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1.  The Micronutrient Genomics Project: a community-driven knowledge base for micronutrient research 
Genes & Nutrition  2010;5(4):285-296.
Micronutrients influence multiple metabolic pathways including oxidative and inflammatory processes. Optimum micronutrient supply is important for the maintenance of homeostasis in metabolism and, ultimately, for maintaining good health. With advances in systems biology and genomics technologies, it is becoming feasible to assess the activity of single and multiple micronutrients in their complete biological context. Existing research collects fragments of information, which are not stored systematically and are thus not optimally disseminated. The Micronutrient Genomics Project (MGP) was established as a community-driven project to facilitate the development of systematic capture, storage, management, analyses, and dissemination of data and knowledge generated by biological studies focused on micronutrient–genome interactions. Specifically, the MGP creates a public portal and open-source bioinformatics toolbox for all “omics” information and evaluation of micronutrient and health studies. The core of the project focuses on access to, and visualization of, genetic/genomic, transcriptomic, proteomic and metabolomic information related to micronutrients. For each micronutrient, an expert group is or will be established combining the various relevant areas (including genetics, nutrition, biochemistry, and epidemiology). Each expert group will (1) collect all available knowledge, (2) collaborate with bioinformatics teams towards constructing the pathways and biological networks, and (3) publish their findings on a regular basis. The project is coordinated in a transparent manner, regular meetings are organized and dissemination is arranged through tools, a toolbox web portal, a communications website and dedicated publications.
PMCID: PMC2989004  PMID: 21189865
Micronutrient; Bioinformatics; Database; Genomics
2.  Nutrigenomic Analysis of Diet-Gene Interactions on Functional Supplements for Weight Management 
Current Genomics  2008;9(4):239-251.
Recent advances in molecular biology combined with the wealth of information generated by the Human Genome Project have fostered the emergence of nutrigenomics, a new discipline in the field of nutritional research. Nutrigenomics may provide the strategies for the development of safe and effective dietary interventions against the obesity epidemic. According to the World Health Organization, more than 60% of the global disease burden will be attributed to chronic disorders associated with obesity by 2020. Meanwhile in the US, the prevalence of obesity has doubled in adults and tripled in children during the past three decades. In this regard, a number of natural dietary supplements and micronutrients have been studied for their potential in weight management. Among these supplements, (–)-hydroxycitric acid (HCA), a natural extract isolated from the dried fruit rind of Garcinia cambogia, and the micronutrient niacin-bound chromium(III) (NBC) have been shown to be safe and efficacious for weight loss. Utilizing cDNA microarrays, we demonstrated for the first time that HCA-supplementation altered the expression of genes involved in lipolytic and adipogenic pathways in adipocytes from obese women and up-regulated the expression of serotonin receptor gene in the abdominal fat of rats. Similarly, we showed that NBC-supplementation up-regulated the expression of myogenic genes while suppressed the expression of genes that are highly expressed in brown adipose tissue in diabetic obese mice. The potential biological mechanisms underlying the observed beneficial effects of these supplements as elucidated by the state-of-the-art nutrigenomic technologies will be systematically discussed in this review.
PMCID: PMC2682937  PMID: 19452041
Insulin resistance; glucose tolerance factor; supplemental chromium; Garcinia cambogia; (-)-hydroxycitric acid; overweight; obesity; diabetes; cardiovascular disease; nutritional interventions; microarrays; nutrigenomics.
3.  Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status 
Mutagenesis  2011;26(1):57-62.
Epidemiological studies reveal strong association between micronutrient deficiencies and development of cancer. Since chromosome breaks and abnormal chromosome segregation, identified as micronuclei (MN), are central to malignant transformation, the influence of micronutrient status upon MN frequency has been the subject of intense research. Motivating this effort is the idea that marginal micronutrient deficiencies lead to allocation of scarce cellular resources towards immediate survival at the expense of maintaining genomic integrity, placing the individual at greater risk for degenerative diseases and cancer in old age. The challenge in identifying an association between individual micronutrients and MN frequency stems from the complexity of human diet, simultaneous presence of multiple micronutrient deficiencies, variable genetic susceptibility and methodological difficulties. A unique model for studying MN in humans is provided by a group of haematological diseases, the chronic haemolytic anaemias associated with high reticulocyte count and absence of splenic function. These disorders may prove valuable for assessing the influence of micronutrient status once the effect of abnormal erythropoiesis on MN formation is adequately understood. Eventually, large population-based studies that can account for the baseline variability in MN frequency, lifestyle and genetic factors may be needed to uncover the DNA-damaging effect of poor diet. Understanding the link between micronutrient status and MN frequency will contribute towards determining optimal micronutrient intake to preserve long-term health.
PMCID: PMC3107612  PMID: 21164183
4.  Micronutrient fortification of food and its impact on woman and child health: a systematic review 
Systematic Reviews  2013;2:67.
Vitamins and minerals are essential for growth and metabolism. The World Health Organization estimates that more than 2 billion people are deficient in key vitamins and minerals. Groups most vulnerable to these micronutrient deficiencies are pregnant and lactating women and young children, given their increased demands. Food fortification is one of the strategies that has been used safely and effectively to prevent vitamin and mineral deficiencies.
