Maternal vitamin C regulates reprogramming of DNA methylation and germline development.

Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3-7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8-10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11-15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.

TET family dioxygenases and the TET activator vitamin C in immune responses and cancer.

Vitamin C serves as a cofactor for Fe(II) and 2-oxoglutarate-dependent dioxygenases including TET family enzymes, which catalyze the oxidation of 5-methylcytosine into 5-hydroxymethylcytosine and further oxidize methylcytosines. Loss-of-function mutations in epigenetic regulators such as TET genes are prevalent in hematopoietic malignancies. Vitamin C deficiency is frequently observed in cancer patients. In this review, we discuss the role of vitamin C and TET proteins in cancer, with a focus on hematopoietic malignancies, T regulatory cells, and other immune system cells.

Any Role of High-Dose Vitamin C for Septic Shock in 2021?

While the use of vitamin C as a therapeutic agent has been investigated since the 1950s, there has been substantial recent interest in the role of vitamin C supplementation in critical illness and particularly, sepsis and septic shock. Humans cannot synthesize vitamin C and rely on exogenous intake to maintain a plasma concentration of approximately 70 to 80 µmol/L. Vitamin C, in healthy humans, is involved with antioxidant function, wound healing, endothelial function, and catecholamine synthesis. Its function in the human body informs the theoretical basis for why vitamin C supplementation may be beneficial in sepsis/septic shock.Critically ill patients can be vitamin C deficient due to low dietary intake, increased metabolic demands, inefficient recycling of vitamin C metabolites, and loss due to renal replacement therapy. Intravenous supplementation is required to achieve supraphysiologic serum levels of vitamin C. While some clinical studies of intravenous vitamin C supplementation in sepsis have shown improvements in secondary outcome measures, none of the randomized clinical trials have shown differences between vitamin C supplementation and standard of care and/or placebo in the primary outcome measures of the trials. There are some ongoing studies of high-dose vitamin C administration in patients with sepsis and coronavirus disease 2019; the majority of evidence so far does not support the routine supplementation of vitamin C in patients with sepsis or septic shock.

Ascorbate: antioxidant and biochemical activities and their importance for in vitro models.

Ascorbate has many biological activities that involve fundamental cellular functions such as gene expression, differentiation, and redox homeostasis. Biochemically, it serves as a cofactor for a large family of dioxygenases (> 60 members) which control transcription, formation of extracellular matrix, and epigenetic processes of histone and DNA demethylation. Ascorbate is also a major antioxidant acting as a very effective scavenger of primary reactive oxygen species. Reduction of Fe(III) by ascorbate is important for cellular uptake of iron via DMT1. Cell culture models are extensively used in toxicology and pharmacology for mechanistic studies of nutrients, drugs and other xenobiotics. High-throughput screens in vitro, such as a large-scale Tox21 program in the US, offers opportunities to assess hazardous properties of a vast and growing number of industrial chemicals. However, cells in typical cultures are severely deficient in ascorbate, raising concerns about their ability to accurately recapitulate toxic and other responses in vivo. Scarcity of ascorbate and a frequently unrecognized use of media with its thiol substitute alters stress sensitivity of cells in different directions. Remediation of ascorbate deficiency in tissue culture restores the physiological state of many cellular processes and it should improve a currently limited toxicity predictability of in vitro bioassays.

The neuropsychiatric effects of vitamin C deficiency: a systematic review.

BACKGROUND: Vitamin C deficiency may be more common than is generally assumed, and the association between vitamin C deficiency and adverse psychiatric effects has been known for centuries. This paper aims to systematically review the evidence base for the neuropsychiatric effects of vitamin C deficiency. METHODS: Relevant studies were identified via systematic literature review. RESULTS: Nine studies of vitamin C deficiency, including subjects both with and without the associated physical manifestations of scurvy, were included in this review. Vitamin C deficiency, including scurvy, has been linked to depression and cognitive impairment. No effect on affective or non-affective psychosis was identified. CONCLUSIONS: Disparate measurement techniques for vitamin C, and differing definitions of vitamin C deficiency were apparent, complicating comparisons between studies. However, there is evidence suggesting that vitamin C deficiency is related to adverse mood and cognitive effects. The vitamin C blood levels associated with depression and cognitive impairment are higher than those implicated in clinical manifestations of scurvy. While laboratory testing for ascorbic acid can be practically difficult, these findings nonetheless suggest that mental health clinicians should be alerted to the possibility of vitamin C deficiency in patients with depression or cognitive impairment. Vitamin C replacement is inexpensive and easy to deliver, although as of yet there are no outcome studies investigating the neuropsychiatric impact of vitamin C replacement in those who are deficient.

