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.

COVID-19 and nutritional deficiency: a review of existing knowledge.

COVID-19 has resulted in an ongoing global pandemic, which spread largely among people who have had close contact with the infected person. The immunopathology of the SARS-CoV-2 virus includes the production of an excess amount of pro-inflammatory cytokines "a cytokine-storm". The respiratory system (main), cardiovascular system and the gastrointestinal tract are the most affected body systems during viral infection. It has been found that most of the patients who require admission to hospital are elderly or have chronic underlying diseases. Higher cases of malnutrition and co-morbidities like diabetes mellitus and cardiovascular diseases are reported in elderly patients due to which, the immune system weakens and hence, the response to the virus is diminished in magnitude. A deficiency of micronutrients results in impaired immune responses leading to improper secretion of cytokines, alterations in secretory antibody response and antibody affinity which increases susceptibility to viral infection. The deficiency of various micronutrients in COVID-19 patient can be treated by appropriate nutritional supplements, prescribed after evaluating the patients' nutritional status. Here we aim to highlight the role of a few particular nutrients namely Vitamin D, Vitamin C, Omega-3 fatty acids, Zinc and Magnesium along with the synergistic roles they play in enhancing immunity and thus, maintaining homeostasis.

A comparison of the chemical biology of hydropersulfides (RSSH) with other protective biological antioxidants and nucleophiles.

The hydropersulfide (RSSH) functional group has received significant recent interest due to its unique chemical properties that set it apart from other biological species. The chemistry of RSSH predicts that one possible biological role may be as a protectant against cellular oxidative and electrophilic stress. That is, RSSH has reducing and nucleophilic properties that may combat the potentially destructive biochemistry of toxicologically relevant oxidants and electrophiles. However, there are currently numerous other molecules that have established roles in this regard. For example, ascorbate and tocopherols are potent antioxidants that quench deleterious oxidative reactions and glutathione (GSH) is a well-established and highly prevalent biological protectant against electrophile toxicity. Thus, in order to begin to understand the possible role of RSSH species as protectants against oxidative/electrophilic stress, the inherent chemical properties of RSSH versus these other protectants will be discussed and contrasted.

The Role of Physiological Vitamin C Concentrations on Key Functions of Neutrophils Isolated from Healthy Individuals.

Vitamin C (ascorbate) is important for neutrophil function and immune health. Studies showing improved immune function have primarily used cells from scorbutic animals or from individuals with infectious conditions or immune cell disorders. Few studies have focused on the requirements of neutrophils from healthy adults. Therefore, we have investigated the role of vitamin C, at concentrations equivalent to those obtained in plasma from oral intakes (i.e., 50-200 µmol/L), on key functions of neutrophils isolated from healthy individuals. Cells were either pre-loaded with dehydroascorbic acid, which is rapidly reduced intracellularly to ascorbate, or the cells were activated in the presence of extracellular ascorbate. We measured the effects of enhanced ascorbate uptake on the essential functions of chemotaxis, oxidant production, programmed cell death and neutrophil extracellular trap (NET) formation. We found that neutrophils isolated from healthy individuals already had replete ascorbate status (0.35 nmol/106 cells), therefore they did not uptake additional ascorbate. However, they readily took up dehydroascorbic acid, thus significantly increasing their intracellular ascorbate concentrations, although this was found to have no additional effect on superoxide production or chemotaxis. Interestingly, extracellular ascorbate appeared to enhance directional mobilityin the presence of the chemoattractant formyl-methionyl-leucyl-phenylalanine (fMLP). Stimulation of the cells in the presence of ascorbate significantly increased intracellular ascorbate concentrations and, although this exhibited a non-significant increase in phosphatidylserine exposure, NET formation was significantly attenuated. Our findings demonstrate the ability of neutrophils to regulate their uptake of ascorbate from the plasma of healthy humans to maintain an optimal level within the cell for proper functioning. Higher oral intakes, however, may help reduce tissue damage and inflammatory pathologies associated with NET formation.

Water-Soluble Vitamins in Human Milk Factors Affecting Their Concentration and Their Physiological Significance.

