research article on vitamin c

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Vitamin C and Immune Function

Affiliations.

1 Department of Pathology, University of Otago, Christchurch, P.O. Box 4345, Christchurch 8140, New Zealand. [email protected].
2 Bayer Consumer Care Ltd., Peter-Merian-Strasse 84, 4002 Basel, Switzerland. [email protected].
PMID: 29099763
PMCID: PMC5707683
DOI: 10.3390/nu9111211

Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C supports epithelial barrier function against pathogens and promotes the oxidant scavenging activity of the skin, thereby potentially protecting against environmental oxidative stress. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen species, and ultimately microbial killing. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis/NETosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements. Furthermore, supplementation with vitamin C appears to be able to both prevent and treat respiratory and systemic infections. Prophylactic prevention of infection requires dietary vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e., 100-200 mg/day), which optimize cell and tissue levels. In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.

Keywords: ascorbate; ascorbic acid; immune system; immunity; infection; lymphocytes; microbial killing; neutrophil function; vitamin C.

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Conflict of interest statement

S.M. is employed by Bayer Consumer Care Ltd., a manufacturer of multivitamins, and wrote the section on ‘Vitamin C insufficiency conditions’. A.C.C. has received funding, as a Key Opinion Leader, from Bayer Consumer Care Ltd.

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The enzyme cofactor activities of vitamin C. Vitamin C is a cofactor of…

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Is a glass of OJ or vitamin C tablets your go-to when the sniffles come? Loading up on this vitamin was a practice spurred by Linus Pauling in the 1970s, a double Nobel laureate and self-proclaimed champion of vitamin C who promoted daily megadoses (the amount in 12 to 24 oranges) as a way to prevent colds and some chronic diseases.

Vitamin C, or ascorbic acid, is a water-soluble vitamin. This means that it dissolves in water and is delivered to the body’s tissues but is not well stored, so it must be taken daily through food or supplements. Even before its discovery in 1932, nutrition experts recognized that something in citrus fruits could prevent scurvy, a disease that killed as many as two million sailors between 1500 and 1800. [1]

Vitamin C plays a role in controlling infections and healing wounds, and is a powerful antioxidant that can neutralize harmful free radicals. It is needed to make collagen , a fibrous protein in connective tissue that is weaved throughout various systems in the body: nervous, immune, bone, cartilage, blood, and others. The vitamin helps make several hormones and chemical messengers used in the brain and nerves. [2]

While megadosing on this vitamin is not uncommon, how much is an optimum amount needed to keep you healthy, and could taking too much be counterproductive?

Recommended Amounts

RDA: The Recommended Dietary Allowance for adults 19 years and older is 90 mg daily for men and 75 mg for women. For pregnancy and lactation, the amount increases to 85 mg and 120 mg daily, respectively. Smoking can deplete vitamin C levels in the body, so an additional 35 mg beyond the RDA is suggested for smokers.
UL: The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health. The UL for vitamin C is 2000 mg daily; taking beyond this amount may promote gastrointestinal distress and diarrhea. Only in specific scenarios, such as under medical supervision or in controlled clinical trials, amounts higher than the UL are sometimes used. [2]

Vitamin C absorption and megadosing

Absorption does not differ if obtaining the vitamin from food or supplements. Vitamin C is sometimes given as an injection into a vein (intravenous) so higher amounts can directly enter the bloodstream. This is usually only seen in medically monitored settings, such as to improve the quality of life in those with advanced stage cancers or in controlled clinical studies. Though clinical trials have not shown high-dose intravenous vitamin C to produce negative side effects, it should be administered only with close monitoring and avoided in those with kidney disease and hereditary conditions like hemochromatosis and glucose 6-phosphate dehydrogenase deficiency.

Vitamin C is involved with numerous metabolic reactions in the body, and obtaining the RDA or slightly higher may be protective against certain disease states. However, a health benefit of taking larger amounts has not been found in people who are generally healthy and well-nourished. Cell studies have shown that at very high concentrations, vitamin C can switch roles and act as a tissue-damaging pro-oxidant instead of an antioxidant. [2,3] Its effects in humans at very high doses well beyond the RDA are unclear, and can lead to increased risk of kidney stones and digestive upset.

Vitamin C and Health

There is interest in the antioxidant role of vitamin C, as research has found the vitamin to neutralize free radical molecules, which in excess can damage cells. Vitamin C is also involved in the body’s immune system by stimulating the activity of white blood cells. Does this translate to protection from certain diseases?

