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Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the unique pathological hallmark of Alzheimer’s disease (AD). Aβ is derived from amyloid β precursor protein (APP) by β- 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 Aβ 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.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF; n = 10) than in non-stone formers (NSF; n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

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.

Vitamins E and A are essential fat-soluble micronutrients critical for immune regulation, bone metabolism, and cellular homeostasis. Current evidence highlights significant gaps in understanding their interdependent relationships and the modulatory effects of age, environmental exposures, and physiological status on their systemic bioavailability. To investigate the relationship between Vitamin E and Vitamin A levels in children aged 0–10.8 years and identify any critical thresholds. This cross-sectional study was conducted from 2018 to 2021 in Ningbo, Zhejiang, China. It involved children aged 0–10.8 years who attended community health service centers for routine health check-ups. To evaluate the relationship between serum Vitamin E and Vitamin A levels, we performed a multivariate linear regression analysis. Furthermore, a smooth curve fitting approach was employed to investigate the dose-response relationship between Vitamin E and Vitamin A. The study included a total of 4,752 participants. Significant variations in baseline Vitamin E and Vitamin A levels were observed across different deficiency categories. The mean Vitamin E level was lowest in the deficiency group (2.4 ± 0.5 µg/mL) and highest in the excess group (7.0 ± 1.6 µg/mL). Similarly, the mean Vitamin A level was lowest in the deficiency group (236.9 ± 60.4 ng/mL) and highest in the excess group (292.4 ± 72.3 ng/mL). A two-phase linear relationship was identified, with a significant threshold effect at a Vitamin E level of 3.579 µg/mL. Below this threshold, the association between Vitamin E and Vitamin A was robust ( β  = 35.829, 95% CI: 30.217, 41.441), while above the threshold, the association weakened significantly ( β  = 9.828, 95% CI: 8.250, 11.406). The likelihood ratio test confirmed the significance of this threshold effect ( p  < 0.001). The study identified a significant threshold at 3.579 µg/mL for Vitamin E, beyond which the association with Vitamin A levels stabilizes. This threshold highlights the importance of maintaining optimal Vitamin E levels to support Vitamin A status, particularly in high-risk groups such as older children and those with limited access to Vitamin E-rich foods. Future longitudinal studies are needed to further validate these findings and explore their implications for public health interventions.

Vitamin A (all-trans-retinol) is a fat-soluble micronutrient which together with its natural derivatives and synthetic analogues constitutes the group of retinoids. They are involved in a wide range of physiological processes such as embryonic development, vision, immunity and cellular differentiation and proliferation. Retinoic acid (RA) is the main active form of vitamin A and multiple genes respond to RA signalling through transcriptional and non-transcriptional mechanisms. Vitamin A deficiency (VAD) is a remarkable public health problem. An adequate vitamin A intake is required in early lung development, alveolar formation, tissue maintenance and regeneration. In fact, chronic VAD has been associated with histopathological changes in the pulmonary epithelial lining that disrupt the normal lung physiology predisposing to severe tissue dysfunction and respiratory diseases. In addition, there are important alterations of the structure and composition of extracellular matrix with thickening of the alveolar basement membrane and ectopic deposition of collagen I. In this review, we show our recent findings on the modification of cell-junction proteins in VAD lungs, summarize up-to-date information related to the effects of chronic VAD in the impairment of lung physiology and pulmonary disease which represent a major global health problem and provide an overview of possible pathways involved.

Background/Objectives: There is limited published research examining lipid-soluble vitamins in human immunodeficiency virus (HIV)-infected pregnant women, particularly in resource-limited settings. Subjects/Methods: This is an observational analysis of 1078 HIV-infected pregnant women enrolled in a trial of vitamin supplementation in Tanzania. Baseline data on sociodemographic and anthropometric characteristics, clinical signs and symptoms, and laboratory parameters were used to identify correlates of low plasma vitamin A (<0.7 μmol/l), vitamin D (<80 nmol/l) and vitamin E (<9.7 μmol/l) status. Binomial regression was used to estimate risk ratios and 95% confidence intervals. Results: Approximately 35, 39 and 51% of the women had low levels of vitamins A, D and E, respectively. Severe anemia (hemoglobin <85 g/l; P <0.01), plasma vitamin E ( P =0.02), selenium ( P =0.01) and vitamin D ( P =0.02) concentrations were significant correlates of low vitamin A status in multivariate models. Erythrocyte Sedimentation Rate (ESR) was independently related to low vitamin A status in a nonlinear manner ( P =0.01). The correlates of low vitamin D status were CD8 cell count ( P =0.01), high ESR (ESR >81 mm/h; P <0.01), gestational age at enrollment (nonlinear; P =0.03) and plasma vitamins A ( P =0.02) and E ( P =0.01). For low vitamin E status, the correlates were money spent on food per household per day ( P <0.01), plasma vitamin A concentration (nonlinear; P <0.01) and a gestational age <16 weeks at enrollment ( P <0.01). Conclusions: Low concentrations of lipid-soluble vitamins are widely prevalent among HIV-infected women in Tanzania and are correlated with other nutritional insufficiencies. Identifying HIV-infected persons at greater risk of poor nutritional status and infections may help inform design and implementation of appropriate interventions.

