Cod Liver Oil, but Not Retinoic Acid, Treatment Restores Bone Thickness in a Vitamin A-Deficient Rat.

Vitamin A plays a prominent role for maintaining optimal bone status, but its impact upon the bone in response to vitamin A deficiency is not well defined. The purpose of this study was to evaluate how replenishing vitamin A by either whole food cod liver oil (COD) or the active metabolite of vitamin A, retinoic acid (RA), altered bone thickness of vitamin A-deficient (VAD) rats. Weanling rats were administered a control diet (CTRL) or VAD diet for 9 weeks. This was followed by four weeks of treatment in which the VAD group was divided into the following 4 subgroups: (1) VAD (9 weeks)-VAD (4 weeks); (2) VAD-CTRL; (3) VAD-COD; and (4) VAD-RA. Compared to controls, VAD rats had thicker bones which showed marked dysplasia. VAD-rats treated with COD produced a thinner bone that was not significantly different from that of untreated rats. In contrast, RA did not significantly change the thicker bone, and also had significantly greater periosteal and endosteal osteoblast numbers compared to VAD-COD. Active osteoclasts were not detected in VAD rats, nor during the treatment period. These findings suggest that the abnormal bone thickness in VAD rats appears to be more effectively restored to bone thickness of untreated control rats when treated with COD.

Vitamin A supplementation ameliorates motor incoordination via modulating RORα in the cerebellum in a valproic acid-treated rat autism model with vitamin A deficiency.

Motor dysfunctions are common comorbidities among autism spectrum disorder (ASD) patients. Abnormal cerebellar development throughout critical periods may have an effect on motor functions and result in motor impairments. Vitamin A (VA) plays a crucial role in the developing process of the nervous system. The correlation of VA deficiency (VAD) and ASD with motor dysfunctions, however, is not clear. Therefore, we built rat models with different VA levels based on the valproic acid (VPA)-treated autism model. ASD rats with VAD showed aggravated motor coordination abnormalities, Purkinje cell loss and impaired dendritic arborization of Purkinje cells compared to ASD rats with normal VA levels (VA normal, VAN). Additionally, the expression levels of retinoid-related orphan receptor α (RORα) and retinoic acid receptor α (RARα) were lower in the cerebellum of ASD rats with VAD than in those of ASD rats with VAN. VA supplementation (VAS) effectively improved motor coordination and cerebellar Purkinje cell abnormalities in ASD rats with VAD. Furthermore, the results of chromatin immunoprecipitation (ChIP) assays confirmed that the enrichment of RARα was detected on the RORα promoter in the cerebellum and that VAS could upregulate the binding capacity of RARα for RORα promoters. These results showed that VAD in autism might result in cerebellar impairments and be a factor aggravating a subtype of ASD with motor comorbidities. The therapeutic effect of VAS on motor deficits and Purkinje neuron impairments in autism might be due to the regulation of RORα by RARα.

Adequate vitamin A liver stores estimated by the modified relative dose response test are positively associated with breastfeeding but not vitamin A supplementation in Senegalese urban children 9-23 months old: A comparative cross-sectional study.

Vitamin A supplementation (VAS) in 6-59-month-old children is recommended but its sustainability is currently questioned. In Senegal, available data suggest that VAS should be maintained, but geographic and age-related specificities need to be addressed to better implement and target VAS programming. The objective of this comparative cross-sectional study, conducted in urban settings of Dakar, was to compare the vitamin A liver stores (VALS) assessed using the modified-relative dose response (MRDR) test between supplemented and non-supplemented 9-23 month-old children and to study their relationship with VAS. The supplemented group (n = 119) received VAS (either 100 000 UI or 200 000 UI) 2 to 6 months before evaluation while the non-supplemented group (n = 110) had not received VAS during the past 6 months. In addition to MRDR, serum retinol concentrations (SR), and biomarkers of subclinical inflammation were measured. Children's health-related data and feeding patterns were collected. Mean MRDR values (VAS: 0.030 ± 0.017, non-VAS: 0.028 ± 0.016, P = 0.389) and inflammation-adjusted SR (VAS: 1.34 ± 0.37, non-VAS: 1.3 ± 0.35, P = 0.515) of children were adequate. Low prevalence of VALS (VAS: 5.2%, non-VAS: 5.4%) and inflammation-adjusted VAD (VAS: 2.6%, non-VAS: 0.9%) were detected despite high presence of infections and inflammation. Children were mostly still being breastfed (VAS: 85.7%, non-VAS: 77.3%) and complementary feeding indicators were similar in both groups. Only breastfeeding was associated with VALS and was found to reduce by 76% at least, the odds of VAD (adjusted OR = 0.24, 95% CI: 0.07-0.8, P = 0.020). Based on MRDR values, VAS was not related to improved VALS and SR as well as VAD reduction among these children with adequate VALS. Reinforcing breastfeeding advocacy and morbidity prevention/control are essential in this setting. Scaling-back VAS in this subpopulation should be examined regarding the risk of hypervitaminosis A after an evaluation of dietary vitamin A intake sufficiency and a more quantitative assessment of VALS.