Lessons in early identification and treatment from a case of disabling vitamin C deficiency in a child with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder is a heterogenous neurodevelopmental condition accompanied by a variety of associated features. Case reports suggest one such associated feature, food selectivity, increases risk for nutritional deficiencies; however, little attention has been given to prevent and treat nutritional deficiencies in youth with autism spectrum disorder. METHOD: Single case report. RESULTS: This single case report presents a child with autism spectrum disorder and food selectivity difficulties that resulted in severe vitamin C deficiency. Although eventually corrected, the nutritional deficiency was debilitating, required invasive interventions, and resulted in significant social/emotional and economic costs. CONCLUSIONS: We review the course of treatment and highlight strategies to prevent and more effectively treat nutritional deficiencies in youth with autism spectrum disorder.

Dietary vitamin C deficiency depresses the growth, head kidney and spleen immunity and structural integrity by regulating NF-κB, TOR, Nrf2, apoptosis and MLCK signaling in young grass carp (Ctenopharyngodon idella).

This study investigated the effects of dietary vitamin C on the growth, and head kidney, spleen and skin immunity, structural integrity and related signaling molecules mRNA expression levels of young grass carp (Ctenopharyngodon idella). A total of 540 grass carp (264.37 ± 0.66 g) were fed six diets with graded levels of vitamin C (2.9, 44.2, 89.1, 133.8, 179.4 and 224.5 mg/kg diet) for 10 weeks. Subsequently, a challenge test was conducted by injection of Aeromonas hydrophila and the survival rate recorded for 14 days. The results indicated that compared with optimal vitamin C supplementation, vitamin C deficiency (2.9 mg/kg diet) decreased lysozyme (LA) and acid phosphatase (ACP) activities, and complement 3 and complement 4 (C4) contents (P < 0.05), down-regulated the mRNA levels of antimicrobial peptides [liver expressed antimicrobial peptide (LEAP) 2A, LEAP-2B, hepcidin, ß-defensin] and anti-inflammatory cytokines-related factors, interleukin (IL) 4/13A, IL-4/13B (only in head kidney), IL-10, IL-11, transforming growth factor (TGF) ß1, TGF-ß2, inhibitor of κBα and eIF4E-binding protein 1 (P < 0.05), and up-regulated pro-inflammatory cytokines-related factors, tumor necrosis factor α, interferon γ2, IL-1ß, IL-6, IL-8, IL-12 P35 (only in spleen), IL-12 P40, IL-15, IL-17D, nuclear factor κB p65, IκB kinases (IKKα, IKKß, IKKγ), target of rapamycin and ribosomal protein S6 kinase 1 mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen immunity and cause inflammation. Meanwhile, compared with optimal vitamin C supplementation, vitamin C deficiency decreased the activities and mRNA levels of copper/zinc superoxide dismutase, manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase, glutathione S-transferases and glutathione reductase (P < 0.05), and down-regulated zonula occludens (ZO) 1, ZO-2, Claudin-b, -c, -3c, -7a, -7b, B-cell lymphoma-2, inhibitor of apoptosis protein, NF-E2-related factor 2 mRNA levels (P < 0.05), increased reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl contents (P < 0.05), and up-regulated Claudin-12, 15a, -15b, Fas ligand, mitogen-activated protein kinase kinase 6, p38 mitogen-activated protein kinase, B-cell lymphoma protein 2 associated X protein, apoptotic protease activating factor-1, caspase-3, -7, -8, -9, Kelch-like ECH-associating protein (Keap) 1a and Keap 1b mRNA levels (P < 0.05) in the head kidney and spleen under injection fish of A. hydrophila, suggesting that vitamin C deficiency could decrease fish head kidney and spleen structural integrity through depression of antioxidative ability, induction of apoptosis and disruption of tight junctional complexes. In addition, except the activities of ACP and MnSOD, and mRNA expression levels of TGF-ß1, Occludin and MnSOD, the effect of vitamin C on fish head kidney, spleen and skin immunity and structural integrity other indicators model are similar under infection of A. hydrophila. Finally, the vitamin C requirement for the growth performance (PWG) of young grass carp was estimated to be 92.8 mg/kg diet. Meanwhile, the vitamin C requirement for against skin lesion morbidity of young grass carp was estimated to be 122.9 mg/kg diet. In addition, based on the biochemical indices [immune indices (LA activity in the head kidney and C4 content in the spleen) and antioxidant indices (MDA content in the head kidney and ROS content in the spleen)] the vitamin C requirements for young grass carp were estimated to be 131.2, 137.5, 135.8 and 129.8 mg/kg diet, respectively.

