8†Unexpected retinopathy in a patient presenting with bilateral optic disc swelling.

A 12-year-old boy presented with 5 day history of blurry vision, 'wobbly eyes', tinnitus and difficulty seeing at night. Local ophthalmology noted bilateral optic disc swelling and referred him urgently for neurological investigations.Clinical Findings: At presentation VA was RE 0.00 and LE 0.2 with normal Ishihara colour vision. His extraocular movements were full without manifest strabismus. Fundoscopy showed bilateral optic disc swelling. Electrophysiology unexpectedly revealed a functionally cone isolated retina with markedly abnormal rod function. Pattern VEPs indicated bilateral macular pathway dysfunction affecting left eye more than right eye. Wide field imaging showed bilateral diffusely scattered yellow-white flecks in the midperiphery of each eye. His kinetic visual fields were moderately restricted bilaterally. MRI showed a Chiari 1 malformation with cerebellar tonsil herniation, but LP opening pressure was normal.Differential diagnosis included RDH5 retinopathy or vitamin A deficiency. On questioning he reported a diet restricted to only meat and biscuits. His vitamin A levels were subnormal at 0.14 umol/L (reference range 0.9-2.5umol/l) and he was started on high-dose Vitamin A supplements.Four months after supplementation retinal appearances had normalised, the rod ERGs recovered, nyctalopia and visual field restriction resolved. PVEPs had improved but an element of LE macular pathway dysfunction remained. Optic disc swelling settled leaving mild temporal pallor, particularly of the LE with some RNFL loss.It is important to recognise nutritional Vitamin A deficiency in children as prompt recognition and treatment can improve symptoms, reverse retinal pathology which we have demonstrated with electrophysiological findings.

The role of genes and environment in the etiology of congenital diaphragmatic hernias.

Structural birth defects are a common cause of abnormalities in newborns. While there are cases of structural birth defects arising due to monogenic defects or environmental exposures, many birth defects are likely caused by a complex interaction between genes and the environment. A structural birth defect with complex etiology is congenital diaphragmatic hernias (CDH), a common and often lethal disruption in diaphragm development. Mutations in more than 150 genes have been implicated in CDH pathogenesis. Although there is generally less evidence for a role for environmental factors in the etiology of CDH, deficiencies in maternal vitamin A and its derivative embryonic retinoic acid are strongly associated with CDH. However, the incomplete penetrance of CDH-implicated genes and environmental factors such as vitamin A deficiency suggest that interactions between genes and environment may be necessary to cause CDH. In this review, we examine the genetic and environmental factors implicated in diaphragm and CDH development. In addition, we evaluate the potential for gene-environment interactions in CDH etiology, focusing on the potential interactions between the CDH-implicated gene, Gata4, and maternal vitamin A deficiency.

Interrelations between Iron and Vitamin A-Studied Using Systems Approach.

A deficiency of vitamin A (VAD) and iron is the most common nutritional problem affecting people worldwide. Given the scale of the problem, the interactions between vitamin A and iron levels are widely studied. However, the exact mechanism of the impact of vitamin A on the regulation of iron metabolism remains unclear. An extremely significant issue becomes a better understanding of the nature of the studied biological phenomenon, which is possible by using a systems approach through developing and analyzing a mathematical model based on a Petri net. To study the considered system, the t-cluster analysis, the significance analysis, and the analysis of the average number of transition firings were performed. The used analyses have allowed distinguishing the most important mechanisms (both subprocesses and elementary processes) positively and negatively regulating an expression of hepcidin and allowed to distinguish elementary processes with a higher frequency of occurrence compared to others. The analysis also allowed to resolve doubts about the discrepancy in literature reports, where VAD leads to positive regulation of hepcidin expression or to negative regulation of hepcidin expression. The more detailed analyses have shown that VAD more frequently positively stimulates hepcidin expression and this mechanism is more significant than the mechanism inhibiting hepcidin expression indirectly by VAD.

ß-carotene improves fecal dysbiosis and intestinal dysfunctions in a mouse model of vitamin A deficiency.