Although some epidemiological studies that follow large groups of people over time have found a protective effect of higher intakes of vitamin C (from food or supplements) from cardiovascular disease and certain cancers, other studies have not. Randomized controlled trials have not found a benefit of vitamin C supplements on the prevalence of cardiovascular disease or cancer. The inconsistency of the data overall prevents the establishment of a specific vitamin C recommendation above the RDA for these conditions. [2]

Vitamin C has also been theorized to protect from eye diseases like cataracts and macular degeneration. Human studies using vitamin C supplements have not shown a consistent benefit, though there appears to be a strong association between a high daily intake of fruit and vegetables and decreased risk of cataracts. [4]

Despite being a popular fix, vitamin C’s cold-fighting potential hasn’t panned out. Reviews of several studies show that megadoses (greater than 500 mg daily) of supplemental vitamin C have no significant effect on the common cold, but may provide a moderate benefit in decreasing the duration and severity of colds in some groups of people. [2] Small trials suggest that the amount of vitamin C in a typical multivitamin taken at the start of a cold might ease symptoms, but for the average person, there is no evidence that megadoses make a difference, or that they prevent colds. [5]

The Physicians’ Health Study II, a randomized, double-blind, placebo-controlled trial of more than 14,000 male physicians, found a modestly reduced risk of new gout cases in men who took vitamin C supplements of 500 mg daily for up to 10 years. [6] Other short-term trials have found that vitamin C may lower blood levels of uric acid, a substance that can lead to gout if there is too much in the body.

Food Sources

Fruits and vegetables are the best sources of this vitamin.

Citrus (oranges, kiwi, lemon, grapefruit)
Bell peppers
Strawberries
Cruciferous vegetables (broccoli, Brussels sprouts , cabbage, cauliflower)
White potatoes

Signs of Deficiency

Vitamin C deficiency is rare in developed countries but may occur with a limited diet that provides less than 10 mg daily for one month or longer. In developed countries, situations at greatest risk for deficiency include eating a diet restricted in fruits and vegetables, smoking or long-term exposure to secondhand smoke, and drug and alcohol abuse. The following are the most common signs of a deficiency.

Skin spots caused by bleeding and bruising from broken blood vessels
Swelling or bleeding of gums, and eventual loss of teeth
Delayed healing of skin wounds
Fatigue, malaise
Iron-deficiency anemia due to decreased absorption of non-heme iron

Did You Know?

Vitamin C improves the absorption of non-heme iron , the type of iron found in plant foods such as leafy greens. Drinking a small glass of 100% fruit juice or including a vitamin-C-rich food with meals can help boost iron absorption.
Vitamin C can be destroyed by heat and light. High-heat cooking temperatures or prolonged cook times can break down the vitamin. Because it is water-soluble, the vitamin can also seep into cooking liquid and be lost if the liquids are not eaten. Quick heating methods or using as little water as possible when cooking, such as stir-frying or blanching, can preserve the vitamin. Foods at peak ripeness eaten raw contain the most vitamin C.
Vitamin C serums and skin creams are popular because normal skin typically contains high concentrations of vitamin C, which stimulates collagen production and protects against damage from UV sunlight. However, research suggests that topical vitamin C may have limited benefits, as very little can penetrate the skin’s surface and will not produce additional benefit if a person obtains adequate vitamin C through food or supplements. [7]

Vitamins and Minerals

Carpenter KJ. The history of scurvy and vitamin C. Cambridge: Cambridge University Press, 1986.
Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids . Washington (DC): National Academies Press (US); 2000.
Poljšak B, Ionescu JG. Pro-oxidant vs. antioxidant effects of vitamin C. Handbook of Vitamin C Research: Daily Requirements, Dietary Sources and Adverse Effects (pp.153-183). January 2009. Nova Science Publishers, Inc.
Huang G, Wu L, Qiu L, Lai J, Huang Z, Liao L. Association between vegetables consumption and the risk of age-related cataract: a meta-analysis. Int J Clin Exp Med . 2015 Oct 15;8(10):18455-61.
Douglas RM, Hemila H, Chalker E, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev . 2007:CD000980.
Juraschek SP, Gaziano JM, Glynn RJ, Gomelskaya N, Bubes VY, Buring JE, Shmerling RH, Sesso HD. Effects of vitamin C supplementation on gout risk: results from the Physicians’ Health Study II trial. The American Journal of Clinical Nutrition . 2022 Sep;116(3):812-9.
Pullar JM, Carr AC, Vissers MC. The roles of vitamin C in skin health. Nutrients . 2017 Aug 12;9(8):866.

Last reviewed March 2023

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Vitamin C in Health and Disease

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (15 July 2017) | Viewed by 817130

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Dear Colleagues,

Vitamin C is a pivotal water soluble electron donor in nature and an essential nutrient in man. Despite its many years as a research focus, new and increasingly regulatory functions of vitamin C in human health are continually being unravelled. This improved mechanistic insight is starting to provide rationales explaining the extensive epidemiological literature that, for decades, has consistently shown strong associations between poor vitamin C status and increased morbidity and mortality.

In this Special Issue, we include original research and literature reviews by experts in the field outlining the roles of vitamin C in early, daily and late life, as well as the roles of deficiency in cardiovascular disease, inflammation and cancer.