Consequences of Vitamin A Deficiency: Immunoglobulin Dysregulation, Squamous Cell Metaplasia, Infectious Disease, and Death.

Vitamin A is an important regulator of immune protection, but it is often overlooked in studies of infectious disease. Vitamin A binds an array of nuclear receptors (e.g., retinoic acid receptor, peroxisome proliferator-activated receptor, retinoid X receptor) and influences the barrier and immune cells responsible for pathogen control. Children and adults in developed and developing countries are often vitamin A-deficient or insufficient, characteristics associated with poor health outcomes. To gain a better understanding of the protective mechanisms influenced by vitamin A, we examined immune factors and epithelial barriers in vitamin A deficient (VAD) mice, vitamin D deficient (VDD) mice, double deficient (VAD+VDD) mice, and mice on a vitamin-replete diet (controls). Some mice received insults, including intraperitoneal injections with complete and incomplete Freund's adjuvant (emulsified with PBS alone or with DNA + Fus-1 peptide) or intranasal inoculations with Sendai virus (SeV). Both before and after insults, the VAD and VAD+VDD mice exhibited abnormal serum immunoglobulin isotypes (e.g., elevated IgG2b levels, particularly in males) and cytokine/chemokine patterns (e.g., elevated eotaxin). Even without insult, when the VAD and VAD+VDD mice reached 3-6 months of age, they frequently exhibited opportunistic ascending bacterial urinary tract infections. There were high frequencies of nephropathy (squamous cell hyperplasia of the renal urothelium, renal scarring, and ascending pyelonephritis) and death in the VAD and VAD+VDD mice. When younger VAD mice were infected with SeV, the predominant lesion was squamous cell metaplasia of respiratory epithelium in lungs and bronchioles. Results highlight a critical role for vitamin A in the maintenance of healthy immune responses, epithelial cell integrity, and pathogen control.

Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism.

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.

Maternal-Fetal Transfer of Vitamin A and Its Impact on Mammalian Embryonic Development.

The placenta, a hallmark of mammalian embryogenesis, allows nutrients to be exchanged between the mother and the fetus. Vitamin A (VA), an essential nutrient, cannot be synthesized by the embryo, and must be acquired from the maternal circulation through the placenta. Our understanding of how this transfer is accomplished is still in its infancy. In this chapter, we recapitulate the early studies about the relationship between maternal dietary/supplemental VA intake and fetal VA levels. We then describe how the discovery of retinol-binding protein (RBP or RBP4), the development of labeling and detection techniques, and the advent of knockout mice shifted this field from a macroscopic to a molecular level. The most recent data indicate that VA and its derivatives (retinoids) and the pro-VA carotenoid, ß-carotene, are transferred across the placenta by distinct proteins, some of which overlap with proteins involved in lipoprotein uptake. The VA status and dietary intake of the mother influence the expression of these proteins, creating feedback signals that control the uptake of retinoids and that may also regulate the uptake of lipids, raising the intriguing possibility of crosstalk between micronutrient and macronutrient metabolism. Many questions remain about the temporal and spatial patterns by which these proteins are expressed and transferred throughout gestation. The answers to these questions are highly relevant to human health, considering that those with either limited or excessive intake of retinoids/carotenoids during pregnancy may be at risk of obtaining improper amounts of VA that ultimately impact the development and health of their offspring.

Bioactive Properties of Carotenoids in Human Health.

Research shows that certain bioactive compounds in our diet have beneficial effects on humanhealth[...].

Serum retinyl esters are positively correlated with analyzed total liver vitamin A reserves collected from US adults at time of death.