Vitamin A deficiency (VAD) results in intestinal inflammation, increased redox stress and reactive oxygen species (ROS) levels, imbalanced inflammatory and immunomodulatory cytokines, compromised barrier function, and perturbations of the gut microbiome. To combat VAD dietary interventions with ß-carotene, the most abundant precursor of vitamin A, are recommended. However, the impact of ß-carotene on intestinal health during VAD has not been fully clarified, especially regarding the VAD-associated intestinal dysbiosis. Here we addressed this question by using Lrat-/-Rbp-/- (vitamin A deficient) mice deprived of dietary preformed vitamin A and supplemented with ß-carotene as the sole source of the vitamin, alongside with WT (vitamin A sufficient) mice. We found that dietary ß-carotene impacted intestinal vitamin A status, barrier integrity and inflammation in both WT and Lrat-/-Rbp-/- (vitamin A deficient) mice on the vitamin A-free diet. However, it did so to a greater extent under overt VAD. Dietary ß-carotene also modified the taxonomic profile of the fecal microbiome, but only under VAD. Given the similarity of the VAD-associated intestinal phenotypes with those of several other disorders of the gut, collectively known as Inflammatory Bowel Disease (IBD) Syndrome, these findings are broadly relevant to the effort of developing diet-based intervention strategies to ameliorate intestinal pathological conditions.

Fenretinide inhibits vitamin A formation from ß-carotene and regulates carotenoid levels in mice.

N-[4-hydroxyphenyl]retinamide, commonly known as fenretinide, a synthetic retinoid with pleiotropic benefits for human health, is currently utilized in clinical trials for cancer, cystic fibrosis, and COVID-19. However, fenretinide reduces plasma vitamin A levels by interacting with retinol-binding protein 4 (RBP4), which often results in reversible night blindness in patients. Cell culture and in vitro studies show that fenretinide binds and inhibits the activity of ß-carotene oxygenase 1 (BCO1), the enzyme responsible for endogenous vitamin A formation. Whether fenretinide inhibits vitamin A synthesis in mammals, however, remains unknown. The goal of this study was to determine if the inhibition of BCO1 by fenretinide affects vitamin A formation in mice fed ß-carotene. Our results show that wild-type mice treated with fenretinide for ten days had a reduction in tissue vitamin A stores accompanied by a two-fold increase in ß-carotene in plasma (P < 0.01) and several tissues. These effects persisted in RBP4-deficient mice and were independent of changes in intestinal ß-carotene absorption, suggesting that fenretinide inhibits vitamin A synthesis in mice. Using Bco1-/- and Bco2-/- mice we also show that fenretinide regulates intestinal carotenoid and vitamin E uptake by activating vitamin A signaling during short-term vitamin A deficiency. This study provides a deeper understanding of the impact of fenretinide on vitamin A, carotenoid, and vitamin E homeostasis, which is crucial for the pharmacological utilization of this retinoid.

Vitamin A deficiency in K14E7HPV expressing transgenic mice facilitates the formation of malignant cervical lesions.

Infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer (CC), but viral infection alone does not guarantee the development of this malignancy. Indeed, deficiencies of dietary micronutrients could favor cervical cancer development in individuals that harbor HR-HPV infections. The status of retinoid levels, natural and synthetic derivatives of vitamin A, is important in maintaining cellular differentiation of the cervical epithelium. Moreover, many studies show a link between deficient intake of retinoids or alteration of the retinoid receptors and CC development. In spite of this, the effect of vitamin A deficiency (VAD) in presence of HR-HPV oncoproteins on cervical carcinogenesis in vivo has not been reported. Transgenic mice expressing E6 or E7 oncoproteins (K14E6 or K14E7 mice, respectively) were used to evaluate the possible role of VAD in the development of malignant cervical lesions. The survival of the mice in VAD condition was studied, and histopathological analysis and immunohistochemical detection of molecular cancer markers such as the tumor suppressor retinoic acid receptor beta (RARß), proliferating cell nuclear antigen (PCNA), cleaved caspase 3, and the tumor suppressor protein p16INK4A (inhibitor of CDK4) were performed. Our results show that K14E6/VAD mice showed moderate cervical dysplasia; notably, K14E7/VAD mice developed severe cervical dysplasia and cervical in situ carcinoma at an early age. VAD synergizes with HPV16E7 oncoprotein expression favoring cervical carcinogenesis in vivo.