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Open access
Published: 21 August 2003

Vitamin C in human health and disease is still a mystery? An overview

K Akhilender Naidu 1

Nutrition Journal volume 2 , Article number: 7 ( 2003 ) Cite this article

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Ascorbic acid is one of the important water soluble vitamins. It is essential for collagen, carnitine and neurotransmitters biosynthesis. Most plants and animals synthesize ascorbic acid for their own requirement. However, apes and humans can not synthesize ascorbic acid due to lack of an enzyme gulonolactone oxidase. Hence, ascorbic acid has to be supplemented mainly through fruits, vegetables and tablets. The current US recommended daily allowance (RDA) for ascorbic acid ranges between 100–120 mg/per day for adults. Many health benefits have been attributed to ascorbic acid such as antioxidant, anti-atherogenic, anti-carcinogenic, immunomodulator and prevents cold etc. However, lately the health benefits of ascorbic acid has been the subject of debate and controversies viz., Danger of mega doses of ascorbic acid? Does ascorbic acid act as a antioxidant or pro-oxidant ? Does ascorbic acid cause cancer or may interfere with cancer therapy? However, the Panel on dietary antioxidants and related compounds stated that the in vivo data do not clearly show a relationship between excess ascorbic acid intake and kidney stone formation, pro-oxidant effects, excess iron absorption. A number of clinical and epidemiological studies on anti-carcinogenic effects of ascorbic acid in humans did not show any conclusive beneficial effects on various types of cancer except gastric cancer. Recently, a few derivatives of ascorbic acid were tested on cancer cells, among them ascorbic acid esters showed promising anticancer activity compared to ascorbic acid. Ascorbyl stearate was found to inhibit proliferation of human cancer cells by interfering with cell cycle progression, induced apoptosis by modulation of signal transduction pathways. However, more mechanistic and human in vivo studies are needed to understand and elucidate the molecular mechanism underlying the anti-carcinogenic property of ascorbic acid. Thus, though ascorbic acid was discovered in 17 th century, the exact role of this vitamin/nutraceutical in human biology and health is still a mystery in view of many beneficial claims and controversies.

Peer Review reports

Historical perspective

The sea voyager/sailors developed a peculiar disease called scurvy when they were on sea. This was found to be due to eating non-perishable items and lack of fresh fruits and vegetables in their diet. A British naval Physician, Lind [ 1 ] documented that there was some substance in citrus fruits that can cure scurvy. He developed a method to concentrate and preserve citrus juice for use by sailors. British Navy was given a daily ration of lime or lemon juice to overcome ascorbic acid deficiency. Ascorbic acid was first isolated from natural sources and structurally characterized by Szent-Gyorgyi, Waugh and King [ 2 , 3 ]. This vitamin was first synthesized by Haworth and Hirst [ 4 ]. Currently ascorbic acid is the most widely used vitamin supplement through out the world.

Sources of Ascorbic acid

Ascorbic acid is widely distributed in fresh fruits and vegetables. It is present in fruits like orange, lemons, grapefruit, watermelon, papaya, strawberries, cantaloupe, mango, pineapple, raspberries and cherries. It is also found in green leafy vegetables, tomatoes, broccoli, green and red peppers, cauliflower and cabbage.

Most of the plants and animals synthesize ascorbic acid from D-glucose or D-galactose. A majority of animals produce relatively high levels of ascorbic acid from glucose in liver (Fig 1 ).

Biosynthesis of L-Ascorbic acid in animals

However, guinea pigs, fruit eating bats, apes and humans can not synthesize ascorbic acid due to the absence of the enzyme L-gulonolactone oxidase. Hence, in humans ascorbic acid has to be supplemented through food and or as tablets.

Ascorbic acid is a labile molecule, it may be lost from foods during cooking/processing even though it has the ability to preserve foods by virtue of its reducing property. Synthetic ascorbic acid is available in a wide variety of supplements viz., tablets, capsules, chewable tablets, crystalline powder, effervescent tablets and liquid form. Buffered ascorbic acid and esterfied form of ascorbic acid as ascorbyl palmitate is also available commercially. Both natural and synthetic ascorbic acid are chemically identical and there are no known differences in their biological activities or bio-availability.

Chemistry of ascorbic acid

L-ascorbic acid (C 6 H 8 O 6 ) is the trivial name of Vitamin C. The chemical name is 2-oxo-L-threo-hexono-1,4-lactone-2,3-enediol. L-ascorbic and dehydroascorbic acid are the major dietary forms of vitamin C [ 5 ]. Ascorbyl palmitate is used in commercial antioxidant preparations. All commercial forms of ascorbic acid except ascorbyl palmitate are soluble in water. L-ascorbic acid and its fatty acid esters are used as food additives, antioxidants, browning inhibitors, reducing agents, flavor stabilizers, dough modifiers and color stabilizers. Ascorbyl palmitate has been used for its greater lipid solubility in antioxidant preparations. In foods, pH influences the stability of ascorbic acid. It exhibits maximal stability between pH 4 and 6 [ 5 ]. Cooking losses of ascorbic acid depend on degree of heating, surface area exposed to water, oxygen, pH and presence of transition metals.