A comprehensive search was done to identify all available evidence for the impact of fortification interventions. Studies were included if food was fortified with a single, dual or multiple micronutrients and impact of fortification was analyzed on the health outcomes and relevant biochemical indicators of women and children. We performed a meta-analysis of outcomes using Review Manager Software version 5.1.
Our systematic review identified 201 studies that we reviewed for outcomes of relevance. Fortification for children showed significant impacts on increasing serum micronutrient concentrations. Hematologic markers also improved, including hemoglobin concentrations, which showed a significant rise when food was fortified with vitamin A, iron and multiple micronutrients. Fortification with zinc had no significant adverse impact on hemoglobin levels. Multiple micronutrient fortification showed non-significant impacts on height for age, weight for age and weight for height Z-scores, although they showed positive trends. The results for fortification in women showed that calcium and vitamin D fortification had significant impacts in the post-menopausal age group. Iron fortification led to a significant increase in serum ferritin and hemoglobin levels in women of reproductive age and pregnant women. Folate fortification significantly reduced the incidence of congenital abnormalities like neural tube defects without increasing the incidence of twinning. The number of studies pooled for zinc and multiple micronutrients for women were few, though the evidence suggested benefit. There was a dearth of evidence for the impact of fortification strategies on morbidity and mortality outcomes in women and children.
Fortification is potentially an effective strategy but evidence from the developing world is scarce. Programs need to assess the direct impact of fortification on morbidity and mortality.
PMCID: PMC3765883  PMID: 23971426
Child; Food; Fortification; Nutrition; Supplementation; Women
5.  Complementary feeding: a Global Network cluster randomized controlled trial 
BMC Pediatrics  2011;11:4.
Inadequate and inappropriate complementary feeding are major factors contributing to excess morbidity and mortality in young children in low resource settings. Animal source foods in particular are cited as essential to achieve micronutrient requirements. The efficacy of the recommendation for regular meat consumption, however, has not been systematically evaluated.
A cluster randomized efficacy trial was designed to test the hypothesis that 12 months of daily intake of beef added as a complementary food would result in greater linear growth velocity than a micronutrient fortified equi-caloric rice-soy cereal supplement. The study is being conducted in 4 sites of the Global Network for Women's and Children's Health Research located in Guatemala, Pakistan, Democratic Republic of the Congo (DRC) and Zambia in communities with toddler stunting rates of at least 20%. Five clusters per country were randomized to each of the food arms, with 30 infants in each cluster. The daily meat or cereal supplement was delivered to the home by community coordinators, starting when the infants were 6 months of age and continuing through 18 months. All participating mothers received nutrition education messages to enhance complementary feeding practices delivered by study coordinators and through posters at the local health center. Outcome measures, obtained at 6, 9, 12, and 18 months by a separate assessment team, included anthropometry; dietary variety and diversity scores; biomarkers of iron, zinc and Vitamin B12 status (18 months); neurocognitive development (12 and 18 months); and incidence of infectious morbidity throughout the trial. The trial was supervised by a trial steering committee, and an independent data monitoring committee provided oversight for the safety and conduct of the trial.
Findings from this trial will test the efficacy of daily intake of meat commencing at age 6 months and, if beneficial, will provide a strong rationale for global efforts to enhance local supplies of meat as a complementary food for young children.
Trial registration
PMCID: PMC3032692  PMID: 21232139
6.  Transformations of summary statistics as input in meta-analysis for linear dose-response models on a logarithmic scale: a methodology developed within EURRECA 
To derive micronutrient recommendations in a scientifically sound way, it is important to obtain and analyse all published information on the association between micronutrient intake and biochemical proxies for micronutrient status using a systematic approach. Therefore, it is important to incorporate information from randomized controlled trials as well as observational studies as both of these provide information on the association. However, original research papers present their data in various ways.
This paper presents a methodology to obtain an estimate of the dose–response curve, assuming a bivariate normal linear model on the logarithmic scale, incorporating a range of transformations of the original reported data.
The simulation study, conducted to validate the methodology, shows that there is no bias in the transformations. Furthermore, it is shown that when the original studies report the mean and standard deviation or the geometric mean and confidence interval the results are less variable compared to when the median with IQR or range is reported in the original study.
The presented methodology with transformations for various reported data provides a valid way to estimate the dose–response curve for micronutrient intake and status using both randomized controlled trials and observational studies.
PMCID: PMC3780718  PMID: 22533574
Methodology; Dose–response; Meta-analysis; EURRECA
7.  Effect of multiple micronutrient supplementation during pregnancy on maternal and birth outcomes 
BMC Public Health  2011;11(Suppl 3):S19.
Given the widespread prevalence of micronutrient deficiencies in developing countries, supplementation with multiple micronutrients rather than iron-folate alone, could be of potential benefit to the mother and the fetus. These benefits could relate to prevention of maternal complications and reduction in other adverse pregnancy outcomes such as small-for-gestational age (SGA) births, low birth weight, stillbirths, perinatal and neonatal mortality. This review evaluates the evidence of the impact of multiple micronutrient supplements during pregnancy, in comparison with standard iron-folate supplements, on specific maternal and pregnancy outcomes of relevance to the Lives Saved Tool (LiST).
