protective value of ALA supplementation from flax-oil, for example. Along with pollutants certain fish acquire high levels of EPA/DHA as predatory species. However, the origin of EPA/DHA in aquatic ecosystems is algae. Certain microalgae produce high levels of EPA or DHA. Now, organically produced DHA-rich microalgae oil is available. Clinical trials with DHA-rich oil indicate comparable efficacies to fish oil for protection from cardiovascular risk factors by lowering plasma triglycerides and oxidative stress. This review discusses 1) omega-3 fatty acids in nutrition and medicine; 2) omega-3s in physiology and gene regulation; 3) possible protective mechanisms of EPA/DHA in major diseases such as coronary heart disease, atherosclerosis, cancer and type 2 diabetes; 4) EPA and DHA requirements considering fish oil safety; and 5) microalgae EPA and DHA-rich oils and recent clinical results.

Bitter melon (Momordica charantia) extract suppresses adrenocortical cancer cell proliferation through modulation of the apoptotic pathway, steroid...

Adrenocortical carcinomas are rare but present with extremely poor prognosis. One of the approaches to control cancer progression and reduce cancer risk is prevention through diet. Bitter melon is widely consumed as a vegetable and especially as a traditional medicine in many countries. In this study, we have used human and mouse adrenocortical cancer cells as an in vitro model to assess the efficacy of bitter melon extract (BME) as an anticancer agent. The protein concentrations of BME and other extracts were measured before use. First, BME treatment of adrenocortical cancer cells resulted in a significantly dose-dependent decrease in cell proliferation. However, we did not observe an antiproliferative effect in adrenocortical cancer cells treated with extracts from blueberry, zucchini, and acorn squash. Second, apoptosis of adrenocortical cancer cells was accompanied by increased caspase-3 activation and poly(ADP-ribose) polymerase cleavage. BME treatment enhanced cellular tumor antigen p53, cyclin-dependent kinase inhibitor 1A (also called p21), and cyclic AMP-dependent transcription factor-3 levels and inhibited G1/S-specific cyclin D1, D2, and D3, and mitogen-activated protein kinase 8 (also called Janus kinase) expression, suggesting an additional mechanism involving cell cycle regulation and cell survival. Third, BME treatment decreased the key proteins involved in steroidogenesis in adrenocortical cancer cells. BME treatment decreased the level of phosphorylation of cyclin-dependent kinase 7, which is required, at least in part, for steroidogenic factor 1 activation. Finally, we observed that BME treatment significantly reduced the level of insulin-like growth factor 1 receptor and its downstream signaling pathway as evidenced by lower levels of phosphorylated RAC-α serine/threonine-protein kinase. Taken together, these data illustrate the inhibitory effect of bitter melon on cell proliferation of adrenocortical cancer through modulation of diverse mechanisms.

Absence of pomegranate ellagitannins in the majority of commercial Pomegranate extracts: implications for standardization and quality control.

The health benefits associated with pomegranate juice have led to the development of pomegranate extracts as botanical dietary supplements. Pomegranates contain hydrolyzable tannins in the form of punicalagins and punicalin as well as tannin-based complex oligomers that account for much of the antioxidant activity in juice. The content of ellagic acid has been used to standardize most pomegranate extract dietary supplements marketed. However, supplements can be adulterated with ellagic acid from less expensive plant sources and undercut this method of standardization. To compare the phytochemical contents and antioxidant activities of commercially available pomegranate extract dietary supplements beyond their content of ellagic acid, a total of 27 different supplements in the form of capsules, tablets, and soft gels were studied. Total phenolics were measured using both gallic acid equivalent (GAE) and ellagic acid equivalent (EAE) assays. Punicalagins, punicalin, and ellagic acid contents were determined by HPLC, whereas antioxidant capacity was measured using the Trolox equivalent antioxidant capacity (TEAC) assay. Of the 27 supplements tested, only 5 had the typical pomegranate tannin profile by HPLC, 17 had ellagic acid as the predominant chemical with minor or no detectable pomegranate tannins, and 5 had no detectable tannins or ellagic acid. Therefore, standardization of pomegranate extract supplements based on their ellagic acid content does not guarantee pomegranate supplement authenticity. Future research is needed to assess the health impact of substituting ellagic acid for the complex mix of phytochemicals in a pomegranate extract dietary supplement.

Dietary flaxseed lignan extract lowers plasma cholesterol and glucose concentrations in hypercholesterolaemic subjects.