Absence of CD36 alters systemic vitamin A homeostasis.

Fatty acid translocase (CD36) is a scavenger receptor with multiple ligands and diverse physiological actions. We recently reported that alcohol-induced hepatic retinoid mobilization is impaired in Cd36-/- mice, leading us to hypothesize that CD36 has a novel role in hepatic vitamin A mobilization. Given the central role of the liver in systemic vitamin A homeostasis we also postulated that absence of CD36 would affect whole-body vitamin A homeostasis. We tested this hypothesis in aging wild type and Cd36-/- mice, as well as mice fed a vitamin A-deficient diet. In agreement with our hypothesis, Cd36-/- mice accumulated hepatic retinyl ester stores with age to a greater extent than wild type mice. However, contrary to expectations, Cd36-/- mice consuming a vitamin A-deficient diet mobilized hepatic retinoid similar to wild type mice. Interestingly, we observed that Cd36-/- mice had significantly reduced white adipose tissue retinoid levels compared to wild type mice. In conclusion, we demonstrate that the absence of CD36 alters whole-body vitamin A homeostasis and suggest that this phenotype is secondary to the impaired chylomicron metabolism previously reported in these mice.

Prevalence of Vitamin A Deficiency among Preschool Children in Ethiopia: A Systematic Review and Meta-Analysis.

BACKGROUND: Vitamin A deficiency is a major nutritional concern in lower-income countries. The aim of this systematic review and meta-analysis was to show the magnitude of vitamin A deficiency among preschoolers in Ethiopia. OBJECTIVE: The present study was aimed at synthesizing qualitatively and quantitatively the existing literature on the prevalence of VAD in preschool children in Ethiopia. METHODS: Studies were searched through the search engine of Google Scholar, Hinari, MEDLINE/PubMed, Cochrane Library, and Africa-Wide Information. Searching was made using the keywords/MeSH of vitamin A deficiency, xerophthalmia, night blindness, Bitot's spot, retinol, children, and Ethiopia. Data were analyzed and compared with the WHO threshold criteria to declare a public health problem. Heterogeneity among studies was assessed using a Cochran Q test and I 2 statistics. A random-effects model with 95% confidence interval was used for prevalence estimations. RESULTS: Of the 13 studies included in clinical analysis, 12 of them reported the prevalence of night blindness and/or Bitot's spot among preschool children in Ethiopia which was above WHO cutoff point for the public health problem 1% and 0.5%, respectively. The prevalence of night blindness significantly decreased from moderate public health problem 4.2% (95% CI: 2.8%-5.7%) in a period from 1990 to 2004 to mild public health problem 0.8% (95% CI: 0.6%-1.0%) in a period from 2005 to 2019. Furthermore, statistically insignificant reduction was observed in the prevalence of Bitot's spot in a period from 1990 to 2004, 2.2% (95% CI: 1.3%-3.2%) to 1.8% (95% CI: 1.2%-2.3%) in a period from 2005 to 2019. Among 8 studies on subclinical vitamin A deficiency, 7 of them indicated a severe public health problem (>20%). The prevalence of subclinical vitamin A deficiency decreased from 55.7% (95% CI: 39.8%-71.6%) in a period from 1990 to 2004 to 28.3% (95% CI: 9.8%-46.7%) in a period from 2005 to 2019, but not statistically significant. CONCLUSIONS: Despite the reduced proportion of night blindness and Bitot's spot, still both clinical and subclinical vitamin A deficiencies remain a public health problem in Ethiopia requiring strengthen intervention through the newly initiated health extension program.

Vitamin A deficiency causes islet dysfunction by inducing islet stellate cell activation via cellular retinol binding protein 1.