Catabolism of Ascorbic acid

Ascorbic acid present in foods is readily available and easily absorbed by active transport in the intestine [ 6 ]. Most of it (80–90%) will be absorbed when the in take is up to 100 mg/day, whereas at higher levels of intake (500 mg/day) the efficiency of absorption of ascorbic acid rapidly declines. Ascorbic acid is sensitive to air, light, heat and easily destroyed by prolonged storage and over processing of food.

Ascorbic acid being a water soluble compound is easily absorbed but it is not stored in the body. The average adult has a body pool of 1.2–2.0 g of ascorbic acid that may be maintained with 75 mg/d of ascorbic acid. About 140 mg/d of ascorbic acid will saturate the total body pool of vitamin C [ 7 ]. The average half life of ascorbic acid in adult human is about 10–20 days, with a turn over of 1 mg/kg body and a body pool of 22 mg/kg at plasma ascorbate concentration of 50 μmol/ L [ 8 , 9 ]. Hence ascorbic acid has to regularly supplemented through diet or tablets to maintain ascorbic acid pool in the body.

The major metabolites of ascorbic acid in human are dehydroascorbic acid, 2,3-diketogulonic acid and oxalic acid (Fig 2 ). The main route of elimination of ascorbic acid and its metabolites is through urine. It is excreted unchanged when high doses of ascorbic acid are consumed. Ascorbic acid is generally non-toxic but at high doses (2–6 g/day) it can cause gastrointestinal disturbances or diarrhea [ 10 , 11 ]. The side effects are generally not serious and can be easily reversed by reducing intake of ascorbic acid. Furthermore, there is no consistent and compelling data on serious health effects of vitamin C in humans [ 11 ].

A deficiency of ascorbic acid leads to scurvy. It is characterized by spongy swollen bleeding gums, dry skin, open sores on the skin, fatigue, impaired wound healing and depression [ 13 ]. Scurvy is of rare occurrence nowadays due to adequate intake ascorbic acid through fresh vegetables and fruits and or supplementation as tablets.

Dietary recommendations of Ascorbic acid

The new average daily intake level that is sufficient to meet the nutritional requirement of ascorbic acid or recommended dietary allowances (RDA) for adults (>19 yr) are 90 mg/day for men and 75 mg/day for women [ 14 ]. Consumption of 100 mg/day of ascorbic acid is found to be sufficient to saturate the body pools (neutrophils, leukocytes and other tissues) in healthy individuals. Based on clinical and epidemiological studies it has been suggested that a dietary intake of 100 mg/day of ascorbic acid is associated with reduced incidence of mortality from heart diseases, stroke and cancer [ 15 ]. However, stress, smoking, alcoholism, fever, viral infections cause a rapid decline in blood levels of ascorbic acid.

Smoking is known to increase the metabolic turnover of ascorbic acid due to its oxidation by free radicals and reactive oxygen species generated by cigarette smoking [ 16 ]. It has been suggested that a daily intake of at least 140 mg/day is required for smokers to maintain a total body pool similar to that of non-smokers consuming 100 mg/day [ 17 ]. Based on latest literature reports, it has been recommended that the RDA for ascorbic acid should be 100–120 mg/day to maintain cellular saturation and optimum risk reduction of heart disease, stroke and cancer in healthy individuals [ 18 ]. There is no scientific evidence to show that even very large doses of vitamin C are toxic or exert serious adverse health effects [ 11 , 19 ]. Furthermore, the panel on dietary antioxidants and related compounds suggested that in vivo data do not clearly show a relationship between excess vitamin C intake and kidney stone formation, pro-oxidant effects, excess iron absorption [ 20 ].

Physiological functions of Ascorbic acid

The physiological functions of ascorbic acid are largely dependent on the oxido-reduction properties of this vitamin. L-ascorbic acid is a co-factor for hydroxylases and monooxygenase enzymes involved in the synthesis of collagen, carnitine and neurotransmitters [ 21 ]. Ascorbic acid accelerates hydroxylation reactions by maintaining the active center of metal ions in a reduced state for optimal activity of enzymes hydroxylase and oxygenase.

Ascorbic acid plays an important role in the maintenance of collagen which represents about one third of the total body protein. It constitutes the principal protein of skin, bones, teeth, cartilage, tendons, blood vessels, heart valves, inter vertebral discs, cornea and eye lens. Ascorbic acid is essential to maintain the enzyme prolyl and lysyl hydroxylase in an active form. The hydroxylation of proline and lysine is carried out by the enzyme prolyl hydroxylase using ascorbic acid as co-factor. Ascorbic acid deficiency results in reduced hydroxylation of proline and lysine, thus affecting collagen synthesis.

Ascorbic acid is essential for the synthesis of muscle carnitine (β-hydroxy butyric acid). [ 22 ]. Carnitine is required for transport and transfer of fatty acids into mitochondria where it can be used for energy production. Ascorbic acid acts as co-factor for hydroxylations involved in carnitine synthesis. Further, ascorbic acid acts as co-factorfor the enzyme dopamine-β-hydroxylase, which catalyzes the conversion of neurotransmitter dopamine to norepinephrine. Thus ascorbic acid is essential for synthesis of catecholamines. In addition, ascorbic acid catalyzes other enzymatic reactions involving amidation necessary for maximal activity of hormones oxytocin, vasopressin, cholecystokinin and alpha-melanotripin [ 23 ].