High dietary intake of vitamin C suppresses age-related thymic atrophy and contributes to the maintenance of immune cells in vitamin C-deficient senescence marker protein-30 knockout mice.

Vitamin C (VC) is an essential nutrient for humans and certain other animals. It has antioxidant properties and has been reported to ameliorate oxidative damage to lipids, DNA and proteins. However, the effects of VC on immune function are poorly understood, especially the influence of long-term high-dose VC intake on the number and function of immune cells. In the present study, to evaluate the immune effects of VC, VC-deficient senescence marker protein-30 knockout (SMP30KO) mice were fed a diet containing the recommended level of VC (20 mg/kg per d; 0·02 % VC) or a high level of VC (200 mg/kg per d; 0·2 % VC) for 1 year. The plasma VC concentration of the 0·02 % group was the same as that of age-matched C57BL/6 mice after 1 year of feeding; however, plasma VC concentration and thymus weight were significantly higher in the 0·2 % VC group than in the 0·02 % VC group. The total counts of leucocytes, lymphocytes, granulocytes and monocytes in the peripheral blood, as well as the number of splenocytes and thymocytes, were all significantly higher in the 0·2 % VC group than in the 0·02 % VC group. In addition, the number of naive T cells in peripheral blood lymphocytes, the number of memory T-cell populations in splenocytes, and the number of cluster of differentiation (CD)4⁺CD8⁺ or CD4⁺CD8⁻ or CD4⁻CD8⁺ T cells in thymocytes were all markedly higher in the 0·2 % VC group than in the 0·02 % VC group after 1 year of dietary treatment. These results suggest that a long-term high-dose intake of VC is effective in the maintenance of immune cells, partly through the suppression of age-related thymic involution in VC-deficient SMP30KO mice.

A review of the literature regarding nutritional supplements and their effect on vaginal flora and preterm birth.

PURPOSE OF REVIEW: The aim of this review was to evaluate recently published review articles which examine the use of nutritional supplements to prevent preterm birth (PTB) by modifying vaginal bacteria. RECENT FINDINGS: Probiotics, vitamin D and vitamin C were all identified as nutritional supplements that have the potential to alter bacterial flora and consequently reduce PTB and treat or prevent genital infections. Evidence shows that probiotics may reduce the incidence of PTB as well as being effective at treating bacterial vaginosis, a known cause for PTB. Low vitamin D levels may be associated with bacterial vaginosis, although no evidence was identified which demonstrated that vitamin D supplementation reduced the risk of having bacterial vaginosis or PTB.There is little evidence regarding vitamin C supplementation, although it does suggest a possible benefit with regard to preterm rupture of membranes; however, this did not appear to reduce rates of PTB. SUMMARY: Although there is evidence that taking probiotics in pregnancy may reduce the incidence of PTB, it is mainly derived from small, poor quality studies. Vitamin D and vitamin C may have potential benefits, but these remain to be proven. Large randomized controlled trials are needed to more accurately evaluate the potential benefits of these low-cost interventions for reducing PTB and its consequences.

Behavioral and monoamine changes following severe vitamin C deficiency.

Severe vitamin C deficiency (ascorbic acid; AA) was induced in gulo-/- mice incapable of synthesizing their own AA. A number of behavioral measures were studied before and during the deprivation period, including a scorbutic period, during which weight loss was observed in the mice. Mice were then resuscitated with AA supplements. During the scorbutic period, gulo-/- mice showed decreased voluntary locomotor activity, diminished physical strength, and increased preference for a highly palatable sucrose reward. These behaviors all returned to control levels following resuscitation. Altered trial times in subordinate mice in the tube test for social dominance in the AA-deprived mice persisted following resuscitation and may signify a depressive-like behavior in these mice. Biochemical analyses were undertaken following a second deprivation period. AA deficiency was accompanied by decreased blood glucose levels, oxidative damage to lipids and proteins in the cortex, and decreases in dopamine and serotonin metabolites in both the cortex and striatum. Given the reasonably high proportions of the population that do not consume sufficient AA in the diet, these data have important implications for physical and psychological function in the general population.

Recent applications of engineered animal antioxidant deficiency models in human nutrition and chronic disease.