Most B vitamins and vitamin C are among the nutrients in milk most strongly affected by maternal status and/or dietary intake. Recent analytical methods are more efficient and valid, revealing major differences in water-soluble vitamins across population groups. An inadequate supply in milk can be detrimental to the breastfed infant's health and development although cutoff points below which risk is increased are often uncertain, and little attention has been paid to adverse effects of low milk water-soluble vitamins on infant health and function. Concentrations change during lactation: thiamine, niacin, and pantothenic acid increase; B6, B12, and ascorbic acid gradually decrease; while riboflavin concentrations are stable, as is choline after an initial increase. Folate fluctuates until stabilizing in late lactation. Water-soluble vitamin concentrations in milk are also influenced by maternal supplementation, and, for some, by parity, preterm delivery, smoking, and maternal illness. However, there is relatively little change in concentrations during a feed nor is diurnal variation a major influence. Reported concentrations are used to set adequate intakes for infants and incremental requirements for lactation. However, the status of available data is poor due to the small number of participants in most studies, uncertainties about maternal nutritional status, and variable times of milk collection postpartum.

Vitamin C and immune cell function in inflammation and cancer.

Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Intracellular levels generally respond to variations in plasma ascorbate availability, and a combination of inadequate intake and increased turnover during severe stress can result in low plasma ascorbate status. Intracellular ascorbate supports essential functions and, in particular, acts as an enzyme cofactor for Fe- or Cu-containing oxygenases. Newly discovered enzymes in this family regulate cell metabolism and epigenetics, and dysregulation of their activity can affect cell phenotype, growth and survival pathways, and stem cell phenotype. This brief overview details some of the recent advances in our understanding of how ascorbate availability can affect the hydroxylases controlling the hypoxic response and the DNA and histone demethylases. These processes play important roles in the regulation of the immune system, altering cell survival pathways, metabolism and functions.

The role of vitamin C in epigenetic regulation.

Vitamin C (L-ascorbic acid) is a micronutrient best known for its anti-scurvy activity in humans. Vitamin C is involved in many biological processes involving enzymatic reactions that are catalyzed by members of dioxygenases which use Fe(II) and 2-oxoglutarate as a co-substrate.The article reviews recent data that suggest the involvement of ascorbate in dioxygenases catalyzed chromatin and DNA modifications which thereby contribute to epigenetic regulation. Concerning chromatin modification, the dioxygenases are involved in distinct demethylation reactions with varying specificity for the position of the lysine on the target histone. TET hydroxylases catalyse the oxidation of methyl groups in the 5 position of cytosine in DNA yielding 5-hydroxymethylcytosine, while further iterative oxidation reactions results in the formation of 5-formylcytosine and 5-carboxylcytosine. A few previous studies demonstrated that ascorbate may enhance generation of 5-hydroxymethylcytosine in cultured cells, probably acting as a cofactor of TETs during hydroxylation of 5-methylcytosine. Physiological concentrations of ascorbate in human serum (10-100 µM) may guarantee stable level of 5-hydroxymethylcytosine, a modification necessary for epigenetic function of the cell. 5-Hydroxymethylcytosine level is substantially decreased in almost all investigated cancers, what may be linked with cancer development. Therefore, it is possible that supplementation with ascorbate could contribute to better management of individual cancer patient. This issue is also discussed in our paper.

Ascorbic acid accumulates as a defense response to Turnip mosaic virus in resistant Brassica rapa cultivars.

We initially observed that Brassica rapa cultivars containing the Turnip mosaic virus (TuMV) resistance gene, Rnt1-1, accumulated a high level of endogenous ascorbic acid (AS) and dehydroascobic acid (DHA) when infected with TuMV. We here hypothesized a possible contribution of an elevated level of AS+DHA (TAA) to the Rnt1-1-mediated resistance, and conducted a series of experiments using B. rapa and Arabidopsis plants. The application of l-galactose (the key substrate in AS synthesis) to a susceptible cultivar could increase the TAA level ~2-fold, and simultaneously lead to some degree of enhanced viral resistance. To confirm some positive correlation between TAA levels and viral resistance, we analyzed two Arabidopsis knockout mutants (ao and vtc1) in the AS pathways; the TAA levels were significantly increased and decreased in ao and vtc1 plants, respectively. While the ao plants showed enhanced resistance to TuMV, vtc1 plants were more susceptible than the control, supporting our hypothesis. When we analyzed the expression profiles of the genes involved in the AS pathways upon TuMV infection, we found that the observed TAA increase was mainly brought about by the reduction of AS oxidation and activation of AS recycling. We then investigated the secondary signals that regulate endogenous TAA levels in response to viral infection, and found that jasmonic acid (JA) might play an important role in TAA accumulation. In conclusion, we reason that the elevated TAA accumulation in B. rapa plants would be at least partly mediated by the JA-dependent signaling pathway and may significantly contribute to viral resistance.