Ascorbic acid is also necessary for the transformation of cholesterol to bile acids as it modulates the microsomal 7 α-hydroxylation, the rate limiting reaction of cholesterol catabolism in liver. In ascorbic acid deficiency, this reaction becomes slowed down thus, resulting in an accumulation of cholesterol in liver, hypercholesterolemia, formation of cholesterol gall stones etc [ 24 ].

Ascorbic acid and iron

Ascorbic acid is known to enhance the availability and absorption of iron from non-heme iron sources [ 25 ]. Ascorbic acid supplementation is found to facilitate the dietary absorption of iron. The reduction of iron by ascorbic acid has been suggested to increase dietary absorption of non-heme iron [ 26 ]. It is well known that in the presence of redox-active iron, ascorbic acid acts as a pro-oxidant in vitro and might contribute to the formation of hydroxyl radical, which eventually may lead to lipid, DNA or protein oxidation [ 27 ]. Thus, ascorbic acid supplementation in individuals with high iron and or bleomycin-detectable iron (BDI) in some preterm infants could be deleterious because it may cause oxidative damage to biomolecules [ 28 – 31 ]. However, no pro-oxidant effect was observed on ascorbic acid supplementation on DNA damage in presence or absence of iron [ 32 ].

Ascorbic acid in health and disease

Ascorbic acid and common cold.

The most widely known health beneficial effect of ascorbic acid is for the prevention or relief of common cold. Pauling [ 33 ] suggested that ingestion of 1–2 g of ascorbic acid effectively prevents/ ameliorate common cold. The role of oral vitamin C in the prevention and treatment of colds remains controversial despite many controlled trials. Several clinical trails with varying doses of ascorbic acid showed that ascorbic acid does not have significant prophylactic effect, but reduced the severity and duration of symptoms of cold during the period of infection. Randomized and non-randomized trials on vitamin C to prevent or treat the common cold showed that consumption of ascorbic acid as high as 1.0 g/day for several winter months, had no consistent beneficial effect on the incidence of common cold. For both preventive and therapeutic trials, there was a consistent beneficial but generally modest therapeutic effect on duration of cold symptoms. There was no clear indication of the relative benefits of different regimes of vitamin C doses. However, in trials that tested vitamin C after cold symptoms occurred, there was some evidence of greater benefits with large dose than with lower doses [ 34 ].

There has been a long-standing debate concerning the role of ascorbic acid in boosting immunity during cold infections. Ascorbic acid has been shown to stimulate immune system by enhancing T-cell proliferation in response to infection. These cells are capable of lysing infected targets by producing large quantities of cytokines and by helping B cells to synthesize immunoglobulins to control inflammatory reactions. Further, it has been shown that ascorbic acid blocks pathways that lead to apoptosis of T-cells and thus stimulate or maintain T cell proliferation to attack the infection. This mechanism has been proposed for the enhanced immune response observed after administration of vitamin C during cold infections [ 35 ].

Ascorbic acid and wound healing

Ascorbic acid plays a critical role in wound repair and healing/regeneration process as it stimulates collagen synthesis. Adequate supplies of ascorbic acid are necessary for normal healing process especially for post-operative patients. It has been suggested that there will be rapid utilization of ascorbic acid for the synthesis of collagen at the site of wound/ burns during post-operative period [ 36 ]. Hence, administration of 500 mg to 1.0 g/day of ascorbic acid are recommended to accelerate the healing process [ 8 ].

Ascorbic acid and atherosclerosis

Lipid peroxidation and oxidative modification of low density lipoproteins (LDL) are implicated in development of atherosclerosis [ 37 ]. Vitamin C protects against oxidation of isolated LDL by different types of oxidative stress, including metal ion dependent and independent processes [ 38 ]. Addition of iron to plasma devoid of ascorbic acid resulted in lipid peroxidation, whereas endogenous and exogenous ascorbic acid was found to inhibit the lipid oxidation in iron-over loaded human plasma [ 39 ]. Similarly, when ascorbic acid was added to human serum supplemented with Cu 2+ , antioxidant activity rather than pro-oxidant effects were observed [ 40 ].

Ascorbic acid is known to prevent the oxidation of LDL primarily by scavenging the free radicals and other reactive oxygen species in the aqueous milieu [ 41 ]. In addition, in vitro studies have shown that physiological concentrations of ascorbic acid strongly inhibit LDL oxidation by vascular endothelial cells [ 42 ]. Adhesion of leukocytes to the endothelium is an important step in initiating atherosclerosis. In vivo studies have demonstrated that ascorbic acid inhibits leukocyte-endothelial cell interactions induced by cigarette smoke [ 43 , 44 ] or oxidized LDL [ 45 ]. Further, lipophilic derivatives of ascorbic acid showed protective effect on lipid-peroxide induced endothelial injury [ 46 ].