Data sources/review methods
A systematic review of randomized controlled trials was conducted. Search engines used were PubMed, the Cochrane Library, the WHO regional databases and hand search of bibliographies. A standardized data abstraction and Child Health Epidemiology Reference (CHERG) adaptation of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) technique were used for data abstraction and overall quality of evidence. Meta-analyses were performed to calculate summary estimates of utility to the LiST model for the specified outcome of incidence of SGA births. We also evaluated the potential impact of multiple micronutrients on neonatal mortality according to the proportion of deliveries occurring in facilities (using a threshold of 60% to indicate functionality of health systems for skilled births).
We included 17 studies for detailed data abstraction. There was no significant benefit of multiple micronutrients as compared to iron folate on maternal anemia in third trimester [Relative risk (RR) = 1.03; 95% confidence interval (CI): 0.87 – 1.22 (random model)]. Our analysis, however, showed a significant reduction in SGA by 9% [RR = 0.91; 95% CI: 0.86 – 0.96 (fixed model)]. In the fixed model, the SGA outcome remained significant only in women with mean body mass index (BMI) ≥ 22 kg/m2. There was an increased risk of neonatal mortality in studies with majority of births at home [RR = 1.47, 95% CI: 1.13-1.92]; such an effect was not evident where ≥ 60% of births occurred in facility settings [RR = 0.94, 95% CI: 0.81-1.09]. Overall there was no increase in the risk of neonatal mortality [RR = 1.05, 95% CI: 0.92 – 1.19 (fixed model)].
This review provides evidence of a significant benefit of MMN supplementation during pregnancy on reducing SGA births as compared to iron-folate, with no significant increase in the risk of neonatal mortality in populations where skilled birth care is available and majority of births take place in facilities. Given comparability of impacts on maternal anemia, the decision to replace iron-folate with multiple micronutrients during pregnancy may be taken in the context of available services in health systems and birth outcomes monitored.
PMCID: PMC3231892  PMID: 21501436
8.  Micronutrient Fortified Milk Improves Iron Status, Anemia and Growth among Children 1–4 Years: A Double Masked, Randomized, Controlled Trial 
PLoS ONE  2010;5(8):e12167.
Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering. Given the limited success of supplementation and health education programs, fortification of foods could be a viable and sustainable option. We report results from a community based double-masked, randomized trial among children 1–4 years evaluating the effects of micronutrients (especially of zinc and iron) delivered through fortified milk on growth, anemia and iron status markers as part of a four group study design, running two studies simultaneously.
Methods and Findings
Enrolled children (n = 633) were randomly allocated to receive either micronutrients fortified milk (MN = 316) or control milk (Co = 317). Intervention of MN milk provided additional 7.8 mg zinc, 9.6 mg iron, 4.2 µg selenium, 0.27 mg copper, 156 µg vitamin A, 40.2 mg vitamin C, and 7.5 mg vitamin E per day (three serves) for one year. Anthropometry was recorded at baseline, mid- and end-study. Hematological parameters were estimated at baseline and end-study. Both groups were comparable at baseline. Compliance was over 85% and did not vary between groups. Compared to children consuming Co milk, children consuming MN milk showed significant improvement in weight gain (difference of mean: 0.21 kg/year; 95% confidence interval [CI] 0.12 to 0.31, p<0.001) and height gain (difference of mean: 0.51 cm/year; 95% CI 0.27 to 0.75, p<0.001). Mean hemoglobin (Hb) (difference of 13.6 g/L; 95% CI 11.1 to 16.0, p<0.001) and serum ferritin levels (difference of 7.9 µg/L; 95% CI 5.4 to 10.5, p<0.001) also improved. Children in MN group had 88% (odds ratio = 0.12, 95% CI 0.08 to 0.20, p<0.001) lower risk of iron deficiency anemia.
Milk provides an acceptable and effective vehicle for delivery of specific micronutrients, especially zinc and iron. Micronutrient bundle improved growth and iron status and reduced anemia in children 1–4 years old.
Trial Registration NCT00255385
PMCID: PMC2921413  PMID: 20730057
9.  Intraindividual Variability in Serum Micronutrients 
Although serum measures of micronutrients are more specific than questionnaires in quantifying nutritional status, the reliability of serum measures depends on between- and within-person variability of circulating micronutrient levels. The extent to which multiple samples per person might improve reliability is useful information for planning studies and interpreting results.
We analyzed levels of 25 micronutrients in serum samples taken from 381 Hawaii women at 4-month intervals. For all subjects and for subjects at the low and high end of the micronutrient distributions, we calculated inter- and intraindividual variability, reliability coefficients, and the number of measurements required to limit attenuation in estimated parameters (ie, to keep estimates close to their true values).