Ascorbic acid intake and oxalate synthesis.

In humans, approximately 60 mg of ascorbic acid (AA) breaks down in the body each day and has to be replaced by a dietary intake of 70 mg in women and 90 mg in men to maintain optimal health and AA homeostasis. The breakdown of AA is non-enzymatic and results in oxalate formation. The exact amount of oxalate formed has been difficult to ascertain primarily due to the limited availability of healthy human tissue for such research and the difficulty in measuring AA and its breakdown products. The breakdown of 60 mg of AA to oxalate could potentially result in the formation of up to 30 mg oxalate per day. This exceeds our estimates of the endogenous production of 10-25 mg oxalate per day, indicating that degradative pathways that do not form oxalate exist. In this review, we examine what is known about the pathways of AA metabolism and how oxalate forms. We further identify how gaps in our knowledge may be filled to more precisely determine the contribution of AA breakdown to oxalate production in humans. The use of stable isotopes of AA to directly assess the conversion of vitamin to oxalate should help fill this void.

Vitamin C: the known and the unknown and Goldilocks.

Vitamin C (Ascorbic Acid), the antiscorbutic vitamin, cannot be synthesized by humans and other primates, and has to be obtained from diet. Ascorbic acid is an electron donor and acts as a cofactor for fifteen mammalian enzymes. Two sodium-dependent transporters are specific for ascorbic acid, and its oxidation product dehydroascorbic acid is transported by glucose transporters. Ascorbic acid is differentially accumulated by most tissues and body fluids. Plasma and tissue vitamin C concentrations are dependent on amount consumed, bioavailability, renal excretion, and utilization. To be biologically meaningful or to be clinically relevant, in vitro and in vivo studies of vitamin C actions have to take into account physiologic concentrations of the vitamin. In this paper, we review vitamin C physiology; the many phenomena involving vitamin C where new knowledge has accrued or where understanding remains limited; raise questions about the vitamin that remain to be answered; and explore lines of investigations that are likely to be fruitful.

[Dual action of vitamin C versus degradation and supplementation]. / Dwukierunkowe dzialanie witaminy C a degradacja i suplementacja.

The article discusses vitamin C from the point of view of its supplementation with food and in the form of oral supplements. The dual action of vitamin C is connected with the presence of oxygen, which may reduce the amount of the vitamin in food products, influence thermal resistance, cause degradation and show an antioxidation effect. Vitamin C stimulates the immune cells and collagen synthesis. It may protect the LDL fraction against oxidation, and therefore it is interesting for cosmetology, rheumatology, immunology and dietetics. The latest research with respect to vitamin C proved that it has the ability to dissolve neurotoxic senile plaques. Equally effective in the treatment of Alzheimer's disease is the oxidised form of vitamin C, i.e. dehydroascorbic acid. Vitamin C may be used in a combined vitamin E supplementation to avoid the pro-oxidative effect and reduce the risk of diabetes mellitus type 2 complications. In the review there is a description of the types of vitamin C degradation depending on a specific factor such as pH, temperature, oxygen, enzyme and the impact of diet on the quantity of the supplied vitamin. The literature data confirmed the positive influence of vitamin C as an addition to food. The last part of the article presents the methods of vitamin C protection used in food processing technology and of determining its content in food products. Additionally, the article describes the problems related to vitamin C oxidation processes during food processing and storage. The presented research results indicate that an adequate diet contains a sufficient amount of vitamin C for healthy people. In the case of chronic patients it is better to use supplementation.

Heavy Metals and Human Health: Mechanistic Insight into Toxicity and Counter Defense System of Antioxidants.

Heavy metals, which have widespread environmental distribution and originate from natural and anthropogenic sources, are common environmental pollutants. In recent decades, their contamination has increased dramatically because of continuous discharge in sewage and untreated industrial effluents. Because they are non-degradable, they persist in the environment; accordingly, they have received a great deal of attention owing to their potential health and environmental risks. Although the toxic effects of metals depend on the forms and routes of exposure, interruptions of intracellular homeostasis include damage to lipids, proteins, enzymes and DNA via the production of free radicals. Following exposure to heavy metals, their metabolism and subsequent excretion from the body depends on the presence of antioxidants (glutathione, α-tocopherol, ascorbate, etc.) associated with the quenching of free radicals by suspending the activity of enzymes (catalase, peroxidase, and superoxide dismutase). Therefore, this review was written to provide a deep understanding of the mechanisms involved in eliciting their toxicity in order to highlight the necessity for development of strategies to decrease exposure to these metals, as well as to identify substances that contribute significantly to overcome their hazardous effects within the body of living organisms.