Background: Minimal human data exist on liver vitamin A (VA) compared with serum biomarkers. Cutoffs of 5% and 10% total serum VA as retinyl esters (REs) suggest a VA intoxication diagnosis. Objectives: We compared total liver VA reserves (TLRs) with the percentage of total serum VA as REs to evaluate hypervitaminosis with the use of US adult autopsy samples. Secondary objectives evaluated serum retinol sensitivity, TLRs among lobes, and hepatic α-retinol concentrations, an α-carotene cleavage product. Design: Matched serum and liver samples were procured from cadavers (n = 27; mean ± SD age: 70.7 ± 14.9 y; range: 49-101 y). TLRs and α-REs were quantified by ultra-performance liquid chromatography. Pearson correlations showed liver and serum associations. Sensitivity and specificity were calculated for >5%, 7.5%, and 10% total serum VA as REs to predict TLRs and for serum retinol <0.7 and 1 µmol/L to predict deficiency. Results: Serum RE concentrations were correlated with TLRs (r = 0.497, P < 0.001). Nine subjects (33%) had hypervitaminosis A (≥1.0 µmol VA/g liver), 2 of whom had >7.5% total serum VA as REs; histologic indicators corroborated toxicity at 3 µmol/g liver. No subject had >10% total serum VA as REs. Serum retinol sensitivity to determine deficiency (TLRs <0.1 µmol VA/g) was 83% at 0.7 and 1 µmol/L. Hepatic α-retinol was positively correlated with age (P = 0.047), but removing an outlier nullified significance. Conclusions: This study evaluated serum REs as a biomarker of VA status against TLRs (gold standard), and abnormal histology suggested that 7.5% total serum VA as REs is diagnostic for toxicity at the individual level in adults. The long-term impact of VA supplements and fortificants on VA status is currently unknown. Considering the high prevalence of hypervitaminotic TLRs in this cohort, and given that many countries are adding preformed VA to processed products, population biomarkers diagnosing hypervitaminosis before toxicity are urgently needed. This trial was registered at clinicaltrials.govas NCT03305042.

ß-Cryptoxanthin and zeaxanthin are highly bioavailable from whole-grain and refined biofortified orange maize in humans with optimal vitamin A status: a randomized, crossover, placebo-controlled trial.

Background: Biofortification of staple crops with ß-carotene is a strategy to reduce vitamin A deficiency, and several varieties are available in some African countries. ß-Cryptoxanthin (BCX)-enhanced maize is currently in field trials. To our knowledge, maize BCX bioavailability has not been assessed in humans. Serum retinol 13C content and xanthophyll concentrations are proposed effectiveness biomarkers for biofortified maize adoption. Objective: We determined the relative difference in BCX and zeaxanthin bioavailability from whole-grain and refined BCX-biofortified maize during chronic feeding compared with white maize and evaluated short-term changes in 13C-abundance in serum retinol. Design: After a 7-d washout, 9 adults (mean ± SD age: 23.4 ± 2.3 y; 5 men) were provided with muffins made from BCX-enhanced whole-grain orange maize (WGOM), refined orange maize (ROM), or refined white maize (RWM) for 12 d in a randomized, blinded, crossover study followed by a 7-d washout. Blood was drawn on days 0, 3, 6, 9, 12, 15, and 19. Carotenoid areas under the curve (AUCs) were compared by using a fixed-effects model. 13C-Abundance in serum retinol was determined by using gas chromatography/combustion/isotope-ratio mass spectrometry on days 0, 12, and 19. Vitamin A status was determined by 13C-retinol isotope dilution postintervention. Results: The serum BCX AUC was significantly higher for WGOM (1.70 ± 0.63 µmol ⋅ L-1 ⋅ d) and ROM (1.66 ± 1.08 µmol ⋅ L-1 ⋅ d) than for RWM (-0.06 ± 0.13 µmol ⋅ L-1 ⋅ d; P < 0.003). A greater increase occurred in serum BCX from WGOM muffins (131%) than from ROM muffins (108%) (P ≤ 0.003). Zeaxanthin AUCs were higher for WGOM (0.94 ± 0.33) and ROM (0.96 ± 0.47) than for RWM (0.05 ± 0.12 µmol ⋅ L-1 ⋅ d; P < 0.003). The intervention did not affect predose serum retinol 13C-abundance. Vitamin A status was within an optimal range (defined as 0.1-0.7 µmol/g liver). Conclusions: BCX and zeaxanthin were highly bioavailable from BCX-biofortified maize. The adoption of BCX maize could positively affect consumers' BCX and zeaxanthin intakes and associated health benefits. This trial is registered at www.clinicaltrials.gov as NCT02800408.