For 18 of the 25 micronutrients, a single measurement provided an estimate within 20% of the true value. For regression coefficients, 2 measurements were needed to limit attenuation to no more than 20% for nearly half of the micronutrients. To achieve no more than 10% attenuation, the number of measurements required ranged from 2 to 10 for correlation and from 3 to 20 for regression coefficients. To achieve no more than 5% attenuation, the corresponding ranges were 3 to 21 for correlation and 6 to 42 regression coefficients. In general, more measurements were required for adequate characterization of subjects with relatively high levels of micronutrients than for subjects with lower levels.
Our analysis suggests that 2 or 3 blood measurements are enough to limit attenuation of regression coefficients within 20% of the true value for most carotenoids and tocopherols. For 10% attenuation or less, 4 or more micronutrient measurements may be needed.
PMCID: PMC2663917  PMID: 18813024
10.  The Influence of Micronutrients in Cell Culture: A Reflection on Viability and Genomic Stability 
BioMed Research International  2013;2013:597282.
Micronutrients, including minerals and vitamins, are indispensable to DNA metabolic pathways and thus are as important for life as macronutrients. Without the proper nutrients, genomic instability compromises homeostasis, leading to chronic diseases and certain types of cancer. Cell-culture media try to mimic the in vivo environment, providing in vitro models used to infer cells' responses to different stimuli. This review summarizes and discusses studies of cell-culture supplementation with micronutrients that can increase cell viability and genomic stability, with a particular focus on previous in vitro experiments. In these studies, the cell-culture media include certain vitamins and minerals at concentrations not equal to the physiological levels. In many common culture media, the sole source of micronutrients is fetal bovine serum (FBS), which contributes to only 5–10% of the media composition. Minimal attention has been dedicated to FBS composition, micronutrients in cell cultures as a whole, or the influence of micronutrients on the viability and genetics of cultured cells. Further studies better evaluating micronutrients' roles at a molecular level and influence on the genomic stability of cells are still needed.
PMCID: PMC3678455  PMID: 23781504
11.  The Extended Nutrigenomics – Understanding the Interplay between the Genomes of Food, Gut Microbes, and Human Host 
Comprehensive investigation of nutritional health effects at the molecular level requires the understanding of the interplay between three genomes, the food, the gut microbial, and the human host genome. Food genomes are researched for discovery and exploitation of macro- and micronutrients as well as specific bioactives, with those genes coding for bioactive proteins and peptides being of central interest. The human gut microbiota encompasses a complex ecosystem in the intestine with profound impact on host metabolism. It is being studied at genomic and, more recently, also at proteomic and metabonomic level. Humans are being characterized at the level of genetic pre-disposition and inter-individual variability in terms of (i) response to nutritional interventions and direction of health trajectories; (ii) epigenetic, metabolic programming at certain life stages with health consequences later in life and even for subsequent generations; and (iii) acute genomic expression as a holistic response to diet, monitored at gene transcript, protein and metabolite level. Modern nutrition science explores health-related aspects of bioactive food components, thereby promoting health, preventing, or delaying the onset of disease, optimizing performance and assessing benefits and risks in individuals and subpopulations. Personalized nutrition means adapting food to individual needs, depending on the human host’s life stage, -style, and -situation. Traditionally, nutrigenomics and nutri(epi)genetics are seen as the key sciences to understand human variability in preferences and requirements for diet as well as responses to nutrition. This article puts the three nutrition and health-relevant genomes into perspective, namely the food, the gut microbial and the human host’s genome, and calls for an “extended nutrigenomics” approach in order to build the future tools for personalized nutrition, health maintenance, and disease prevention. We discuss examples of these genomes, proteomes, transcriptomes, and metabolomes under the definition of genomics as the overarching term covering essentially all Omics rather than the sole study of DNA and RNA.
PMCID: PMC3268576  PMID: 22303317
nutrigenomics; nutrigenetics; epigenetics; personalized nutrition; biomarker; bioactive; gut microbiota
12.  The role of nutrition in children's neurocognitive development, from pregnancy through childhood 
This review examines the current evidence for a possible connection between nutritional intake (including micronutrients and whole diet) and neurocognitive development in childhood. Earlier studies which have investigated the association between nutrition and cognitive development have focused on individual micronutrients, including omega-3 fatty acids, vitamin B12, folic acid, choline, iron, iodine, and zinc, and single aspects of diet. The research evidence from observational studies suggests that micronutrients may play an important role in the cognitive development of children. However, the results of intervention trials utilizing single micronutrients are inconclusive. More generally, there is evidence that malnutrition can impair cognitive development, whilst breastfeeding appears to be beneficial for cognition. Eating breakfast is also beneficial for cognition. In contrast, there is currently inconclusive evidence regarding the association between obesity and cognition. Since individuals consume combinations of foods, more recently researchers have become interested in the cognitive impact of diet as a composite measure. Only a few studies to date have investigated the associations between dietary patterns and cognitive development. In future research, more well designed intervention trials are needed, with special consideration given to the interactive effects of nutrients.