Ascorbic acid regulation in stress responses during acute cold exposure and following recovery in juvenile Chinese soft-shelled turtle (Pelodiscus sinensis).

Intense temperature change often leads to increased oxidative stress in many animals with a few exceptions, including the turtle. To date, little is known about the mechanism of protective antioxidative defenses in turtles during acute temperature change, specifically the role that the antioxidant ascorbic acid (AA) plays. In this study, Chinese soft-shelled turtles (Pelodiscus sinensis) were initially acclimated at 28°C (3 wks), exposed to acute cold condition (8°C, 8 h) and finally placed in recovery (28°C, 24 h). L-Gulonolactone oxidase (GLO) mRNA exhibited a stable transcription pattern during the intense thermal fluctuation. GLO activity also remained stable, which validated the mRNA expression pattern. The similar Q10 values for GLO activity in the different treatment groups at incubation temperatures of 28°C and 8°C indicated that the GLO activity response to thermal change exhibited a temperature-dependent enzymatic kinetic characteristic. The AA storage was tissue-specific as well as the AA re-supply in the recovery period, with brain as the priority. Despite the insufficient transport during cold exposure, the plasma AA reservoir greatly contributed to the redistribution of AA during recovery. Depending on the prominent GLO activity, the high level of tissue-specific AA storage and the extraordinary plasma AA transport potential, the Chinese soft-shelled turtle endured severe thermal fluctuations with no apparent oxidative stress. However, the significant decrease in AA concentration in the brain tissue during acute cold exposure suggested that such a strategy may not be sufficient for prolonged cold exposure.

Nitric oxide participates in the regulation of the ascorbate-glutathione cycle by exogenous jasmonic acid in the leaves of wheat seedlings under drought stress.

In this paper, we investigated whether nitric oxide (NO) participated in the regulation of the ascorbate-glutathione (AsA-GSH) cycle by exogenous jasmonic acid (JA) in the leaves of wheat seedlings under drought stress. The findings of our study showed that drought stress significantly enhanced the AsA-GSH cycle by upregulating the activities of ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), and dehydroascorbate reductase (DHAR). Drought stress also markedly increased electrolyte leakage (EL), malondialdehyde (MDA) content, NO content, and significantly reduced the ratios of reduced ascorbate/dehydroascorbic acid (AsA/DHA) and reduced glutathione/oxidized glutathione (GSH/GSSG) compared with control. Exogenous JA significantly increased the above indicators, compared with drought stress alone. All these effects of JA were inhibited by pretreatment with NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). Meanwhile, exogenous JA markedly decreased MDA content and electrolyte leakage of wheat leaves under drought stress. Pretreatment with cPTIO reversed the above effects of exogenous JA. Our findings indicated that NO induced by exogenous JA upregulated the activity of the AsA-GSH cycle and had important role in drought tolerance.

[Vitamin C­ structure, properties, occurrence and functions].

In this paper the structure of vitamin C, its physical and chemical characteristics, and occurrence are presented. The biological role of ascorbic acid, the human body's demand for this vitamin, and its deficiency symptoms are specified.

There's life in the old dog yet: vitamin C as a therapeutic option in endothelial dysfunction.

The use of vitamin C against different diseases has been controversially and emotionally discussed since Linus Pauling published his cancer studies. In vitro and animal studies showed promising results and explained the impact of vitamin C, particularly in cases with endothelial dysfunction. Indeed, studies (reviewed in this issue of Critical Care by Oudemans-van Straaten and colleagues) using high-dose vitamin C and the parenteral route of application seem to be more successful than oral vitamin C delivery.

Vitamin C revisited.