A number of studies have been carried out in humans to determine the protective effect of ascorbic acid supplementation (500–100 mg/day) on in vivo and ex vivo lipid peroxidation in healthy individuals and smoker. The findings are inconclusive as ascorbic acid supplementation showed a reduction or no change in lipid peroxidation products [ 10 , 47 – 50 ]. In this context, it is important to note that during ex vivo LDL oxidation studies, water soluble ascorbic acid is removed during initial LDL isolation step itself. Therefore, no change in ex vivo would be expected [ 15 ]. Overall, both in vitro and in vivo experiments showed that ascorbic acid protects isolated LDL and plasma lipid peroxidation induced by various radical or oxidant generating systems. However, a recent report demonstrated that large doses of exogenous iron (200 mg) and ascorbic acid (75 mg) promoted the release of iron from iron binding proteins and also enhanced in vitro lipid peroxidation in serum of guinea pigs. This finding supports the hypothesis that high intake of iron along with ascorbic acid could increase in vivo lipid peroxidation of LDL and therefore could increase risk of atherosclerosis [ 51 ]. However, Chen et al., [ 52 ] demonstrated that ascorbic acts as an antioxidant towards lipids even in presence of iron over load in in vivo systems.

Numerous studies have looked at the association between ascorbic acid intake and the risk of developing cardiovascular disease (CHD). A large prospective epidemiological study in Finnish men and women suggested that high intake of ascorbic acid was associated with a reduced risk of death from CHD in women and not in men [ 53 ]. Similarly, another study showed that high intake of ascorbic acid in American men and women appeared to benefit only women [ 54 , 55 ]. A third American cohort study suggested that cardiovascular mortality was reduced in both sexes by vitamin C [ 56 ]. In the UK, a study showed that the risk of stroke in those with highest intake of vitamin C was only half that of subjects with the lowest intake and no evidence suggestive of lower rate of CHD in those with high vitamin C intake [ 57 ]. However, a recent meta analysis on the role of ascorbic acid and antioxidant vitamins showed no evidence of significant benefit in prevention of CHD [ 58 ]. Thus, no conclusive evidence is available on the possible protective effect of ascorbic acid supplementation on cardiovascular disease.

Ascorbic acid and Cancer

Nobel laureate Pauling and Cameron advocated use of high doses of ascorbic acid (> 10 g/day) to cure and prevent cold infections and in the treatment of cancer [ 34 , 59 ]. The benefits included were increased sense of well being/ much improved quality of life, prolongation of survival times in terminal patients and complete regression in some cases [ 60 – 62 ]. However, clinical studies on cancer patients carried out at Mayo Clinic showed no significant differences between vitamin C and placebo groups in regard to survival time [ 63 ]. Cameron and Pauling [ 23 ] believed that ascorbic acid combats cancer by promoting collagen synthesis and thus prevents tumors from invading other tissues. However, researchers now believe that ascorbic acid prevents cancer by neutralizing free radicals before they can damage DNA and initiate tumor growth and or may act as a pro-oxidant helping body's own free radicals to destroy tumors in their early stages [ 64 – 66 ].

Extensive animal, clinical and epidemiological studies were carried out on the role of ascorbic acid in the prevention of different types of cancers. A mixture of ascorbic acid and cupric sulfate significantly inhibited human mammary tumor growth in mice, while administered orally [ 67 ]. Ascorbic acid decreased the incidence of kidney tumors by estradiol or diethylstilbesterol in hamsters due to decrease in the formation of genotoxic metabolites viz., diethylstilbesterol-4'-4"-qunione [ 68 ]. Ascorbic acid and its derivatives were shown to be cytotoxic and inhibited the growth of a number of malignant and non-malignant cell lines in vitro and in vivo [ 69 – 72 ]. Ascorbic acid has been reported to be cytotoxic to some human tumor cells viz., neuorblastoma [ 73 ], osteosarcoma and retinoblastoma [ 74 ]. A number of ascorbic acid isomers/ derivatives were synthesized and tested on tumor cell lines. Roomi et al., 1998 [ 75 ] demonstrated that substitution at 2- or 6- and both at 2,6-positions in ascorbic acid have marked cytotoxicity on malignant cells. Ascorbate-6-palmitate and ascorbate-6-stearate, the fatty acid esters of ascorbic acid were found to be more potent inhibitors of growth of murine leukemia cells compared to ascorbate 2-phosphate, ascorbate 6-phosphate and or ascorbate 6-sulfate respectively [ 75 ].

Among ascorbic acid derivatives, fatty acid esters of ascorbic acid viz., ascorbyl palmitate and ascorbyl stearate have attracted considerable interest as anticancer compounds in view of their lipophilic nature as they can easily cross cell membranes and blood brain barrier [ 76 ]. Ascorbic acid and ascorbyl esters have been shown to inhibit the proliferation of mouse glioma and human brain tumor cells viz., glioma (U-373) and glioblastoma (T98G) cells and renal carcinoma cells [ 77 – 79 ]. Ascorbyl stearate was found to be more potent than sodium ascorbate in inhibiting proliferation of human glioblastoma cells [ 80 ]. Ascorbyl-6-O-palmitate and ascorbyl-2-O-phosphate-6-O-palmitate also showed anti-metastatic effect by inhibiting invasion of human fibrosarcoma HT-1080 cells through matrigel and pulmonary metastasis of mouse melanoma model systems [ 81 ].