Dietary antioxidants are essential nutrients that inhibit the oxidation of biologically important molecules and suppress the toxicity of reactive oxygen or nitrogen species. When the total antioxidant capacity is insufficient to quench these reactive species, oxidative damage occurs and contributes to the onset and progression of chronic diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancer. However, epidemiological studies that examine the relationship between antioxidants and disease outcome can only identify correlative associations. Additionally, many antioxidants also have prooxidant effects. Thus, clinically relevant animal models of antioxidant function are essential for improving our understanding of the role of antioxidants in the pathogenesis of complex diseases as well as evaluating the therapeutic potential and risks of their supplementation. Recent progress in gene knockout mice and virus-based gene expression has potentiated these areas of study. Here, we review the current genetically modified animal models of dietary antioxidant function and their clinical relevance in chronic diseases. This review focuses on the 3 major antioxidants in the human body: vitamin C, vitamin E, and uric acid. We examine genetic models of vitamin C synthesis (guinea pig, Osteogenic Disorder Shionogi rat, Gulo(-/-) and SMP30(-/-) mouse mutants) and transport (Slc23a1(-/-) and Slc23a2(-/-) mouse mutants), vitamin E transport (Ttpa(-/-) mouse mutant), and uric acid synthesis (Uox(-/-) mouse mutant). The application of these models to current research goals is also discussed.

The discovery of vitamin C.

The term 'scurvy' for the disease resulting from prolonged vitamin C deficiency had origins in 'scorbutus' (Latin), 'scorbut' (French), and 'Skorbut' (German). Scurvy was a common problem in the world's navies and is estimated to have affected 2 million sailors. In 1747, James Lind conducted a trial of six different treatments for 12 sailors with scurvy: only oranges and lemons were effective in treating scurvy. Scurvy also occurred on land, as many cases occurred with the 'great potato famine' in Ireland in 1845. Many animals, unlike humans, can synthesize their own vitamin C. Axel Holst and Theodor Frölich fortuitously produced scurvy in the guinea pig, which like humans requires vitamin C in the diet. In 1928, Albert Szent-Györgyi isolated a substance from adrenal glands that he called 'hexuronic acid'. Four years later, Charles Glen King isolated vitamin C in his laboratory and concluded that it was the same as 'hexuronic acid'. Norman Haworth deduced the chemical structure of vitamin C in 1933.

Derivation and application of a mathematical model for long bone growth.

The objective of this work was to develop a mathematical model of long bone growth and to gain insights regarding growth disorders. A cell balance (mass balance of moving cells) assessment was performed on the three regions of the growth plate, to determine the variables (including number of proliferating cells, and division rate of proliferating cells) that influence tibia growth rate. Once this relationship was established, clinical data were used to understand how tibia growth rate and number of proliferating cells change with time. These equations were then inserted into the model to determine how cell division rate changes with time. The model was utilized to determine the influence of growth time, and to measure changes in vitamin C deficiency, Indian hedgehog (IHH) expression, and bone morphogenetic protein-2 (BMP-2) implants on tibia length. According to the model, a 10-month discrepancy in growth time between the two tibias is required to produce clinically significant leg asymmetry. In addition, vitamin C deficiency, IHH overexpression, and BMP-2 implants can all affect tibia length. These bioactive molecules have the greatest effect on tibia growth rate when these perturbations occur early in life for extended periods of time. The results are significant for modeling and predicting the effects of perturbations, including bioactive implants, on long bone growth.

Striae gravidarum, vitamin C and other related factors.

BACKGROUND: Striae gravidarum, a clinical condition commonly seen in pregnant women, produces serious cosmetic problems and may lead to psychological problems. AIM: The present study investigated whether there was any relation between the presence of striae in primigravid pregnant women and blood vitamin C levels, and factors thought to contribute to the formation of striae such as family history, weight gained during pregnancy, smoking status, abdominal and thigh circumference, and age. METHODS: Overall, 69 primigravid women attending routine antenatal follow-up and, using prophylactic iron and vitamin preparations, underwent investigation. All were pregnant 36 or more weeks. Scoring was based on striae examination and whether striae were present. The relation between the presence of striae, vitamin C blood levels, and other factors was investigated. RESULTS AND CONCLUSIONS: Multiple logistic regression analysis showed a significant relation between the presence of striae and blood vitamin C levels (p = 0.046) and between the presence of striae and family history (p = 0.023). No significant relation was found between the presence of striae and age, weight gained during pregnancy, abdominal and thigh circumference, or smoking status. It was concluded that further, more comprehensive studies on the issue are required.

Nutritional status of 8- to 12-year-old children with height below or at 25th percentile associated with height in the Seoul metropolitan area.