This narrative review summarizes the role of vitamin C in mitigating oxidative injury-induced microcirculatory impairment and associated organ failure in ischemia/reperfusion or sepsis. Preclinical studies show that high-dose vitamin C can prevent or restore microcirculatory flow impairment by inhibiting activation of nicotinamide adenine dinucleotide phosphate-oxidase and inducible nitric oxide synthase, augmenting tetrahydrobiopterin, preventing uncoupling of oxidative phosphorylation, and decreasing the formation of superoxide and peroxynitrite, and by directly scavenging superoxide. Vitamin C can additionally restore vascular responsiveness to vasoconstrictors, preserve endothelial barrier by maintaining cyclic guanylate phosphatase and occludin phosphorylation and preventing apoptosis. Finally, high-dose vitamin C can augment antibacterial defense. These protective effects against overwhelming oxidative stress due to ischemia/reperfusion, sepsis or burn seems to mitigate organ injury and dysfunction, and promote recovery after cardiac revascularization and in critically ill patients, in the latter partially in combination with other antioxidants. Of note, several questions remain to be solved, including optimal dose, timing and combination of vitamin C with other antioxidants. The combination obviously offers a synergistic effect and seems reasonable during sustained critical illness. High-dose vitamin C, however, provides a cheap, strong and multifaceted antioxidant, especially robust for resuscitation of the circulation. Vitamin C given as early as possible after the injurious event, or before if feasible, seems most effective. The latter could be considered at the start of cardiac surgery, organ transplant or major gastrointestinal surgery. Preoperative supplementation should consider the inhibiting effect of vitamin C on ischemic preconditioning. In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.

The effect of vitamin C intake on the risk of hyperuricemia and serum uric acid level in Korean Multi-Rural Communities Cohort.

OBJECTIVE: The aim of this study was to determine the association between vitamin C intake and risk of hyperuricemia or serum uric acid levels in male and female subjects in the Korean Multi-Rural Communities Prospective Cohort. METHODS: This cross-sectional analysis was conducted in 9400 subjects enrolled in the Korean Multi-Rural Communities Cohort Study. The risk of hyperuricemia was assessed in five quintiles (Q1 to Q5) according to dietary and total vitamin C intake using multivariate-adjusted logistic regression models. Relationships between serum uric acid levels and vitamin C intake were evaluated using linear regression analysis after adjustment for covariates. Information about dietary components was collected using validated food frequency questionnaires. RESULTS: Dietary vitamin C intake, but not total vitamin C intake, was significantly different between hyperuricemic and non-hyperuricemic subjects in males (P=0.01) and females (P=0.02). The risk of hyperuricemia decreased with increased dietary vitamin C intake in male and female subjects after multivariate adjustment (P for trend=0.002 in males and P for trend=0.02 in females). An effect of total vitamin C intake on hyperuricemia risk was identified in females (P for trend=0.04), but not males (P for trend=0.06). Serum uric acid level was linearly associated with total vitamin C intake in females (ß=-0.0001, P=0.01), but not with dietary vitamin C intake in either gender. CONCLUSION: This study showed that vitamin C intake might be in part responsible for hyperuricemia or serum uric acid level in the Korean Multi-Rural Communities Cohort.

Antioxidants in food: content, measurement, significance, action, cautions, caveats, and research needs.

There are a multitude of antioxidants in foods, especially in foods of plant origin. Higher intake of antioxidant-rich foods is clearly associated with better health and functional longevity. The specific agents and mechanisms responsible are not yet clear, but there is convincing evidence that including more plant-based, antioxidant-rich foods, herbs, and beverages in the diet is effective in promoting health and lowering risk of various age-related diseases. The content of some individual antioxidants, such as vitamin C, in food can be measured, but it is not feasible to attempt to measure each antioxidant separately, and methods have been developed to assess the "total antioxidant content" of foods. One of the most widely used methods is the ferric reducing/antioxidant power (FRAP) assay, which is relatively simple, quick, sensitive, and inexpensive to perform. There are many published studies that have used the FRAP assay, and these have generated a very large database of total antioxidant content of foods that can help guide food choices for increased antioxidant intake. The FRAP assay has also been used to assess the bioavailability of antioxidants in foods and to investigate the effects of growing conditions, storage, processing, and cooking method on the total antioxidant content of food. The test can be employed as a quality control check device, and to detect adulteration of food. Furthermore, in a modified form (FRASC), the assay can measure ascorbic acid content almost simultaneously with the total antioxidant content of the sample. In this chapter, basic concepts of oxidation and the role of antioxidants, as well as the types and action of different antioxidants in foods will be reviewed briefly, and the underpinning concepts and evidence for health benefits of increased intake of dietary antioxidants will be discussed, with some focus on vitamin C, and also in the context of our evolutionary development. The basic concepts and limitations of measuring "total antioxidant content" of food will be presented. The FRAP assay and the modified version FRASC will be described, and the total antioxidant content (as the FRAP value) of a range of foods will be presented. Finally, issues of bioavailability and redox balance will be discussed in relation to the biological significance and molecular action of antioxidants in foods, some caution and caveats are presented about overcoming biological barriers to absorption of antioxidant phytochemicals, and research needs to further our understanding in the important area of food, antioxidants, and health will be highlighted.