Lignans, derived from flaxseed, are phyto-oestrogens being increasingly studied for their health benefits. An 8-week, randomised, double-blind, placebo-controlled study was conducted in fifty-five hypercholesterolaemic subjects, using treatments of 0 (placebo), 300 or 600 mg/d of dietary secoisolariciresinol diglucoside (SDG) from flaxseed extract to determine the effect on plasma lipids and fasting glucose levels. Significant treatment effects were achieved (P < 0.05 to < 0.001) for the decrease of total cholesterol (TC), LDL-cholesterol (LDL-C) and glucose concentrations, as well as their percentage decrease from baseline. At weeks 6 and 8 in the 600 mg SDG group, the decreases of TC and LDL-C concentrations were in the range from 22.0 to 24.38 % respectively (all P < 0.005 compared with placebo). For the 300 mg SDG group, only significant differences from baseline were observed for decreases of TC and LDL-C. A substantial effect on lowering concentrations of fasting plasma glucose was also noted in the 600 mg SDG group at weeks 6 and 8, especially in the subjects with baseline glucose concentrations > or = 5.83 mmol/l (lowered 25.56 and 24.96 %; P = 0.015 and P = 0.012 compared with placebo, respectively). Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and enterolactone were all significantly raised in the groups supplemented with flaxseed lignan. The observed cholesterol-lowering values were correlated with the concentrations of plasma SECO and ED (r 0.128-0.302; P < 0.05 to < 0.001). In conclusion, dietary flaxseed lignan extract decreased plasma cholesterol and glucose concentrations in a dose-dependent manner.

Dietary sources and antioxidant effects of ergothioneine.

Ergothioneine is a native membrane-impermeable thiol compound that is specifically accumulated in cells via the organic cation transporter OCTN1. In humans, OCTN1 and ergothioneine have been implicated in the etiopathogenesis of autoimmune disorders. However, available evidence about dietary sources and the functional role of ergothioneine in human physiology is scarce. Here, we analyzed the ergothioneine content in common foods using liquid chromatography tandem-mass spectrometry. Additionally, we assessed the protective potency of ergothioneine against various oxidative stressors in OCTN1-expressing cells in comparison with the main intracellular thiol antioxidant glutathione by evaluating cell viability with the MTT reduction assay. Only some food contained ergothioneine with highest concentrations detected in specialty mushrooms, kidney, liver, black and red beans, and oat bran. Ergothioneine exhibited cell protection only against copper(II)-induced toxicity but was far less potent than glutathione, indicting that ergothioneine is not involved in the intracellular antioxidant thiol defense system.

Non-Soy Legume Consumption Lowers Cholesterol Levels: A Meta-Analysis of Randomized Controlled Trials

Background and Aims Studies evaluating the effect of legume consumption on cholesterol have focused on soybeans, however non-soy legumes, such as a variety of beans, peas, and some seeds, are commonly consumed in Western countries. We conducted a meta-analysis of randomized controlled trials evaluating the effects of non-soy legume consumption on blood lipids. Methods and Results Studies were retrieved by searching MEDLINE (from January 1966 through July 2009), EMBASE (from January 1980 to July 2009), and the Cochrane Collaboration's Central Register of Controlled Clinical Trials using the following terms as medical subject headings and keywords: fabaceae not soybeans not isoflavones and diet or dietary fiber and cholesterol or hypercholesterolemia or triglycerides or cardiovascular diseases. Bibliographies of all retrieved articles were also searched. From 140 relevant reports, 10 randomized clinical trials were selected which compared a non-soy legume diet to control, had a minimum duration of 3 weeks, and reported blood lipid changes during intervention and control. Data on sample size, participant characteristics, study design, intervention methods, duration, and treatment results were independently abstracted by 2 investigators using a standardized protocol. Data from 10 trials representing 268 participants were examined using a random-effects model. Pooled mean net change in total cholesterol for those treated with a legume diet compared to control was −11.8 mg/dL (95% confidence interval [CI], −16.1 to −7.5); mean net change in low density lipoprotein cholesterol was −8.0 mg/dL (95% CI, −11.4 to −4.6). Conclusion These results indicate that a diet rich in legumes other than soy decreases total and LDL cholesterol.

Plant-based foods as a source of lipotropes for human nutrition: a survey of in vivo studies.

