Selective production of retinol by engineered Saccharomyces cerevisiae through the expression of retinol dehydrogenase.

Retinol is a fat-soluble vitamin A that is widely used in the food and pharmaceutical industries. Currently, retinol is commercially produced by chemical synthesis. Microbial production of retinol has been alternatively explored but restricted to a mixture of retinoids including retinol, retinal, and retinoic acid. Thus, we introduced heterologous retinol dehydrogenase into retinoids mixture-producing Saccharomyces cerevisiae for the selective production of retinol using xylose. Expression of human RDH10 and Escherichia coli ybbO led to increase in retinol production, but retinal remained as a major product. In contrast, S. cerevisiae harboring human RDH12 produced retinol selectively with negligible production of retinal. The resulting strain (SR8A-RDH12) produced retinol only. However, more glycerol was accumulated due to intracellular redox imbalance. Therefore, Lactococcus lactis noxE coding for H2 O-forming NADH oxidase was additionally introduced to resolve the redox imbalance. The resulting strain produced 52% less glycerol and more retinol with a 30% higher yield than a parental strain. As the produced retinol was not stable, we examined culture and storage conditions including temperature, light, and antioxidants for the optimal production of retinol. In conclusion, we achieved selective production of retinol efficiently from xylose by introducing human RDH12 and NADH oxidase into S. cerevisiae.

RNAseq studies reveal distinct transcriptional response to vitamin A deficiency in small intestine versus colon, uncovering novel vitamin A-regulated genes.

Vitamin A (VA) deficiency remains prevalent in resource limited areas. Using Citrobacter rodentium infection in mice as a model for diarrheal diseases, previous reports showed reduced pathogen clearance and survival due to vitamin A deficient (VAD) status. To characterize the impact of preexisting VA deficiency on gene expression patterns in the intestines, and to discover novel target genes in VA-related biological pathways, VA deficiency in mice were induced by diet. Total mRNAs were extracted from small intestine (SI) and colon, and sequenced. Differentially Expressed Gene (DEG), Gene Ontology (GO) enrichment, and co-expression network analyses were performed. DEGs compared between VAS and VAD groups detected 49 SI and 94 colon genes. By GO information, SI DEGs were significantly enriched in categories relevant to retinoid metabolic process, molecule binding, and immune function. Three co-expression modules showed significant correlation with VA status in SI; these modules contained four known retinoic acid targets. In addition, other SI genes of interest (e.g., Mbl2, Cxcl14, and Nr0b2) in these modules were suggested as new candidate genes regulated by VA. Furthermore, our analysis showed that markers of two cell types in SI, mast cells and Tuft cells, were significantly altered by VA status. In colon, "cell division" was the only enriched category and was negatively associated with VA. Thus, these data suggested that SI and colon have distinct networks under the regulation of dietary VA, and that preexisting VA deficiency could have a significant impact on the host response to a variety of disease conditions.

Disproportionate Vitamin A Deficiency in Women of Specific Ethnicities Linked to Differences in Allele Frequencies of Vitamin A-Related Polymorphisms.

Background: While the current national prevalence rate of vitamin A deficiency (VAD) is estimated to be less than 1%, it is suggested that it varies between different ethnic groups and races within the U.S. We assessed the prevalence of VAD in pregnant women of different ethnic groups and tested these prevalence rates for associations with the vitamin A-related single nucleotide polymorphism (SNP) allele frequencies in each ethnic group. Methods: We analyzed two independent datasets of serum retinol levels with self-reported ethnicities and the differences of allele frequencies of the SNPs associated with vitamin A metabolism between groups in publicly available datasets. Results: Non-Hispanic Black and Hispanic pregnant women showed high VAD prevalence in both datasets. Interestingly, the VAD prevalence for Hispanic pregnant women significantly differed between datasets (p = 1.973 × 10-10, 95%CI 0.04-0.22). Alleles known to confer the risk of low serum retinol (rs10882272 C and rs738409 G) showed higher frequencies in the race/ethnicity groups with more VAD. Moreover, minor allele frequencies of a set of 39 previously reported SNPs associated with vitamin A metabolism were significantly different between the populations of different ancestries than those of randomly selected SNPs (p = 0.030). Conclusions: Our analysis confirmed that VAD prevalence varies between different ethnic groups/races and may be causally associated with genetic variants conferring risk for low retinol levels. Assessing genetic variant information prior to performing an effective nutrient supplementation program will help us plan more effective food-based interventions.