Numerous reports are available in literature on cytotoxic and anti-carcinogenic effect of ascorbic acid and its derivatives in different tumor model systems. However, the molecular mechanisms underlying the anti-carcinogenic potential of ascorbic acid are not completely elucidated. Recently, Naidu et al [ 80 ] demonstrated that ascorbyl stearate inhibited cell proliferation by interfering with cell cycle, reversed the phenotype and induced apoptosis by modulation of insulin-like growth factor 1-receptor expression in human brain tumor glioblastoma (T98G) cells. They also studied the effect of ascorbyl stearate on cell proliferation, cell cycle, apoptosis and signal transduction in a panel of human ovarian and pancreatic cancer cells. Treatment with ascorbyl stearate resulted in concentration-dependent inhibition of cell proliferation and also clonogenicity of ovarian/ pancreatic cancer cells [ 82 , 83 ]. The anti-proliferative effect was found to be due to the arrest of cells in S/G2-M phase of cell cycle, with increased fraction of apoptotic cells. The cell cycle perturbations were found to be associated with ascorbyl stearate induced reduction in the expression and phosphorylation of IGF-I receptor, while the expression of EGFR and PDGFR remained unchanged. These changes were also associated with activated ERK1/2 but late reduction in AKT phosphorylation. Overexpression of IGF-I receptor in OVCAR-3 cells had no protective effect, however ectopic expression of a constitutively active AKT2 did offer protection from the cytotoxic effects of ascorbyl stearate. In conclusion, ascorbyl stearate-induced anti-proliferative and apoptotic effects in ovarian cancer were found to be mediated through cell cycle arrest and modulation of the IGF-IR and PI3K/AKT2 survival pathways [ 83 ].

A plethora of epidemiological studies were carried out to find out the association of ascorbic acid with various types of cancers including breast, esophageal, lung, gastric, pancreatic, colorectal, prostate, cervical and ovarian cancer etc. The results were found to be inconclusive in most types of cancers except gastric cancer [ 84 ]. One of the most consistent epidemiological findings on vitamin C has been an association with high intake of ascorbic acid or vitamin C rich foods and reduced risk of stomach cancer. Considerable biochemical and physiological evidence suggests that ascorbic acid functions as a free radical scavenger and inhibit the formation of potentially carcinogenic N-nitroso compounds from nitrates, nitrite in stomach and thus offer protection against stomach cancer [ 85 – 87 ].

Low intake of ascorbic acid and other vitamins was associated with an increased risk of cervical cancer in two of three studies reported [ 88 – 91 ]. This relationship needs further study because the results suggest that other nutrients including vitamin E, carotenoids, retinoic acid either individually or in synergy with ascorbic acid may impart a protective effect against various cancers. Current evidences suggest that vitamin C alone may not be sufficient as an intervention in the treatment of most active cancers, as it appears to be preventive than curative. However, vitamin C supplementation has shown to improve the quality of life and extend longevity in cancer patients, hence it could be considered as an adjuvant in cancer therapy.

Dehydroascorbic acid, the oxidized form of ascorbic acid was shown to cross the blood brain barrier by means of facilitative transport and was suggested to offer neuroprotection against cerebral ischemia by augmenting antioxidant levels of brain [ 92 ].

Controversies on health benefits of Ascorbic acid

Does ascorbic acid acts as antioxidant or pro-oxidant.

Vitamin C is an important dietary antioxidant, it significantly decreases the adverse effect of reactive species such as reactive oxygen and nitrogen species that can cause oxidative damage to macromolecules such as lipids, DNA and proteins which are implicated in chronic diseases including cardiovascular disease, stroke, cancer, neurodegenerative diseases and cataractogenesis [ 93 ].

As shown in Table 2 , ascorbic acid is a potent water soluble antioxidant capable of scavenging/ neutralizing an array of reactive oxygen species viz., hydroxyl, alkoxyl, peroxyl, superoxide anion, hydroperoxyl radicals and reactive nitrogen radicals such as nitrogen dioxide, nitroxide, peroxynitrite at very low concentrations [ 15 ]. In addition ascorbic acid can regenerate other antioxidants such as α-tocopheroxyl, urate and β-carotene radical cation from their radical species [ 94 ]. Thus, ascorbic acid acts as co-antioxidant for α-tocopherol by converting α-tocopheroxyl radical to α-tocopherol and helps to prevent the α-tocopheroxyl radical mediated peroxidation reactions [ 95 ].