Modulation of Intestinal Immune and Barrier Functions by Vitamin A: Implications for Current Understanding of Malnutrition and Enteric Infections in Children.

The micronutrient vitamin A refers to a group of compounds with pleiotropic effects on human health. These molecules can modulate biological functions, including development, vision, and regulation of the intestinal barrier. The consequences of vitamin A deficiency and supplementation in children from developing countries have been explored for several years. These children live in an environment that is highly contaminated by enteropathogens, which can, in turn, influence vitamin A status. Vitamin A has been described to modulate gene expression, differentiation and function of diverse immune cells; however, the underlying mechanisms are not fully elucidated. This review aims to summarize the most updated advances on elucidating the vitamin A effects targeting intestinal immune and barrier functions, which may help in further understanding the burdens of malnutrition and enteric infections in children. Specifically, by covering both clinical and in vivo/in vitro data, we describe the effects of vitamin A related to gut immune tolerance/homeostasis, intestinal barrier integrity, and responses to enteropathogens in the context of the environmental enteric dysfunction. Some of the gaps in the literature that require further research are also highlighted.

Retinol dehydrogenase 11 is essential for the maintenance of retinol homeostasis in liver and testis in mice.

Retinol dehydrogenase 11 (RDH11) is a microsomal short-chain dehydrogenase/reductase that recognizes all-trans- and cis-retinoids as substrates and prefers NADPH as a cofactor. Previous work has suggested that RDH11 contributes to the oxidation of 11-cis-retinol to 11-cis-retinaldehyde during the visual cycle in the eye's retinal pigment epithelium. However, the role of RDH11 in metabolism of all-trans-retinoids remains obscure. Here, we report that microsomes isolated from the testes and livers of Rdh11-/- mice fed a regular diet exhibited a 3- and 1.7-fold lower rate of all-trans-retinaldehyde conversion to all-trans-retinol, respectively, than the microsomes of WT littermates. Testes and livers of Rdh11-/- mice fed a vitamin A-deficient diet had ∼35% lower levels of all-trans-retinol than those of WT mice. Furthermore, the conversion of ß-carotene to retinol via retinaldehyde as an intermediate appeared to be impaired in the testes of Rdh11-/-/retinol-binding protein 4-/-(Rbp4-/-) mice, which lack circulating holo RBP4 and rely on dietary supplementation with ß-carotene for maintenance of their retinoid stores. Together, these results indicate that in mouse testis and liver, RDH11 functions as an all-trans-retinaldehyde reductase essential for the maintenance of physiological levels of all-trans-retinol under reduced vitamin A availability.

Single High-Dose Vitamin A Supplementation to Neonatal Piglets Results in a Transient Dose Response in Extrahepatic Organs and Sustained Increases in Liver Stores.

Background: Neonatal vitamin A (VA) supplementation is being evaluated as a public health policy for preventing infant mortality, but inconsistencies in mortality trials demand mechanistic work to determine biological plausibility.Objectives: We investigated the absorption, distribution, and storage of single large oral VA doses administered shortly after birth.Methods: Fifty pregnant sows (Sus scrofas domesticas) were fed a VA-free diet. Male and female newborn piglets (n = 313) were orally administered 0, 25,000, 50,000, or 200,000 IU VA in oil within 12 h of birth when mean ± SD weight was 1.56 ± 0.25 kg. Blood was drawn to determine absorption and storage 0.5-240 h after administration. Metabolic and postnatal dose-timing substudies were performed. Liver, lung, kidney, spleen, and adrenal VA concentrations were determined 7-240 h after administration.Results: Serum retinol and retinyl ester concentrations responded to treatment (P < 0.0001); however, differences between groups disappeared by 96 h. Liver VA concentrations responded to treatment (P < 0.0001), which persisted for 240 h. Liver VA for control piglets at 10 d (mean ± SD: 0.05 ± 0.02 µmol/g) was ≤0.1 µmol/g (deficiency), whereas groups that received VA maintained concentrations >0.1 µmol/g. Extrahepatic tissue VA concentrations displayed treatment effects (P ≤ 0.0077); groups that received treatments had higher VA concentrations than controls at early time points. Lung, kidney, and spleen VA did not differ between groups by 96 h, whereas adrenal glands did not differ by 240 h. Body weight was affected by treatment (P = 0.0002); VA-deficient piglets weighed 23-29% more than all treated groups 240 h after administration.Conclusions: A high dose of VA administered to newborn piglets was well absorbed, appeared in serum primarily as retinyl esters, and was taken up dose-dependently in all tissues studied; however, enhancement did not persist in sera, lungs, kidneys, spleens, or adrenal glands. Short-term impacts of retinoid signaling on weight gain remain to be elucidated, and longer follow-up studies are needed.