Background: Vitamin A (VA) plays an essential role in pancreatic homeostasis. Islet stellate cells (ISCs) are VA-storing cells in pancreatic islets. Herein, we have investigated the effect of VA on glucose homeostasis trough regulation of ISCs function in dietary VA deficiency model mice. Methods: Male C57BL/6 mice were randomly fed a VA-sufficient, a VA-deficient (VAD) or a VAD-rescued diet. Glucose metabolism was assessed by glucose tolerance tests and immunohistochemistry. ISCs activation degree was evaluated by immunofluorescence, quantitative PCR and western blotting in both, retinol-treated cultured ISCs and model mice. Changes in ISCs phenotype and their effect on islets were assessed by lentiviral transduction and enzyme-linked immunosorbent assays in a co-culture system. Results: VAD mice showed irregular shaped islet, glucose intolerance, islet size distribution excursions, and upregulated expression of α-smooth muscle actin (α-SMA, marker of ISCs activation). Reintroduction of dietary VA restored pancreatic VA levels, endocrine hormone profiles, and inhibited ISCs activation. Incubation with retinol increased the expression of VA signaling factors in ISCs, including cellular retinol binding protein 1 (CRBP1). The knockdown of CRBP1 maintained the quiescent ISCs phenotype and reduced the damage of activated ISCs on islet function. Conclusions: VA deficiency reduced islet function by activating ISCs in VAD mice. Restoring ISCs quiescence via CRBP1 inhibition could reverse the impairment of islet function caused by activated ISCs exposure.

Changes in Intestinal Microbiota Are Associated with Islet Function in a Mouse Model of Dietary Vitamin A Deficiency.

AIMS: The underlying mechanisms involved in Vitamin A- (VA-) related changes in glucose metabolic disorders remain unclear. Recent evidence suggests that intestinal microbiota is closely linked to the metabolic syndrome. Here, we explored whether and how intestinal microbiota affects glucose homeostasis in VA-deficient diet-fed mice. METHODS: Six-week-old male C57BL/6 mice were randomly placed on either a VA-sufficient (VAS) or VA-deficient (VAD) diet for 10 weeks. Subsequently, a subclass of the VAD diet-fed mice was switched to a VA-deficient rescued (VADR) diet for an additional 8 weeks. The glucose metabolic phenotypes of the mice were assessed using glucose tolerance tests and immunohistochemistry staining. Changes in intestinal microbiota were assessed using 16S gene sequencing. The intestinal morphology, intestinal permeability, and inflammatory response activation signaling pathway were assessed using histological staining, western blots, quantitative-PCR, and enzyme-linked immunosorbent assays. RESULTS: VAD diet-fed mice displayed reduction of tissue VA levels, increased area under the curve (AUC) of glucose challenge, reduced glucose-stimulated insulin secretion, and loss of ß cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and ß cell mass. Redundancy analysis showed intestinal microbiota diversity was significantly associated with AUC of glucose challenge and κB signaling pathway activation. Reintroduction of dietary VA to VAD diet-fed mice restored tissue VA levels, endocrine hormone profiles, and inflammatory response, which are similar to those observed following VAS-controlled changes in intestinal microbiota. CONCLUSIONS: We found intestinal microbiota effect islet function via controlling intestinal inflammatory phenotype in VAD diet-fed mice. Intestinal microbiota influences could be considered as an additional mechanism for the effect of endocrine function in a VAD diet-driven mouse model.

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11ß-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11ß-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11ß-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11ß-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11ß-HSD1.

Vitamin A and its metabolic pathway play a determinant role in high-fructose-induced triglyceride accumulation of the visceral adipose depot of male Wistar rats.