Vitamin A-fortified rice increases total body vitamin A stores in lactating Thai women measured by retinol isotope dilution: a double-blind, randomized, controlled trial.

BACKGROUND: Lactating women are at increased risk for vitamin A (VA) deficiency due to demands for breast milk content and limited hepatic stores for women in some countries. Previously, consumption of triple-fortified rice, which included VA, iron, and zinc, successfully improved the VA status of Thai children in whom their total body VA stores (TBSs) were doubled in 2 mo. OBJECTIVE: This study assessed the efficacy of consuming VA-fortified rice, which delivered 500 µg retinol activity equivalents (RAEs)/d, on TBSs and estimated total liver VA reserves (TLRs) in Thai lactating women using the retinol isotope dilution (RID) test. METHODS: A randomized controlled trial was conducted with 70 lactating women (n = 35/group) who received either VA-fortified rice (500 µg RAEs/d) or unfortified rice for 14 wk on weekdays only. Serum retinol concentrations (SRs), C-reactive protein, and TBSs were assessed before and after the intervention. The paired 13C-RID test was used to measure TBSs. After a baseline blood sample, 2.0 µmol [14,15]-13C2-retinyl acetate was administered orally. A follow-up blood sample was drawn 14 d later. The RID test was repeated after the intervention. RESULTS: TBSs increased significantly (P < 0.05) in the intervention group from 240 (182, 316) to 331 (251, 447) [geometric means (95% CIs)] µmol retinol, and this change in TBSs was significantly higher (P < 0.05) than that in the control group [+52.9 (-74, 453) compared with -4.3 (-106, 275) µmol retinol]. Estimated TLRs indicated a high prevalence of VA deficiency among these lactating women. Initial and final SRs did not differ by group and did not change over the course of the intervention. CONCLUSION: VA-fortified rice improved the VA status of lactating women by increasing TBSs. A targeted approach to disseminate VA interventions among vulnerable groups should be considered in some contexts. This trial was registered at clinicaltrials.gov as NCT03056625.

Human Microfibrillar-Associated Protein 4 (MFAP4) Gene Promoter: A TATA-Less Promoter That Is Regulated by Retinol and Coenzyme Q10 in Human Fibroblast Cells.

Elastic fibers are one of the major structural components of the extracellular matrix (ECM) in human connective tissues. Among these fibers, microfibrillar-associated protein 4 (MFAP4) is one of the most important microfibril-associated glycoproteins. MFAP4 has been found to bind with elastin microfibrils and interact directly with fibrillin-1, and then aid in elastic fiber formation. However, the regulations of the human MFAP4 gene are not so clear. Therefore, in this study, we firstly aimed to analyze and identify the promoter region of the human MFAP4 gene. The results indicate that the human MFAP4 promoter is a TATA-less promoter with tissue- and species-specific properties. Moreover, the promoter can be up-regulated by retinol and coenzyme Q10 (coQ10) in Detroit 551 cells.

Protein Kinase C Alpha (PKCα) overexpression leads to a better response to retinoid acid therapy through Retinoic Acid Receptor Beta (RARß) activation in mammary cancer cells.

PURPOSE: Retinoids have proved to be effective for hematologic malignancies treatment but till nowadays, their use as single agent for the solid tumor's management is still controversial. All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, exerts non-genomic interactions with different members of the protein kinase C (PKC) family, recognized modulators of different tumor progression pathways. To determine whether a group of patients could become benefited employing a retinoid therapy, in this study we have evaluated whether PKCα expression (a poor prognosis marker in breast cancer) could sensitizes mammary cells to ATRA treatment. METHODS: PKCα overexpression was achieved by stable transfection and confirmed by western blot. Transfected PKC functionality was determined by nuclear translocation-induction and confocal microscopy. In vitro proliferation was evaluated by cell counting and cell cycle distribution was analyzed by flow cytometry. In vivo studies were performed to evaluate orthotopic tumor growth and experimental lung colonization. Retinoic acid response elements (RARE) and AP1 sites-dependent activity was studied by gene reporter assays and retinoic acid receptors (RARs) were measured by RT-qPCR. RESULTS: Our findings suggest that high PKCα levels improve the differentiation response to ATRA in a RAR signaling-dependent manner. Moreover, RARß expression appears to be critical to induce ATRA sensitization, throughout AP1 trans-repression. CONCLUSION: Here we propose that retinoids could lead a highly personalized anticancer treatment, bringing benefits to patients with aggressive breast tumors resulting from high PKCα expression but, an adequate expression of the RARß receptor is required to ensure the effect on this process.