While recent data on vitamin A deficiency (VAD) prevalence is lacking, the 2004 Côte d'Ivoire Nutrition and Mortality Survey reported that 26.7% of children aged 6-59 months were affected by VAD, and approximately 60% were at risk. Since 2016, the government has transitioned from mass campaigns to routine vitamin A supplementation (VAS) delivery integrated into health services. However, evidence on the cost-effectiveness of the routine distribution approaches is limited. This study evaluated the cost, coverage, and cost-effectiveness of three routine VAS delivery strategies across two health districts in northern Côte d'Ivoire. A mixed-methods study evaluated three routine VAS delivery strategies - routine-fixed, advanced community-based, and catch-up - across two health districts, Ferkessédougou and Niakaramadougou, in northern Côte d'Ivoire. The quantitative cost data were collected via a structured tool covering six cost categories: planning, procurement, training, social mobilization, distribution, and supervision. VAS coverage was assessed through a post-event coverage survey (PECS) via a two-stage cluster sampling methodology. A cost-effectiveness analysis determined the cost per child supplemented, the cost per DALY averted, and a sensitivity analysis tested the robustness of the findings under different cost scenarios. The total program cost for July-December 2023 was 25.5 million FCFA, with personnel costs comprising over 70% of expenditures. In Ferkessédougou, the routine advanced community-based strategy was the most cost-effective, at 458 FCFA per child in rural areas (versus 596 FCFA for the routine-fixed facility-based approach in the same area). In Niakaramadougou, the December catch-up was more cost-effective in rural areas (606 FCFA per child) than the routine-fixed approach (714 FCFA). Across both districts combined, the routine-fixed strategy averaged roughly 651 FCFA per child supplemented, and the cost per DALY averted ranged from 30,093 FCFA (advanced strategy in Ferkessédougou) to 89,550 FCFA (catch-up Jul 2023 in Niakaramadougou) - all below Côte d'Ivoire's cost-effectiveness threshold (0.5 x GDP per capita; approximately USD 1,265). All three strategies were cost-effective, though the advanced community-based strategy achieved the best balance of reach and efficiency. Scaling advanced strategies within health system constraints may enhance sustainability and coverage in low-resource settings.

Vitamin A supplementation (VAS) programs targeted at children aged 6–59 months are implemented in many countries. By improving immune function, vitamin A (VA) reduces mortality associated with measles, diarrhea, and other illnesses. There is currently a debate regarding the relevance of VAS, but amidst the debate, researchers acknowledge that the majority of nationally-representative data on VA status is outdated. To address this data gap and contribute to the debate, we examined data from 82 countries implementing VAS programs, identified other VA programs, and assessed the recentness of national VA deficiency (VAD) data. We found that two-thirds of the countries explored either have no VAD data or data that were >10 years old (i.e., measured before 2006), which included twenty countries with VAS coverage ≥70%. Fifty-one VAS programs were implemented in parallel with at least one other VA intervention, and of these, 27 countries either had no VAD data or data collected in 2005 or earlier. To fill these gaps in VAD data, countries implementing VAS and other VA interventions should measure VA status in children at least every 10 years. At the same time, the coverage of VA interventions can also be measured. We identified three countries that have scaled down VAS, but given the lack of VA deficiency data, this would be a premature undertaking in most countries without appropriate status assessment. While the global debate about VAS is important, more attention should be directed towards individual countries where programmatic decisions are made.

Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.

Although broad-scale data might suggest low prevalence, millions of children in India still suffer from Vitamin A and Vitamin D deficiencies despite India's existing guidelines for Vitamin A deficiency. To address the issue, the Government of India has recommended fortification of oil and milk to improve Vitamin A and Vitamin D consumption. However, there is limited information on the health benefits and cost-effectiveness of fortifying oil and milk at scale. To estimate the health benefits and cost-effectiveness of supplementation programme and fortification of milk and oil among children under 5 years, pregnant women, women in the reproductive age group, and the elderly. To measure the health benefits associated with supplementation and fortification of oil and milk, the number of DALYs that are currently lost due to Vitamin A and Vitamin D deficiencies were estimated. For Vitamin A related mortality, a reduction of 4%, 12% and 23% were assumed while the assumptions for estimating morbidity benefits were derived from Global Burden of Disease. For the costing exercise, we considered the following two scenarios: (1) high-dose vitamin A supplementation for children and pregnant women; (2) industrial fortification of oil for children, pregnant women, women in the reproductive age group, and the elderly. Overall, intervention related to Vitamin A could avert 1,119,044 Years of Life Lost (YLLs) at a 23% reduction, 194,616 YLLs at 4%, and 583,849 YLLs at 12% and 28,534 YLDs. Intervention related to Vitamin D could avert 99,219 YLDs. The total cost for supplying supplements to approximately 109,965 thousand children and 26,920 thousand pregnant women is around 26 million USD. The cost to fortify is 7.6 million USD for oil and 9.8 million USD for milk fortification for children and women. The overall cost effectiveness ratio of the fortification programme is 150. Fortification could emerge as a potentially superior long-term solution, considering the widespread consumption of oil and milk, offering a broader reach to the population.