Vitamin A supplementation redirects the flow of retinyl esters from peripheral to central organs of neonatal rats raised under vitamin A-marginal conditions.

Background: Vitamin A (VA; retinol) supplementation is used to reduce child mortality in countries with high rates of malnutrition. Existing research suggests that neonates (<1 mo old) may have a limited capacity to store VA in organs other than the liver; however, knowledge about VA distribution and kinetics in individual, nonhepatic organs is limited.Objective: We examined retinol uptake and turnover in nonhepatic organs, including skin, brain, and adipose tissue, in neonatal rats without and after VA supplementation.Design: Sprague-Dawley neonatal rats (n = 104) were nursed by mothers fed a VA-marginal diet (0.35 mg retinol/kg diet) and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil (control), both containing 1.8 µCi of [3H]retinol. Subsequently, pups (n = 4 · group-1 · time-1) were killed at 13 different times from 30 min to 24 d after dosing. The fractional and absolute transfer of chylomicron retinyl esters (CM-REs), retinol bound to retinol-binding protein (RBP-ROH), and total retinol were estimated in WinSAAM software.Results: VA supplementation redirected the flow of CM-REs from peripheral to central organs and accumulated mainly in the liver. The RBP-ROH released from the liver was acquired mainly by the peripheral tissues but not retained efficiently, causing repeated recycling of retinol between plasma and tissues (541 compared with 5 times in the supplemented group and control group, respectively) and its rapid turnover in all organs, except the brain and white adipose tissue. Retinol stores in the liver lasted for ∼2 wk before being gradually transferred to other organs.Conclusions: VA supplementation administered in a single high dose during the first month after birth is readily acquired but not retained efficiently in peripheral tissues of neonatal rats, suggesting that a more frequent, lower-dose supplementation may be necessary to maintain steady VA concentrations in rapidly developing neonatal tissues.

Marginal vitamin A deficiency facilitates Alzheimer's pathogenesis.

Deposition of amyloid ß protein (Aß) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer's disease (AD). Aß is derived from amyloid ß precursor protein (APP) by ß- and γ-secretase cleavages and turned over by glia in the central nervous system (CNS). Vitamin A deficiency (VAD) has been shown to affect cognitive functions. Marginal vitamin A deficiency (MVAD) is a serious and widespread public health problem among pregnant women and children in developing countries. However, the role of MVAD in the pathogenesis of AD remains elusive. Our study showed that MVAD is approximately twofold more prevalent than VAD in the elderly, and increased cognitive decline is positively correlated with lower VA levels. We found that MVAD, mostly prenatal MVAD, promotes beta-site APP cleaving enzyme 1 (BACE1)-mediated Aß production and neuritic plaque formation, and significantly exacerbates memory deficits in AD model mice. Supplementing a therapeutic dose of VA rescued the MVAD-induced memory deficits. Taken together, our study demonstrates that MVAD facilitates AD pathogenesis and VA supplementation improves cognitive deficits. These results suggest that VA supplementation might be a potential approach for AD prevention and treatment.

Improvement of anthropometric and biochemical, but not of vitamin A, status in adolescents who undergo Roux-en-Y gastric bypass: a 1-year follow up study.