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.

Increased Risk of High Body Fat and Altered Lipid Metabolism Associated to Suboptimal Consumption of Vitamin A Is Modulated by Genetic Variants rs5888 (SCARB1), rs1800629 (UCP1) and rs659366 (UCP2).

Obesity is characterized by an excessive body fat percentage (BF%). Animal and cell studies have shown benefits of vitamin A (VA) on BF% and lipid metabolism, but it is still controversial in humans. Furthermore, although some genetic variants may explain heterogeneity in VA plasma levels, their role in VA metabolic response is still scarcely characterized. This study was designed as a combination of an observational study involving 158 male subjects followed by a study with a well-balanced genotype-phenotype protocol, including in the design an ex vivo intervention study performed on isolated peripheral blood mononuclear cells (PBMCs) of the 41 former males. This is a strategy to accurately identify the delivery of Precision Nutrition recommendations to targeted subjects. The study assesses the influence of rs5888 (SCARB1), rs659366 (UCP2), and rs1800629 (UCP1) variants on higher BF% associated with suboptimal VA consumption and underlines the cellular mechanisms involved by analyzing basal and retinoic acid (RA) response on PBMC gene expression. Data show that male carriers with the major allele combinations and following suboptimal-VA diet show higher BF% (adjusted ANOVA test p-value = 0.006). Genotype-BF% interaction is observed on oxidative/inflammatory gene expression and also influences lipid related gene expression in response to RA. Data indicate that under suboptimal consumption of VA, carriers of VA responsive variants and with high-BF% show a gene expression profile consistent with an impaired basal metabolic state. The results show the relevance of consuming VA within the required amounts, its impact on metabolism and energy balance, and consequently, on men's adiposity with a clear influence of genetic variants SCARB1, UCP2 and UCP1.

Nuclear Receptors, Ligands and the Mammalian B Cell.

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.

Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport.

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6's vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6's vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.

Non-photopic and photopic visual cycles differentially regulate immediate, early, and late phases of cone photoreceptor-mediated vision.

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

Carotenoid biofortification in crop plants: citius, altius, fortius.

Carotenoids are indispensable for human health, required as precursors of vitamin A and efficient antioxidants. However, these plant pigments that play a vital role in photosynthesis are represented at insufficient levels in edible parts of several crops, which creates a need for increasing their content or optimizing their composition through biofortification. In particular, vitamin A deficiency, a severe health problem affecting the lives of millions in developing countries, has triggered the development of a series of high-provitamin A crops, including Golden Rice as the best-known example. Further carotenoid-biofortified crops have been generated by using genetic engineering approaches or through classical breeding. In this review, we depict carotenoid metabolism in plants and provide an update on the development of carotenoid-biofortified plants and their potential to meet needs and expectations. Furthermore, we discuss the possibility of using natural variation for carotenoid biofortification and the potential of gene editing tools. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

Role of Vitamins A and D in BCR-ABL Arf-/- Acute Lymphoblastic Leukemia.

The effects of vitamin A and/or vitamin D deficiency were studied in an Arf-/- BCR-ABL acute lymphoblastic leukemia murine model. Vitamin D sufficient mice died earlier (p = 0.003) compared to vitamin D deficient (VDD) mice. Vitamin A deficient (VAD) mice fared worst with more rapid disease progression and decreased survival. Mice deficient for vitamins A and D (VADD) had disease progression similar to VAD mice. Regulatory T cells, previously shown to associate with poor BCR-ABL leukemia control, were present at higher frequencies among CD4+ splenocytes of vitamin A deficient vs. sufficient mice. In vitro studies demonstrated 1,25-dihydroxyvitamin D (1,25(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1,25(OH)2VD3 induced CXCL12 expression in vivo and in vitro in stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D plus leukemia reprogrammed the marrow increasing production of collagens, potentially trapping ALL blasts. Vitamin A (all trans retinoic acid, ATRA) treated leukemic cells had increased apoptosis, decreased cells in S-phase, and increased cells in G0/G1. ATRA signaled through the retinoid X receptor to decrease BCR-ABL leukemic cell viability. In conclusion, vitamin A and D deficiencies have opposing effects on mouse survival from BCR-ABL ALL.