Here, we tested a hypothesis that vitamin A and/or its metabolic pathways are involved in the high-fructose-mediated alteration in adipose tissue biology. For this purpose, weanling male Wistar rats were provided with one of the following diets: control (C), control with vitamin A deficiency (C-VAD), high fructose (HFr), and HFr with VAD (HFr-VAD) for 16 weeks, except that half of the C-VAD diet-fed rats were shifted to HFr diet (C-VAD(s)HFr), after 8-week period. Compared with control, feeding of HFr diet significantly increased the triglyceride content (P ≤ .01) and thus adipocyte size (hypertrophy) (P ≤ .001) in visceral adipose depot; retroperitoneal white adipose tissue (RPWAT) and these changes were corroborated with de novo lipogenesis, as evidenced by the increased glycerol-3-phosphate dehydrogenase activity (P ≤ .01) and up-regulation of lipogenic pathway transcripts, fructose transporter, and aldehyde dehydrogenase 1 A1. On the contrary, the absence of vitamin A in the HFr diet (HFr-VAD) failed to exert these changes; however, it induced adipocyte hyperplasia. Further, vitamin A deficiency-mediated changes were reversed by replenishment, as evident from the group that was shifted from C-VAD to HFr diet. In conclusion, vitamin A and its metabolic pathway play a key determinant role in the high-fructose-induced triglyceride accumulation and adipocyte hypertrophy of visceral white adipose depot. SIGNIFICANCE OF THE STUDY: Here, we report the metabolic impact of high-fructose feeding under vitamin A-sufficient and vitamin A-deficient conditions. Feeding of high-fructose diet induced triglyceride accumulation and adipocyte hypertrophy of the visceral white adipose depots. These changes corroborated with augmented expression of vitamin A and lipid metabolic pathway genes. Contrarily, absence of vitamin A in the high-fructose diet did not elicit such responses, while vitamin A replenishment reversed the changes exerted by vitamin A deficiency. To our knowledge, this is the first study to report the role of vitamin A and its metabolic pathway in the high-fructose-induced triglyceride synthesis and its accumulation in visceral adipose depot and thus provide a new insight and scope to understand these nutrients interaction in clinical conditions.

Vitamin A deficiency is associated with body mass index and body adiposity in women with recommended intake of vitamin A.

INTRODUCTION: evidence indicates that vitamin A is involved in regulating fat mass. A low consumption of vitamin A has been reported in individuals with obesity, as have lower concentrations of this vitamin, than in eutrophic individuals when their dietary intake of vitamin A is not significantly different. OBJECTIVE: to investigate vitamin A nutritional status and its association with body mass index (BMI) and body fat in women who have the recommended dietary intake of vitamin A. METHODS: cross-sectional study with 200 women, paired by age and by the dietary intake of vitamin A recommended. Participants were divided into four groups, according to BMI. Anthropometric data were evaluated (weight, BMI and waist circumference [WC]), as well as the diagnosis of night blindness (NB). Lipid and glycemic profiles were measured. The cut-off points for deficiency of serum concentrations of retinol and ß-carotene were < 1.05 µmol/l and 40 µg/dl, respectively. The recommended dietary intake of vitamin A was 700 µg/day. RESULTS: there was a significant drop in retinol concentrations according to BMI (p < 0.001) and WC (p < 0.001). We found ß-carotene to behave similarly (p = 0.005; p < 0.001). We found NB in 7.5% of overweight (OW) cases and 20.0% of obesity class II (OII), and no functional alteration was found in the eutrophic group (EU). Inadequate levels of retinol and ß-carotene increased the odds ratio for the occurrence of OW, obesity class I (OI) and OII, as well as inadequate WC. CONCLUSION: even with recommended intake of vitamin A, we found a biochemical and functional inadequacy of vitamin A nutritional status,associated with overweight, obesity and body adiposity.

Identification of Competing Endogenous RNA Regulatory Networks in Vitamin A Deficiency-Induced Congenital Scoliosis by Transcriptome Sequencing Analysis.