Increased consumption of plant products is associated with lower chronic disease prevalence. This is attributed to the great diversity of healthy phytochemicals present in these foods. The most investigated physiological effects have been their antioxidant, anti-carcinogenic, hypolipidemic, and hypoglycemic properties. Although less studied in humans, some compounds were very early on shown to be lipotropic in animals, i.e., the capacity to hasten the removal of fat from liver and/or reduce hepatic lipid synthesis or deposits by mainly increasing phospholipid synthesis via the transmethylation pathway for triglyceride-rich lipoprotein exportation from the liver and enhanced fatty acid β-oxidation and/or down- and up-regulation of genes involved in lipogenic and fatty acid oxidation enzyme synthesis, respectively. The main plant lipotropes are choline, betaine, myo-inositol, methionine, and carnitine. Magnesium, niacin, pantothenate, and folates also indirectly support the overall lipotropic effect. The exhaustive review of rat studies investigating phytochemical effect on hepatic lipid metabolism suggests that some fatty acids, acetic acid, melatonin, phytic acid, some fiber compounds, oligofructose, resistant starch, some phenolic acids, flavonoids, lignans, stilbenes, curcumin, saponins, coumarin, some plant extracts, and some solid foods may be lipotropic. However, this remains to be confirmed in humans, for whom intervention studies are practically non-existent. Supplemental materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition® to view the free supplemental file.

Vitamins C and E and Beta Carotene Supplementation and Cancer Risk: A Randomized Controlled Trial

Background Observational studies suggested that a diet high in fruits and vegetables, both of which are rich with antioxidants, may prevent cancer development. However, findings from randomized trials of the association between antioxidant use and cancer risk have been mostly negative. Methods From 8171 women who were randomly assigned in the Women's Antioxidant Cardiovascular Study, a double-blind, placebo-controlled 2 × 2 × 2 factorial trial of vitamin C (500 mg of ascorbic acid daily), natural-source vitamin E (600 IU of α-tocopherol every other day), and beta carotene (50 mg every other day), 7627 women who were free of cancer before random assignment were selected for this study. Diagnoses and deaths from cancer at a specific site were confirmed by use of hospital reports and the National Death Index. Cox proportional hazards regression models were used to assess hazard ratios (represented as relative risks [RRs]) of common cancers associated with use of antioxidants, either individually or in combination. Subgroup analyses were conducted to determine if duration of use modified the association of supplement use with cancer risk. All statistical tests were two-sided. Results During an average 9.4 years of treatment, 624 women developed incident invasive cancer and 176 women died from cancer. There were no statistically significant effects of use of any antioxidant on total cancer incidence. Compared with the placebo group, the RRs were 1.11 (95% confidence interval [CI] = 0.95 to 1.30) in the vitamin C group, 0.93 (95% CI = 0.79 to 1.09) in the vitamin E group, and 1.00 (95% CI = 0.85 to 1.17) in the beta carotene group. Similarly, no effects of these antioxidants were observed on cancer mortality. Compared with the placebo group, the RRs were 1.28 (95% CI = 0.95 to 1.73) in the vitamin C group, 0.87 (95% CI = 0.65 to 1.17) in the vitamin E group, and 0.84 (95% CI = 0.62 to 1.13) in the beta carotene group. Duration and combined use of the three antioxidants also had no effect on cancer incidence and cancer death. Conclusions Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality.

Evolution of the human diet: linking our ancestral diet to modern functional foods as a means of chronic disease prevention.

The evolution of the human diet over the past 10,000 years from a Paleolithic diet to our current modern pattern of intake has resulted in profound changes in feeding behavior. Shifts have occurred from diets high in fruits, vegetables, lean meats, and seafood to processed foods high in sodium and hydrogenated fats and low in fiber. These dietary changes have adversely affected dietary parameters known to be related to health, resulting in an increase in obesity and chronic disease, including cardiovascular disease (CVD), diabetes, and cancer. Some intervention trials using Paleolithic dietary patterns have shown promising results with favorable changes in CVD and diabetes risk factors. However, such benefits may be offset by disadvantages of the Paleolithic diet, which is low in vitamin D and calcium and high in fish potentially containing environmental toxins. More advantageous would be promotion of foods and food ingredients from our ancestral era that have been shown to possess health benefits in the form of functional foods. Many studies have investigated the health benefits of various functional food ingredients, including omega-3 fatty acids, polyphenols, fiber, and plant sterols. These bioactive compounds may help to prevent and reduce incidence of chronic diseases, which in turn could lead to health cost savings ranging from $2 to $3 billion per year as estimated by case studies using omega-3 and plant sterols as examples. Thus, public health benefits should result from promotion of the positive components of Paleolithic diets as functional foods.

Dietary roles of non-starch polysaccharides in human nutrition: a review.