Molecular characterization and safety assessment of biofortified provitamin A rice.

Part of the studies involved in safety assessment of genetically engineered crops includes characterizing the organization, integrity, and stability of the inserted DNA and evaluating the potential allergenicity and toxicity of newly-expressed proteins. Molecular characterization of the introduced DNA in provitamin A biofortified rice event GR2E confirmed insertion of a single copy of the transfer-DNA in the genome and its inheritance as a single locus. Nucleotide sequencing of the inserted DNA confirmed it was introduced without modifications. The phytoene synthase, and carotene desaturase proteins did not display sequence similarity with allergens or toxins. Both proteins were rapidly digested in simulated gastric fluid and their enzymatic activity was inhibited upon heat treatment. Acute oral toxicity testing of the protein in mice demonstrated lack of adverse effects. These evidences substantiated the lack of any identifiable hazards for both proteins and in combination with other existing comparative analyses provided assurance that food derived from this rice is safe. This conclusion is in line with those of the regulatory agencies of US Food and Drug Administration, Health Canada and Food Standard Australia and New Zealand.

The mitochondrial PKCδ/retinol signal complex exerts real-time control on energy homeostasis.

The review focuses on the role of vitamin A (retinol) in the control of energy homeostasis, and on the manner in which certain retinoids subvert this process, leading potentially to disease. In eukaryotic cells, the pyruvate dehydrogenase complex (PDHC) is negatively regulated by four pyruvate dehydrogenase kinases (PDKs) and two antagonistically acting pyruvate dehydrogenase phosphatases (PDPs). The second isoform, PDK2, is regulated by an autonomous mitochondrial signal cascade that is anchored on protein kinase Cδ (PKCδ), where retinoids play an indispensible co-factor role. Along with its companion proteins p66Shc, cytochrome c, and vitamin A, the PKCδ/retinol complex is located in the intermembrane space of mitochondria. At this site, and in contrast to cytosolic locations, PKCδ is activated by the site-specific oxidation of its cysteine-rich activation domain (CRD) that is configured into a complex RING-finger. Oxidation involves the transfer of electrons from cysteine moieties to oxidized cytochrome c, a step catalyzed by vitamin A. The PKCδ/retinol signalosome monitors the internal cytochrome c redox state that reflects the workload of the respiratory chain. Upon sensing demands for energy PKCδ signals the PDHC to increase glucose-derived fuel flux entering the KREBS cycle. Conversely, if excessive fuel flux surpasses the capacity of the respiratory chain, threatening the release of damaging reactive oxygen species (ROS), the polarity of the cytochrome c redox system is reversed, resulting in the chemical reduction of the PKCδ CRD, restoration of the RING-finger, refolding of PKCδ into the inactive, globular form, and curtailment of PDHC output, thereby constraining the respiratory capacity within safe margins. Several retinoids, notably anhydroretinol and fenretinide, capable of displacing retinol from binding sites on PKCδ, can co-activate PKCδ signaling but, owing to their extended system of conjugated double bonds, are unable to silence PKCδ in a timely manner. Left in the ON position, PKCδ causes chronic overload of the respiratory chain leading to mitochondrial dysfunction. This review explores how defects in the PKCδ signal machinery potentially contribute to metabolic and degenerative diseases.

Carotenoids and fatty liver disease: Current knowledge and research gaps.