BACKGROUND/AIMS: Congenital scoliosis (CS) is a result of anomalous development of vertebrae and is frequently associated with somitogenesis malformation. Although noncoding RNAs (ncRNAs) have been recently determined to be involved in the pathogenesis of CS, the competing endogenous RNA (ceRNA) regulatory networks in CS remain largely unknown. METHODS: Sequencing was conducted to explore the ncRNA expression profiles in rat embryos (gestation day 9) following vitamin A deficiency (VAD) (n = 9 for the vitamin A deficiency-induced congenital scoliosis (VAD-CS) group and n = 4 for the control group). Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was conducted to verify the expression levels of selected mRNAs, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs). Bioinformatics analysis was used to discover the possible relationships and functions of the ceRNAs. RESULTS: A total of 749 mRNAs, 56 miRNAs, 685 lncRNAs, and 70 circRNAs were identified to have significantly different expression levels in the two groups. Wnt, PI3K-ATK, FoxO, EGFR, and mTOR were found to be the most significant pathways involved in VAD-CS pathogenesis. The circRNA/miRNA/mRNA and lncRNA/miRNA/mRNA networks of CS were built, and the gene expression mechanisms regulated by ncRNAs were unveiled via the ceRNA regulatory networks. CONCLUSION: We comprehensively identified ceRNA regulatory networks of embryonic somite development in VAD-CS as well as revealed the contribution of different ncRNA expression profiles. Our data demonstrate the association between mRNAs and ncRNAs in the pathogenic mechanism of CS.

Vitamin A Deficiency and the Lung.

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.

Early Life Vitamin C Deficiency Does Not Alter Morphology of Hippocampal CA1 Pyramidal Neurons or Markers of Synaptic Plasticity in a Guinea Pig Model.

Approximately 15% of the Western world population, including pregnant women and their children, is characterized as vitamin C (vitC) deficient. In guinea pigs, early life vitC deficiency causes spatial memory deficits, decreased hippocampal volume and neuron numbers, in otherwise clinically healthy animals. We hypothesized that vitC deficiency leads to decreased brain-derived neurotrophic factor and synaptic plasticity markers in selected brain areas (frontal cortex, hippocampus and striatum) and cause morphological changes in cornu ammonis 1 pyramidal neurons of the hippocampus either through a direct effect or indirectly by increased oxidative stress. Fifty-seven female guinea pigs were allocated to three groups receiving either 1390, 100 or 0⁻50 mg vitC/kg feed for 11 weeks. Dietary vitC levels were reflected in the plasma, cortical and adrenal gland levels, however, redox imbalance was only present in the adrenal glands allowing for the investigation of a direct influence of vitC deficiency on the chosen parameters in the brain. Synaptic plasticity markers were not affected in the investigated brain areas and no differences in isolated pyramidal neuron morphology was recorded. Based on our findings, it appears that vitC deficiency may primarily elicit impaired neuronal function through increased levels of oxidative stress.

Vitamin A bio-modulates apoptosis via the mitochondrial pathway after hypoxic-ischemic brain damage.

Our previous studies demonstrated that vitamin A deficiency (VAD) can impair the postnatal cognitive function of rats by damaging the hippocampus. The present study examined the effects of retinoic acid (RA) on apoptosis induced by hypoxic-ischemic damage in vivo and in vitro, and investigated the possible signaling pathway involved in the neuroprotective anti-apoptotic effects of RA. Flow cytometry, immunofluorescence staining and behavioral tests were used to evaluate the neuroprotective and anti-apoptotic effects of RA. The protein and mRNA levels of RARα, PI3K, Akt, Bad, caspase-3, caspase-8, Bcl-2, Bax, and Bid were measured with western blotting and real-time PCR, respectively. We found impairments in learning and spatial memory in VAD group compared with vitamin A normal (VAN) and vitamin A supplemented (VAS) group. Additionally, we showed that hippocampal apoptosis was weaker in the VAN group than that in VAD group. Relative to the VAD group, the VAN group also had increased mRNA and protein levels of RARα and PI3K, and upregulated phosphorylated Akt/Bad levels in vivo. In vitro, excessively low or high RA signaling promoted apoptosis. Furthermore, the effects on apoptosis involved the mitochondrial membrane potential (MMP). These data support the idea that sustained VAD following hypoxic-ischemic brain damage (HIBD) inhibits RARα, which downregulates the PI3K/Akt/Bad and Bcl-2/Bax pathways and upregulates the caspase-8/Bid pathway to influence the MMP, ultimately producing deficits in learning and spatial memory in adolescence. This suggests that clinical interventions for HIBD should include suitable doses of VA.

Competition between ethanol clearance and retinoic acid biosynthesis in the induction of fetal alcohol syndrome.