PMCID: PMC3607807  PMID: 23532379
nutrition; cognitive development; children; micronutrients; diet quality
13.  Genome and low-iron response of an oceanic diatom adapted to chronic iron limitation 
Genome Biology  2012;13(7):R66.
Biogeochemical elemental cycling is driven by primary production of biomass via phototrophic phytoplankton growth, with 40% of marine productivity being assigned to diatoms. Phytoplankton growth is widely limited by the availability of iron, an essential component of the photosynthetic apparatus. The oceanic diatom Thalassiosira oceanica shows a remarkable tolerance to low-iron conditions and was chosen as a model for deciphering the cellular response upon shortage of this essential micronutrient.
The combined efforts in genomics, transcriptomics and proteomics reveal an unexpected metabolic flexibility in response to iron availability for T. oceanica CCMP1005. The complex response comprises cellular retrenchment as well as remodeling of bioenergetic pathways, where the abundance of iron-rich photosynthetic proteins is lowered, whereas iron-rich mitochondrial proteins are preserved. As a consequence of iron deprivation, the photosynthetic machinery undergoes a remodeling to adjust the light energy utilization with the overall decrease in photosynthetic electron transfer complexes.
Beneficial adaptations to low-iron environments include strategies to lower the cellular iron requirements and to enhance iron uptake. A novel contribution enhancing iron economy of phototrophic growth is observed with the iron-regulated substitution of three metal-containing fructose-bisphosphate aldolases involved in metabolic conversion of carbohydrates for enzymes that do not contain metals. Further, our data identify candidate components of a high-affinity iron-uptake system, with several of the involved genes and domains originating from duplication events. A high genomic plasticity, as seen from the fraction of genes acquired through horizontal gene transfer, provides the platform for these complex adaptations to a low-iron world.
PMCID: PMC3491386  PMID: 22835381
14.  Micronutrient Intakes among Women of Reproductive Age in Vietnam 
PLoS ONE  2014;9(2):e89504.
Micronutrient deficiencies are a public health concern worldwide negatively affecting maternal and child health outcomes. The primary underlying causes of micronutrient deficiencies are insufficient intake and poor bioavailability of micronutrients. However, reliable data on micronutrient intakes are sparse. The objectives of this study were to identify the key local food sources providing the majority of micronutrients and assess the adequacy and determinants of micronutrient intakes.
The study used data from a survey of 4,983 rural women of reproductive age (WRA) participating in a preconception micronutrient supplementation trial in Vietnam. Micronutrient intakes were assessed using a validated 107-item semi-quantitative food-frequency questionnaire. Multivariate linear and logistic regression analyses were used to examine the association between socioeconomic status and micronutrient intakes.
Starchy staples were the main source of iron and zinc (37% and 54%, respectively) with only a small proportion from meat (10% and 18%, respectively). The primary source of folate and vitamin A were vegetables; vitamin B12 came from meat and eggs. The proportion of the population with intakes below the estimated average requirement was 25% for iron, 16% for zinc, 54% for folate, 64% for vitamin B12 and 27% for vitamin A. Socioeconomic status was the main determinant of micronutrient intakes. WRA in the highest quintile consumed 26% more iron, 19% more zinc, 36% more folate, 82% more vitamin B12 and 47% more vitamin A compared to those in the lowest quintile. Women in the upper quintiles of SES were more likely to obtain nutrients from more nutritious and higher bioavailable foods than those in the lowest quintile.
Underprivileged women were at increased risk for insufficient micronutrient intakes due to poor diet quality. Targeted efforts to promote the consumption of local nutrient rich foods along with educational programs and social development are needed.
PMCID: PMC3931833  PMID: 24586831
15.  Micronutrients and pregnancy; effect of supplementation on pregnancy and pregnancy outcomes: a systematic review 
Nutrition Journal  2013;12:20.
Every year more than 20 million infants are born with low birth weight worldwide. About 3.6 million infants die during the neonatal period. More than one third of child deaths are thought to be attributable to maternal and child under nutrition.
To systematically review the effect of supplementing various combinations and types of micronutrients on the course and outcomes of pregnancy.
Electronic search of Medline, Pub Med, Health Internetwork access to Research Initiative, and Google Scholar databases was conducted. Outcomes of interest were birth weight, low birth weight, small size for gestational age, prenatal mortality and neonatal mortality. After exclusion of irrelevant /incomplete ones, 17 out of 115 articles were considered for the final analysis.
Majority of the articles reviewed favored the supplementation of micronutrients to pregnant mother. Some studies suggested calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia. The remaining articles reviewed, showed significant benefit of Multiple Micronutrients supplementation during pregnancy in reducing low birth weight, small for Gestational Age births as compared to the usual iron-folate supplements.
Supplying micronutrients, mainly multiple micronutrients have beneficial effect in reducing the risk of low birth weight and other complications. Further studies at various combination and doses of micronutrient supplements are recommended.