Carotenoids form an important part of the human diet, consumption of which has been associated with many health benefits. With the growing global burden of liver disease, increasing attention has been paid on the possible beneficial role that carotenoids may play in the liver. This review focuses on carotenoid actions in non-alcoholic fatty liver disease (NAFLD), and alcoholic liver disease (ALD). Indeed, many human studies have suggested an association between decreased circulating levels of carotenoids and increased incidence of NAFLD and ALD. The literature describing supplementation of individual carotenoids in rodent models of NAFLD and ALD is reviewed, with particular attention paid to ß-carotene and lycopene, but also including ß-cryptoxanthin, lutein, zeaxanthin, and astaxanthin. The effect of beta-carotene oxygenase 1 and 2 knock-out mice on hepatic lipid metabolism is also discussed. In general, there is evidence to suggest that carotenoids have beneficial effects in animal models of both NAFLD and ALD. Mechanistically, these benefits may occur via three possible modes of action: 1) improved hepatic antioxidative status broadly attributed to carotenoids in general, 2) the generation of vitamin A from ß-carotene and ß-cryptoxanthin, leading to improved hepatic retinoid signaling, and 3) the generation of apocarotenoid metabolites from ß-carotene and lycopene, that may regulate hepatic signaling pathways. Gaps in our knowledge regarding carotenoid mechanisms of action in the liver are highlighted throughout, and the review ends by emphasizing the importance of dose effects, mode of delivery, and mechanism of action as important areas for further study. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

Carotenoid metabolism at the intestinal barrier.

Carotenoids exert a rich variety of physiological functions in mammals and are beneficial for human health. These lipids are acquired from the diet and metabolized to apocarotenoids, including retinoids (vitamin A and its metabolites). The small intestine is a major site for their absorption and bioconversion. From here, carotenoids and their metabolites are distributed within the body in triacylglycerol-rich lipoproteins to support retinoid signaling in peripheral tissues and photoreceptor function in the eyes. In recent years, much progress has been made in identifying carotenoid metabolizing enzymes, transporters, and binding proteins. A diet-responsive regulatory network controls the activity of these components and adapts carotenoid absorption and bioconversion to the bodily requirements of these lipids. Genetic variability in the genes encoding these components alters carotenoid homeostasis and is associated with pathologies. We here summarize the advanced state of knowledge about intestinal carotenoid metabolism and its impact on carotenoid and retinoid homeostasis of other organ systems, including the eyes, liver, and immune system. The implication of the findings for science-based intake recommendations for these essential dietary lipids is discussed. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

The molecular aspects of absorption and metabolism of carotenoids and retinoids in vertebrates.

Vitamin A is an essential nutrient necessary for numerous basic physiological functions, including reproduction and development, immune cell differentiation and communication, as well as the perception of light. To evade the dire consequences of vitamin A deficiency, vertebrates have evolved specialized metabolic pathways that enable the absorption, transport, and storage of vitamin A acquired from dietary sources as preformed retinoids or provitamin A carotenoids. This evolutionary advantage requires a complex interplay between numerous specialized retinoid-transport proteins, receptors, and enzymes. Recent advances in molecular and structural biology resulted in a rapid expansion of our understanding of these processes at the molecular level. This progress opened new avenues for the therapeutic manipulation of retinoid homeostasis. In this review, we summarize current research related to the biochemistry of carotenoid and retinoid-processing proteins with special emphasis on the structural aspects of their physiological actions. This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.

Strategies to achieve adequate vitamin A intake for young children: options for Cameroon.

Meeting children's vitamin A (VA) needs remains a policy priority. Doing so efficiently is a fiscal imperative and protecting at-risk children during policy transitions is a moral imperative. Using the Micronutrient Intervention Modeling tool and data for Cameroon, we predict the impacts and costs of alternative VA intervention programs, identify the least-cost strategy for meeting targets nationally, and compare it to a business-as-usual (BAU) strategy over 10 years. BAU programs effectively cover ∼12.8 million (m) child-years (CY) and cost ∼$30.1 m; ∼US$2.34 per CY effectively covered. Improving the VA-fortified oil program, implementing a VA-fortified bouillon cube program, and periodic VA supplements (VAS) in the North macroregion for 3 years effectively cover ∼13.1 m CY at a cost of ∼US$9.5 m, or ∼US$0.71 per CY effectively covered. The tool then identifies a sequence of subnational policy choices leading from the BAU toward the more efficient strategy, while addressing VA-attributable mortality concerns. By year 4, fortification programs are predicted to eliminate inadequate VA intake in the South and Cities macroregions, but not the North, where VAS should continue until additional delivery platforms are implemented. This modeling approach offers a concrete example of the strategic use of data to follow the Global Alliance for VA framework and do so efficiently.