BACKGROUND: The aim of this study was to describe anthropometric, biochemical, co-morbidity, and vitamin A nutritional status in severely obese adolescents before and 30, 180, and 365 days after Roux-en-Y gastric bypass (RYGB). SETTING: Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. METHODS: Sixty-four adolescents (15-19 years old) with a body mass index≥40 kg/m2 were enrolled in a prospective follow-up study. Vitamin A status was evaluated before surgery (T0), and 30 (T30), 180 (T180), and 365 (T365) days after surgery, applying biochemical and functional indicators. Anthropometric measures, lipid profile, glycemia, and basal insulin also were assessed. No patients were lost during follow-up. RESULTS: Before surgery, 26.6% of the sample group experienced vitamin A deficiency (VAD). Serum retinol levels dropped significantly 30 days after surgery and then returned to basal levels. There was a significant increase in the prevalence of ß-carotene deficiency and night blindness throughout the postsurgery period. A significant reduction in blood glucose, insulin resistance, lipid profile, and anthropometric parameters was observed. CONCLUSION: The finding that oral daily supplementation with 5000 IU retinol acetate failed to reverse VAD and night blindness after RYGB is highly significant. We recommend assessment of VAD and night blindness in extremely obese adolescents before and after RYGB. We further recommend monitoring for an additional 180 days (for VAD) and 365 days (for night blindness) after surgery, with particular attention to daily supplementation needs.

Effect of routine prenatal supplementation on vitamin concentrations in maternal serum and breast milk.

OBJECTIVE: The aim of the present study was to assess the effect of multivitamin supplements and their different vitamin A sources on retinol concentrations in serum and colostrum milk of postpartum women. METHODS: This was a retrospective cross-sectional study composed of healthy postpartum women attending two Brazilian private maternity wards (N = 100). According to the type of multivitamin taken during pregnancy, the women were assigned to one of four groups: control group (CG; n = 25), formulation 1 (F1; n = 25), formulation 2 (F2; n = 25), and formulation 3 (F3; n = 25). Blood and colostrum samples were collected under fasting conditions and retinol was analyzed by high-performance liquid chromatography. Dietary vitamin A was assessed using a food frequency questionnaire. Retinol concentrations <20 µg/dL (<0.70 µmol/L) in serum and <60 µg/dL (2.10 µmol/L) in colostrum were considered indicative of vitamin A deficiency. RESULTS: Of women in the control group, 12% (n = 3) presented serum retinol levels below the cut-off value for adequacy; this was not observed in the supplemented groups. Evaluating the retinol content in breast milk, supplemented groups F1 and F3 presented 4% (n = 1) of inadequacy cases, whereas F2 presented 40% (n = 10). The concentrations found in the F2 and F3 groups were statistically different (P < 0.05). CONCLUSIONS: The use of multivitamin supplements containing vitamin A during pregnancy prevents vitamin A deficiency regardless of the source administered. In breast milk, supplementation with ß-carotene provided a lower concentration of vitamin A compared with retinol.

Rescue of Hypovitaminosis A Induces Non-Amyloidogenic Amyloid Precursor Protein (APP) Processing.

Retinoic acid, the bioactive metabolite of beta-carotene or vitamin A, plays a pleiotropic, multifunctional role in vertebrate development. Studies in rodents revealed that a diet deficient in vitamin A results in a complex neonatal syndrome (the VAD syndrome), manifested in many organs. In humans, the function of retinoic acid (RA) extends into adulthood, where it has important roles in fertility, vision, and suppression of neoplastic growth. In recent years, it has also been suggested that retinoic acid might potentially act as a therapeutically relevant drug in attenuating or even preventing neurodegenerative diseases such as Alzheimer's disease (AD). Here, we report that VAD leads to an increase in A-beta peptide levels while only minor effects were observed on expression levels of the amyloid precursor protein (APP) processing proteinases in wild type mice. In line with these findings, rescue of hypovitaminosis reduced A-beta amount to baseline and induced sApp-alpha secretion in combination with an increase of alpha-secretase Adam10. By comparing retinoic acid treatment starting from a full nutrition status and a "VAD" situation in human neuroblastoma cells, we show that while intensities of differential gene expression were higher in replenished cells, a large overlap in AD-related, regulated genes was observed. Our data suggest that hypovitaminosis A can contribute to onset or progression of AD by increasing synthesis of A-beta peptides and that several AD-related genes such as ADAM10 or BDNF are regulated by retinoic acid. We suggest that dietary supplementation with retinoic acid derivatives is likely to have a beneficial effect on AD-pathology in individuals with hypovitaminosis and patients with normal vitamin A status.

Maternal supplementation with a megadose of vitamin A reduces colostrum level of α-tocopherol: a randomised controlled trial.