Nonstarch polysaccharides (NSPs) occur naturally in many foods. The physiochemical and biological properties of these compounds correspond to dietary fiber. Nonstarch polysaccharides show various physiological effects in the small and large intestine and therefore have important health implications for humans. The remarkable properties of dietary NSPs are water dispersibility, viscosity effect, bulk, and fermentibility into short chain fatty acids (SCFAs). These features may lead to diminished risk of serious diet related diseases which are major problems in Western countries and are emerging in developing countries with greater affluence. These conditions include coronary heart disease, colo-rectal cancer, inflammatory bowel disease, breast cancer, tumor formation, mineral related abnormalities, and disordered laxation. Insoluble NSPs (cellulose and hemicellulose) are effective laxatives whereas soluble NSPs (especially mixed-link β-glucans) lower plasma cholesterol levels and help to normalize blood glucose and insulin levels, making these kinds of polysaccharides a part of dietary plans to treat cardiovascular diseases and Type 2 diabetes. Moreover, a major proportion of dietary NSPs escapes the small intestine nearly intact, and is fermented into SCFAs by commensal microflora present in the colon and cecum and promotes normal laxation. Short chain fatty acids have a number of health promoting effects and are particularly effective in promoting large bowel function. Certain NSPs through their fermented products may promote the growth of specific beneficial colonic bacteria which offer a prebiotic effect. Various modes of action of NSPs as therapeutic agent have been proposed in the present review. In addition, NSPs based films and coatings for packaging and wrapping are of commercial interest because they are compatible with several types of food products. However, much of the physiological and nutritional impact of NSPs and the mechanism involved is not fully understood and even the recommendation on the dose of different dietary NSPs intake among different age groups needs to be studied.

Can grapefruit juice influence ethinylestradiol bioavailability?

The effects of grapefruit juice on the bioavailability of 17 alpha-ethinylestradiol (EE2) after a single oral administration of 50 micrograms EE2 have been investigated. The pharmacokinetics of EE2 were studied in an open, randomized, cross-over study in which 13 healthy volunteers were administered the drug with herbal tea or grapefruit juice (naringin, 887 mg/ml). In contrast to herbal tea, grapefruit juice increased the peak plasma concentration (Cmax) significantly to 137% (mean; range 64% to 214%, p = 0.0088) and increased the area under plasma concentration-time curve from 0 to 8 hours (AUC0-8) to 128% (mean; range 81% to 180%, p = 0.0186). This study shows that grapefruit juice increases the bioavailable amount of EE2. A possible explanation may be that grapefruit juice inhibits the metabolic degradation of EE2. Whether the increased bioavailability of EE2 following grapefruit juice administration is of clinical importance should be investigated in long-term studies.

The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy.

Recent studies confirm that dietary methionine restriction increases both mean and maximal lifespan in rats and mice, achieving "aging retardant" effects very similar to those of caloric restriction, including a suppression of mitochondrial superoxide generation. Although voluntary caloric restriction is never likely to gain much popularity as a pro-longevity strategy for humans, it may be more feasible to achieve moderate methionine restriction, in light of the fact that vegan diets tend to be relatively low in this amino acid. Plant proteins - especially those derived from legumes or nuts - tend to be lower in methionine than animal proteins. Furthermore, the total protein content of vegan diets, as a function of calorie content, tends to be lower than that of omnivore diets, and plant protein has somewhat lower bioavailability than animal protein. Whole-food vegan diets that moderate bean and soy intake, while including ample amounts of fruit and wine or beer, can be quite low in methionine, while supplying abundant nutrition for health (assuming concurrent B12 supplementation). Furthermore, low-fat vegan diets, coupled with exercise training, can be expected to promote longevity by decreasing systemic levels of insulin and free IGF-I; the latter effect would be amplified by methionine restriction - though it is not clear whether IGF-I down-regulation is the sole basis for the impact of low-methionine diets on longevity in rodents.

Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention.

BACKGROUND: Studies indicate that intake of vitamin D in the range from 1,100 to 4,000 IU/d and a serum 25-hydroxyvitamin D concentration [25(OH)D] from 60-80 ng/ml may be needed to reduce cancer risk. Few community-based studies allow estimation of the dose-response relationship between oral intake of vitamin D and corresponding serum 25(OH)D in the range above 1,000 IU/d. MATERIALS AND METHODS: A descriptive study of serum 25(OH)D concentration and self-reported vitamin D intake in a community-based cohort (n = 3,667, mean age 51.3 ± 13.4 y). RESULTS: Serum 25(OH)D rose as a function of self-reported vitamin D supplement ingestion in a curvilinear fashion, with no intakes of 10,000 IU/d or lower producing 25(OH)D values above the lower-bound of the zone of potential toxicity (200 ng/ml). Unsupplemented all-source input was estimated at 3,300 IU/d. The supplemental dose ensuring that 97.5% of this population achieved a serum 25(OH)D of at least 40 ng/ml was 9,600 IU/d. CONCLUSION: Universal intake of up to 40,000 IU vitamin D per day is unlikely to result in vitamin D toxicity.