Several models have been proposed to explain the neurodevelopmental syndrome induced by exposure of human embryos to alcohol, which is known as fetal alcohol spectrum disorder (FASD). One of the proposed models suggests a competition for the enzymes required for the biosynthesis of retinoic acid. The outcome of such competition is development under conditions of reduced retinoic acid signaling. Retinoic acid is one of the biologically active metabolites of vitamin A (retinol), and regulates numerous embryonic and differentiation processes. The developmental malformations characteristic of FASD resemble those observed in vitamin A deficiency syndrome as well as from inhibition of retinoic acid biosynthesis or signaling in experimental models. There is extensive biochemical and enzymatic overlap between ethanol clearance and retinoic acid biosynthesis. Several lines of evidence suggest that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for the aldehyde dehydrogenase activity available. In adults, this competition also extends to the alcohol dehydrogenase activity. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase, further supporting the competition model. All of the evidence supports the reduction of retinoic acid signaling as the etiological trigger in the induction of FASD.

Roux-en-Y Gastric Bypass Aggravates Vitamin A Deficiency in the Mother-Child Group.

OBJECTIVE: The objectives of this study are to compare the nutritional status of vitamin A in women who previously underwent Roux-en-Y gastric bypass (RYGB) who became pregnant or did not, in the same period after surgery, and to assess its effects on mother and child health. METHODOLOGY: A retrospective longitudinal study conducted with women who previously underwent RYGB, paired by age and BMI measured before surgery, divided into group 1 (G1) comprising 77 women who did not become pregnant and group 2 (G2) with 39 women in their third gestational trimester. Both groups were assessed before surgery (T0) and in the same interval after surgery: less than or equal to 1 year (T1) or over 1 year (T2), during a maximum of 2 years. Serum concentrations of retinol and ß-carotene, night blindness (NB), and gestational and neonatal complications were investigated [urinary tract infection, iron deficiency anemia, hypertensive syndrome of pregnancy, dumping syndrome, birth weight, gestational age at birth (GAB), and correlation between weight and GAB]. Data were analyzed by the Statistical Package for Social Sciences 21.0 (p < 0.05). RESULTS: RYGB reduced the serum levels of retinol and ß-carotene, especially before the first postsurgical year. When associated with pregnancy, inadequacy rate was 55% higher in T1 and T2. Comparing G1 to G2, we noted that pregnancy in women undergoing RYGB can contribute to increased inadequacy of retinol and ß-carotene, reaching a higher percentage of women with NB after 1 postsurgical year. High prevalence of pregnancy/neonatal complications was found in T1 and T2. NB was correlated with inadequacy of ß-carotene. CONCLUSION: Pregnancy after RYGB aggravates vitamin A deficiency, increases the percentage of NB cases, and can contribute to pregnancy and neonatal complications even in 1 postsurgical year.

All-trans retinoic acid ameliorates hepatic stellate cell activation via suppression of thioredoxin interacting protein expression.

Activation of hepatic stellate cells (HSCs) is the effector factor of hepatic fibrosis and hepatocellular carcinoma (HCC) development. Accumulating evidence suggests that retinoic acids (RAs), derivatives of vitamin A, contribute to prevention of liver fibrosis and carcinogenesis, however, regulatory mechanisms of RAs still remain exclusive. To elucidate RA signaling pathway, we previously performed a genome-wide screening of RA-responsive genes by in silico analysis of RA-response elements, and identified 26 RA-responsive genes. We found that thioredoxin interacting protein (TXNIP), which inhibits antioxidant activity of thioredoxin (TRX), was downregulated by all-trans retinoic acid (ATRA). In the present study, we demonstrate that ATRA ameliorates activation of HSCs through TXNIP suppression. HSC activation was attenuated by TXNIP downregulation, whereas potentiated by TXNIP upregulation, indicating that TXNIP plays a crucial role in activation of HSCs. Notably, we showed that TXNIP-mediated HSC activation was suppressed by antioxidant N-acetylcysteine. In addition, ATRA treatment or downregulation of TXNIP clearly declined oxidative stress levels in activated HSCs. These data suggest that ATRA plays a key role in inhibition of HSC activation via suppressing TXNIP expression, which reduces oxidative stress levels.