BACKGROUND: Childhood is the best time to establish healthful dietary habits through adulthood. However, as of yet, there is relatively little research on the nutritional status of children with low height. This study aimed to evaluate the nutritional status of school-aged children with low height. METHODS: This study was implemented in the Seoul metropolitan area with 8- to 12-year-old Korean children (n = 93) who fall below the 25th percentile (<= P25) for height. Nutritional status was assessed using anthropometry and dietary assessment. Dietary assessment was carried out using a 24-hour recall on a typical and quantitative food frequency questionnaire. The Pearson' s correlation analysis was conducted to determine associations between height and nutrient intake. RESULTS: The mean percentiles of height were 19.5(th) for boys, and 19.0(th) for girls, respectively. Nutrients ingested below the Estimated Average Requirement (EAR) of the Dietary Reference Intakes for Koreans (KDRIs), considered inadequate, were folic acid, calcium, vitamin C, and iron. Significant differences between recommended and consumed servings of food groups were observed in the meat, fish, egg, and legume group (p = 0.039), vegetable group (p < 0.001), and fruit group (p = 0.044). The height percentiles of the subjects were negatively correlated with calories derived from carbohydrates (p < 0.001). CONCLUSIONS: School-aged children living in the Seoul metropolitan area, with height <= P25, consumed inadequate nutrients and insufficient food groups, which may put the children in a low height percentile. More efforts to provide education on adequate dietary intake and to monitor the nutritional status of children are needed to improve dietary adequacy based on food groups and to increase the growth of children with low height.

Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination.

Vitamin C (L-ascorbic acid) has been known as an antioxidant for most people. However, its physiological role is much larger and encompasses very different processes ranging from facilitation of iron absorption through involvement in hormones and carnitine synthesis for important roles in epigenetic processes. Contrarily, high doses act as a pro-oxidant than an anti-oxidant. This may also be the reason why plasma levels are meticulously regulated on the level of absorption and excretion in the kidney. Interestingly, most cells contain vitamin C in millimolar concentrations, which is much higher than its plasma concentrations, and compared to other vitamins. The role of vitamin C is well demonstrated by miscellaneous symptoms of its absence-scurvy. The only clinically well-documented indication for vitamin C is scurvy. The effects of vitamin C administration on cancer, cardiovascular diseases, and infections are rather minor or even debatable in the general population. Vitamin C is relatively safe, but caution should be given to the administration of high doses, which can cause overt side effects in some susceptible patients (e.g., oxalate renal stones). Lastly, analytical methods for its determination with advantages and pitfalls are also discussed in this review.

Vitamin C deficiency mimicking inflammatory bone disease of the hand.

BACKGROUND: Severe vitamin C deficiency, or scurvy, encompasses a syndrome of multisystem abnormalities due to defective collagen synthesis and antioxidative functions. Among the more common presentations is a combination of oral or subcutaneous hemorrhage with lower extremity pain, the latter often exhibiting inflammatory bone changes on magnetic resonance imaging (MRI). CASE PRESENTATION: A 12-year-old male with anorexia nervosa presented with asymmetric painful swelling of multiple fingers of both hands. Imaging demonstrated soft tissue and bone marrow edema of several phalanges, without arthritis, concerning for an inflammatory process. Extensive imaging and laboratory evaluations were largely unrevealing, with the exception of a severely low vitamin C level and a moderately low vitamin D level. A diagnosis of scurvy was made and supplementation was initiated. Within 3 weeks of treatment, serum levels of both vitamins normalized and the digital abnormalities resolved on physical exam. CONCLUSIONS: This represents the first description of scurvy manifesting with bone and soft tissue changes limited to the hands. There must be a high index of suspicion for scurvy in children with restricted dietary intake or malabsorption who have bone pain, irrespective of location of the lesions.

Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence.

Vitamins and minerals are essential to humans as they play essential roles in a variety of basic metabolic pathways that support fundamental cellular functions. In particular, their involvement in energy-yielding metabolism, DNA synthesis, oxygen transport, and neuronal functions makes them critical for brain and muscular function. These, in turn, translate into effects on cognitive and psychological processes, including mental and physical fatigue. This review is focused on B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12), vitamin C, iron, magnesium and zinc, which have recognized roles in these outcomes. It summarizes the biochemical bases and actions of these micronutrients at both the molecular and cellular levels and connects them with cognitive and psychological symptoms, as well as manifestations of fatigue that may occur when status or supplies of these micronutrients are not adequate.