PMCID: PMC3585818  PMID: 23368953
16.  Biofortification of wheat grain with iron and zinc: integrating novel genomic resources and knowledge from model crops 
Wheat, like many other staple cereals, contains low levels of the essential micronutrients iron and zinc. Up to two billion people worldwide suffer from iron and zinc deficiencies, particularly in regions with predominantly cereal-based diets. Although wheat flour is commonly fortified during processing, an attractive and more sustainable solution is biofortification, which requires developing new varieties of wheat with inherently higher iron and zinc content in their grains. Until now most studies aimed at increasing iron and zinc content in wheat grains have focused on discovering natural variation in progenitor or related species. However, recent developments in genomics and transformation have led to a step change in targeted research on wheat at a molecular level. We discuss promising approaches to improve iron and zinc content in wheat using knowledge gained in model grasses. We explore how the latest resources developed in wheat, including sequenced genomes and mutant populations, can be exploited for biofortification. We also highlight the key research and practical challenges that remain in improving iron and zinc content in wheat.
PMCID: PMC3930855  PMID: 24600464
nutritional enhancement; cereals; transgenic; genomics; model to crop
17.  Effects of micronutrients on metal toxicity. 
Environmental Health Perspectives  1998;106(Suppl 1):203-216.
There is growing evidence that micronutrient intake has a significant effect on the toxicity and carcinogenesis caused by various chemicals. This paper examines the effect of micronutrient status on the toxicity of four nonessential metals: cadmium, lead, mercury, and arsenic. Unfortunately, few studies have directly examined the effect of dietary deficiency or supplementation on metal toxicity. More commonly, the effect of dietary alteration must be deduced from the results of mechanistic studies. We have chosen to separate the effect of micronutrients on toxic metals into three classes: interaction between essential micronutrients and toxic metals during uptake, binding, and excretion; influence of micronutrients on the metabolism of toxic metals; and effect of micronutrients on secondary toxic effects of metals. Based on data from mechanistic studies, the ability of micronutrients to modulate the toxicity of metals is indisputable. Micronutrients interact with toxic metals at several points in the body: absorption and excretion of toxic metals; transport of metals in the body; binding to target proteins; metabolism and sequestration of toxic metals; and finally, in secondary mechanisms of toxicity such as oxidative stress. Therefore, people eating a diet deficient in micronutrients will be predisposed to toxicity from nonessential metals.
PMCID: PMC1533267  PMID: 9539014
18.  A factorial randomized controlled trial to evaluate the effect of micronutrients supplementation and regular aerobic exercise on maternal endothelium-dependent vasodilatation and oxidative stress of the newborn 
Trials  2011;12:60.
Many studies have suggested a relationship between metabolic abnormalities and impaired fetal growth with the development of non-transmissible chronic diseases in the adulthood. Moreover, it has been proposed that maternal factors such as endothelial function and oxidative stress are key mechanisms of both fetal metabolic alterations and subsequent development of non-transmissible chronic diseases. The objective of this project is to evaluate the effect of micronutrient supplementation and regular aerobic exercise on endothelium-dependent vasodilation maternal and stress oxidative of the newborn.
Methods and design
320 pregnant women attending to usual prenatal care in Cali, Colombia will be included in a factorial randomized controlled trial. Women will be assigned to the following intervention groups: 1. Control group: usual prenatal care (PC) and placebo (maltodextrine). 2. Exercise group: PC, placebo and aerobic physical exercise. 3. Micronutrients group: PC and a micronutrients capsule consisting of zinc (30 mg), selenium (70 μg), vitamin A (400 μg), alphatocopherol (30 mg), vitamin C (200 mg), and niacin (100 mg). 4. Combined interventions Group: PC, supplementation of micronutrients, and aerobic physical exercise. Anthropometric measures will be taken at the start and at the end of the interventions.
Since in previous studies has been showed that the maternal endothelial function and oxidative stress are related to oxidative stress of the newborn, this study proposes that complementation with micronutrients during pregnancy and/or regular physical exercise can be an early and innovative alternative to strengthen the prevention of chronic diseases in the population.
Trial registration
PMCID: PMC3059275  PMID: 21356082
19.  Pomegranate Extracts in the Management of Men's Urologic Health: Scientific Rationale and Preclinical and Clinical Data 
Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical in vitro and in vivo studies. Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in the management of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.
PMCID: PMC3622365  PMID: 23589721
20.  Lipophilic Micronutrients and Adipose Tissue Biology 
Nutrients  2012;4(11):1622-1649.
Lipophilic micronutrients (LM) constitute a large family of molecules including several vitamins (A, D, E, K) and carotenoids. Their ability to regulate gene expression is becoming increasingly clear and constitutes an important part of nutrigenomics. Interestingly, adipose tissue is not only a main storage site for these molecules within the body, but it is also subjected to the regulatory effects of LM. Indeed, several gene regulations have been described in adipose tissue that could strongly impact its biology with respect to the modulation of adipogenesis, inflammatory status, or energy homeostasis and metabolism, among others. The repercussions in terms of health effects of such regulations in the context of obesity and associated pathologies represent an exciting and emerging field of research. The present review will focus on the regulatory effects of vitamin A, D, E and K as well as carotenoids on adipose tissue biology and physiology, notably in the context of obesity and associated disorders.