BACKGROUND: Maternal supplementation with vitamin A is one of the strategies for controlling its deficiency in the mother-child dyad, although studies with animals showed that supplementation with high doses of vitamin A reduces the levels of α-tocopherol (vitamin E) in the mother's serum and milk. The objective of the present study was to assess the influence of maternal supplementation with vitamin A on the concentration of retinol and α-tocopherol in human milk. METHODS: Healthy puerperal women were randomly distributed into a control group (n = 44) and a supplemented group (n = 44). Blood and colostrum samples were collected after delivery, and mature milk samples were collected 30 days later. The supplemented group received 200 000 IU of retinyl palmitate after the first colostrum collection. The retinol and α-tocopherol levels in the samples were determined by high-performance liquid chromatography. RESULTS: The mean (SD) retinol and α-tocopherol levels in the maternal serum were considered adequate at 46.4 (15.9) and 1023.6 (380.4) µg dL(-1) , respectively. The colostrum retinol levels of the supplemented group increased significantly 24 h after the intervention (P < 0.001). However, the retinol levels in the mature milk of both groups did not differ (P > 0.05). Moreover, after maternal supplementation with vitamin A, the colostrum α-tocopherol level decreased by 16.4%, which is a significant reduction (P < 0.05). However, vitamin A supplementation did not affect the α-tocopherol level of mature milk (P > 0.05). CONCLUSIONS: Maternal supplementation with high doses of vitamin A increased the colostrum level of this nutrient but reduced the bioavailability of α-tocopherol, which may harm the newborn's health because newborns have limited vitamin E reserves.

Carotenoids and ß-carotene in orange fleshed sweet potato: A possible solution to vitamin A deficiency.

The present study, in line with a plant-food-based approach to address vitamin A deficiency, reports the analysis of total carotenoids, and trans- and cis-ß-carotenes, in different varieties of raw and boiled orange-fleshed sweet potatoes (OFSP). Carotenoids were isolated using acetone-petroleum ether extraction followed by spectrophotometric determination. trans- and cis-ß-Carotenes were analyzed by reversed-phase HPLC method using a mobile phase containing acetonitrile:methanol:2-propanol in the ratio of 85:15:33 with 0.01% ammonium acetate. Intra-varietal difference in carotenoids as well as trans- and cis-ß-carotenes were noted in both the raw and boiled potatoes. Carotenoid content was found to be higher in the raw potatoes compared to the boiled samples from the same variety. Amongst the OFSP varieties, Kamalasundari (BARI SP-2) was found to contain the most carotenoids in both the raw and boiled samples. ß-Carotene was significantly higher in the Kamalsundari and BARI SP-5 varieties. trans-ß-Carotene was found to be the major carotenoid in all of the raw potatoes, but boiling was associated with an increase in cis-ß-carotene and a decrease in the trans isomer. Kamalsundari and BARI SP-5 orange-fleshed sweet potatoes have the potential to be used as food-based supplements to reduce vitamin A deficiency.

The effects of vitamin A supplementation with measles vaccine on leucocyte counts and in vitro cytokine production.

As WHO recommends vitamin A supplementation (VAS) at vaccination contacts after age 6 months, many children receive VAS together with measles vaccine (MV). We aimed to investigate the immunological effect of VAS given with MV. Within a randomised placebo-controlled trial investigating the effect on overall mortality of providing VAS with vaccines in Guinea-Bissau, we conducted an immunological sub-study of VAS v. placebo with MV, analysing leucocyte counts, whole blood in vitro cytokine production, vitamin A status and concentration of C-reactive protein (CRP). VAS compared with placebo was associated with an increased frequency of CRP ≥ 5 mg/l (28 v. 12%; P=0·005). Six weeks after supplementation, VAS had significant sex-differential effects on leucocyte, lymphocyte, monocyte and basophil cell counts, decreasing them in males but increasing them in females. Mainly in females, the effect of VAS on cytokine responses differed by previous VAS: in previous VAS recipients, VAS increased the pro-inflammatory and T helper cell type 1 (Th1) cytokine responses, whereas VAS decreased these responses in previously unsupplemented children. In previous VAS recipients, VAS was associated with increased IFN-γ responses to phytohaemagglutinin in females (geometric mean ratio (GMR): 3·97; 95% CI 1·44, 10·90) but not in males (GMR 0·44; 95% CI 0·14, 1·42); the opposite was observed in previously unsupplemented children. Our results corroborate that VAS provided with MV has immunological effects, which may depend on sex and previous VAS. VAS may increase the number of leucocytes, but also repress both the innate and lymphocyte-derived cytokine responses in females, whereas this repression may be opposite if the females have previously received VAS.