PMCID: PMC3509510  PMID: 23201837
adipose tissue; adipocytes; vitamins; micronutrients; obesity; insulin resistance; inflammation; metabolism; adipogenesis
21.  Effects of micronutrient fortified milk and cereal food for infants and children: a systematic review 
BMC Public Health  2012;12:506.
Micronutrient deficiency is a common public health problem in developing countries, especially for infants and children in the first two years of life. As this is an important time window for child development, micronutrient fortified complementary feeding after 6 months of age, for example with milk or cereals products, in combination with continued breastfeeding, is recommended. The overall effect of this approach is unclear.
We performed a Systematic Review and Meta-analysis to assess the impact of micronutrient fortified milk and cereal food on the health of infants and little children (aged 6 months to 5 years) compared to non-fortified food. We reviewed randomized controlled trials using electronic databases (MEDLINE and Cochrane library searches through FEB 2011), reference list screening and hand searches. Three reviewers assessed 1153 studies for eligibility and extracted data. One reviewer assessed risk of bias using predefined forms.
We included 18 trials in our analysis (n = 5’468 children; range of mean hemoglobin values: 9.0 to 12.6 g/dl). Iron plus multi micronutrient fortification is more effective than single iron fortification for hematologic outcomes. Compared to non-fortified food, iron multi micronutrient fortification increases hemoglobin levels by 0.87 g/dl (95%-CI: 0.57 to 1.16; 8 studies) and reduces risk of anemia by 57% (relative risk 0.43; 95%-CI 0.26 to 0.71; absolute risk reduction 22%; number needed to treat 5 [95%-CI: 4 to 6]; 6 Studies). Compared to non-fortified food, fortification increases serum levels of vitamin A but not of zinc. Information about functional health outcomes (e.g. weight gain) and morbidity was scarce and evidence is inconclusive. Risk of bias is unclear due to underreporting, but high quality studies lead to similar results in a sensitivity analysis.
Multi micronutrient fortified milk and cereal products can be an effective option to reduce anemia of children up to three years of age in developing countries. On the basis of our data the evidence for functional health outcomes is still inconclusive.
PMCID: PMC3444335  PMID: 22770558
Micronutrients; Fortification; Milk; Cereals
22.  Effectiveness of Micronutrient Powders (MNP) in women and children 
BMC Public Health  2013;13(Suppl 3):S22.
More than 3.5 million women and children under five die each year in poor countries due to underlying undernutrition. Many of these are associated with concomitant micronutrient deficiencies. In the last decade point of use or home fortification has emerged to tackle the widespread micronutrient deficiencies. We in this review have estimated the effect of Micronutrient Powders (MNPs) on the health outcomes of women and children.
We systematically reviewed literature published up to November 2012 to identify studies describing the effectiveness of MNPs. We used a standardized abstraction and grading format to estimate the effect of MNPs by applying the standard Child Health Epidemiology Reference Group (CHERG) rules.
We included 17 studies in this review. MNPs significantly reduced the prevalence of anemia by 34% (RR: 0.66, 95% CI: 0.57-0.77), iron deficiency anemia by 57% (RR: 0.43, 95% CI: 0.35-0.52) and retinol deficiency by 21% (RR: 0.79, 95% CI: 0.64, 0.98). It also significantly improved the hemoglobin levels (SMD: 0.98, 95% CI: 0.55-1.40). While there were no statistically significant impacts observed for serum ferritin and zinc deficiency. Our analysis shows no impact of MNPs on various anthropometric outcomes including stunting (RR: 0.92, 95% CI: 0.81, 1.04), wasting (RR: 1.13, 95% CI: 0.91, 1.40), underweight (RR:0.96, 95% CI: 0.83, 1.10), HAZ (SMD: 0.04, 95% CI: -0.13, 0.22), WAZ (SMD: 0.05, 95% CI: -0.12, 0.23) and WHZ (SMD: 0.04, 95% CI: -0.13, 0.21), although showing favorable trends. MNPs were found to be associated with significant increase in diarrhea (RR: 1.04, 95% CI: 1.01, 1.06) with non-significant impacts on fever and URI.
Our analysis of the effect of MNPs in children suggests benefit in improving anemia and hemoglobin however the lack of impact on growth and evidence of increased diarrhea requires careful consideration before recommending the intervention for implementing at scale.
PMCID: PMC3847468  PMID: 24564207
23.  Micronutrient levels and nutritional status of school children living in Northwest Ethiopia 
Nutrition Journal  2012;11:108.
Several micronutrients are essential for adequate growth of children. However, little information is available on multiple micronutrient status of school children in Ethiopia. The present study was designed to evaluate the relationship between multiple micronutrient levels and nutritional status among school children.
In this cross-sectional study, anthropometric data, blood and stool samples were collected from 100 children at Meseret Elementary School in Gondar town, Northwest Ethiopia. Serum concentration of magnesium, calcium, iron, copper, zinc, selenium and molybdenum were measured by inductively coupled plasma mass spectrometer. Anthropometric indices of weight-for-age, height-for-age and BMI-for-age were used to estimate the children's nutritional status. Stool samples were examined by standard microscopic methods for intestinal parasites.
The prevalence of stunting, underweight, wasting and intestinal parasitoses among school children was 23%, 21%, 11% and18%, respectively. The mean serum levels of magnesium, calcium, iron, copper, zinc, selenium and molybdenum were 2.42±0.32 (mg/dl), 15.31±2.14 (mg/dl), 328.19±148.91 (μg/dl), 191.30±50.17 (μg/dl), 86.40±42.40 (μg/dl), 6.32±2.59 (μg/dl), and 0.23±0.15 (μg/dl), respectively. Selenium deficiency, zinc deficiency and magnesium deficiency occurred in 62%, 47%, and 2% of the school children, respectively. Height-for-age showed significant positive correlation with the levels of copper and molybdenum (p = 0.01) and with the levels of magnesium (p = 0.05).
Deficiencies of selenium and zinc were high among the school children although the deficiencies were not significantly related with their nutritional status. The prevalence of both malnutrition and intestinal parasitism was not negligible. These calls for the need to undertake multicentre studies in various parts of the country to substantiate the data obtained in the present study so that appropriate and beneficial strategies for micronutrient supplementation and interventions on nutritional deficiencies can be planned.
PMCID: PMC3574837  PMID: 23237638
School children; Nutritional status; Micronutrients; Gondar; Ethiopia
24.  Effect on longitudinal growth and anemia of zinc or multiple micronutrients added to vitamin A: a randomized controlled trial in children aged 6-24 months 
BMC Public Health  2010;10:145.
The benefits of zinc or multiple micronutrient supplementations in African children are uncertain. African children may differ from other populations of children in developing countries because of differences in the prevalence of zinc deficiency, low birth weight and preterm delivery, recurrent or chronic infections such as HIV, or the quality of complementary diets and genetic polymorphisms affecting iron metabolism.
The aim of this study was to ascertain whether adding zinc or multiple micronutrients to vitamin A supplementation improves longitudinal growth or reduces prevalence of anemia in children aged 6-24 months.
Randomized, controlled double-blinded trial of prophylactic micronutrient supplementation to children aged 6-24 months. Children in three cohorts - 32 HIV-infected children, 154 HIV-uninfected children born to HIV-infected mothers, and 187 uninfected children born to HIV-uninfected mothers - were separately randomly assigned to receive daily vitamin A (VA) [n = 124], vitamin A plus zinc (VAZ) [n = 123], or multiple micronutrients that included vitamin A and zinc (MM) [n = 126].
Among all children there were no significant differences between intervention arms in length-for-age Z scores (LAZ) changes over 18 months. Among stunted children (LAZ below -2) [n = 62], those receiving MM had a 0.7 Z-score improvement in LAZ versus declines of 0.3 in VAZ and 0.2 in VA (P = 0.029 when comparing effects of treatment over time). In the 154 HIV-uninfected children, MM ameliorated the effect of repeated diarrhea on growth. Among those experiencing more than six episodes, those receiving MM had no decline in LAZ compared to 0.5 and 0.6 Z-score declines in children receiving VAZ and VA respectively (P = 0.06 for treatment by time interaction). After 12 months, there was 24% reduction in proportion of children with anemia (hemoglobin below 11 g/dL) in MM arm (P = 0.001), 11% in VAZ (P = 0.131) and 18% in VA (P = 0.019). Although the within arm changes were significant; the between-group differences were not significant.
Daily multiple micronutrient supplementation combined with vitamin A was beneficial in improving growth among children with stunting, compared to vitamin A alone or to vitamin A plus zinc. Effects on anemia require further study.
Trial registration
This study is registered with, number .NCT00156832.
PMCID: PMC2847544  PMID: 20298571
25.  Prevention of Mutation, Cancer, and Other Age-Associated Diseases by Optimizing Micronutrient Intake 
Journal of Nucleic Acids  2010;2010:725071.
I review three of our research efforts which suggest that optimizing micronutrient intake will in turn optimize metabolism, resulting in decreased DNA damage and less cancer as well as other degenerative diseases of aging. (1) Research on delay of the mitochondrial decay of aging, including release of mutagenic oxidants, by supplementing rats with lipoic acid and acetyl carnitine. (2) The triage theory, which posits that modest micronutrient deficiencies (common in much of the population) accelerate molecular aging, including DNA damage, mitochondrial decay, and supportive evidence for the theory, including an in-depth analysis of vitamin K that suggests the importance of achieving optimal micronutrient intake for longevity. (3) The finding that decreased enzyme binding constants (increased Km) for coenzymes (or substrates) can result from protein deformation and loss of function due to an age-related decline in membrane fluidity, or to polymorphisms or mutation. The loss of enzyme function can be compensated by a high dietary intake of any of the B vitamins, which increases the level of the vitamin-derived coenzyme. This dietary remediation illustrates the importance of understanding the effects of age and polymorphisms on optimal micronutrient requirements. Optimizing micronutrient intake could have a major effect on the prevention of cancer and other degenerative diseases of aging.
PMCID: PMC2945683  PMID: 20936173

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