AH - + Fe 3+ - - - → A • - + Fe 2+ + H +

AH - + Cu 2+ - - - → A • - + Cu + + H +

H 2 O 2 + Fe 2+ - - - → HO • + Fe 3+ + - OH

H 2 O 2 + Cu + - - - → HO • + Cu 2+ + - OH

LOOH + Fe 2+ - - - → LO• + Fe 3+ + - OH

LOOH + Cu + - - - → LO + Cu + + - OH

HO • , LO • - - - → Lipid peroxidation

Adapted from Carr and Frei [ 15 ]

These radical species are highly reactive and can trigger lipid peroxidation reactions. Thus the question arises whether vitamin C acts as a pro-oxidant in in vivo conditions? The answer appears to be "no" as though these reactions occur readily in vitro , its relevance in in vivo has been a matter of debate concerning ready availability of catalytically active free metal ions in vivo [ 94 ]. In biological systems, iron is not freely available, but it is bound to proteins like transferrin, hemoglobin and ferretin. Mobilization of iron from these biomolecules may be required before it can catalyze lipid peroxidation. Further, the concentration of free metal ions in in vivo is thought to be very low as iron and other metals are sequestered by various metal binding proteins [ 94 ]. Another factor that may affect pro-oxidant vs antioxidant property of ascorbic acid is its concentration. The in vitro data suggest that at low concentrations ascorbic acid act as a pro-oxidant, but as an antioxidant at higher levels [ 96 ]. Moreover, a recent report demonstrated that large doses of exogenous iron (200 mg) and ascorbic acid (75 mg) promote the release of iron from iron binding proteins and also enhance in vitro lipid peroxidation in serum of guinea pigs. This finding supports the hypothesis that high intake of iron along with ascorbic acid could increase in vivo lipid peroxidation of LDL and therefore could increase risk of atherosclerosis [ 52 ]. However, another study demonstrated that in iron-overloaded plasma, ascorbic acid acts as an antioxidant and prevent oxidative damage to lipids in vivo [ 97 ].

Is ascorbic acid harmful to cancer patients?

Agus et al [ 98 ] have reported that the tumor cells contain large amounts of ascorbic acid, although the role of ascorbic acid in tumors is not yet known. They have established that vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. It is speculated that high levels of ascorbic acid in cancer cells may interfere with chemotherapy or radiation therapy since these therapies induce cell death by oxidative mechanism. Thus, ascorbic acid supplementation might make cancer treatment less effective because, ascorbic acid being a strong antioxidant may scavenge or neutralize the oxidative stress induced by chemotherapy in cancer patients. However, more studies are needed to understand the role of ascorbic acid in tumors cells and the speculative contraindication of ascorbic acid for cancer chemotherapy.

Does ascorbic acid cause cancer ?

Recently, it has been reported that lipid hydroperoxide can react with ascorbic acid to form products that could potentially damage DNA, suggesting that it may form genotoxic metabolites from lipid hydroperoxides implicating that ascorbic acid may enhance mutagenesis and risk of cancer. Lee et al [ 99 ], demonstrated that ascorbic acid induces decomposition of lipid hydroperoxide (13-( S )-hydroperoxy-( Z,E )-9,11-octadecadienoic acid;(13-HPODE) in presence of transition metals to DNA-reactive bifunctional electro-philes namely 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal and 4-hydroxy-2-nonenal. 4-oxo-2-nonenal being a genotoxin can react with DNA bases to form mutations [ 100 ] or apoptosis [ 101 ].

Thus, the above process can give rise to substantial amounts of DNA damage in vivo . However there are many questions, which need to be considered before we accept the hypothesis that ascorbic acid can cause cancer by producing genotoxic metabolites from lipids. The hydroperoxides formed through lipid peroxidation reaction are rapidly reduced to aldehydes by a number of enzymes. Further, ascorbic acid being a strong antioxidant effectively inhibits the formation of lipid peroxides as ascorbic acid forms the first line of antioxidant defense mechanism in human plasma. The formation of lipid hydroperoxides occur only after ascorbic acid has been exhausted. Hence, interaction of ascorbic acid and hydroperoxide may not arise in human plasma. Recently, high intracellular vitamin C was reported to prevent oxidation-induced mutations in human cells [ 102 ]. Thus, the physiological relevance of these results is yet to be established in in vivo experiments.

Ascorbic acid is one of the important and essential vitamins for human health. It is needed for many physiological functions in human biology. Fresh fruits, vegetables and also synthetic tablets supplement the ascorbic acid requirement of the body. However, stress, smoking, infections and burns deplete the ascorbic acid reserves in the body and demands higher doses of ascorbic acid supplementation. Based on available biochemical, clinical and epidemiological studies, the current RDA for ascorbic acid is suggested to be 100–120 mg/day to achieve cellular saturation and optimum risk reduction of heart diseases, stroke and cancer in healthy individuals. In view of its antioxidant property, ascorbic acid and its derivatives are widely used as preservatives in food industry. Many health benefits have been attributed to ascorbic acid namely antioxidant, anti-atherogenic and anti-carcinogenic activity. Lately some of these beneficial effects of ascorbic acid are contradicted. The relation between ascorbic acid and cancer is still a debatable as the molecular mechanism underlying anti-carcinogenic activity of ascorbic acid is not clearly elucidated. Regarding the pro-oxidant activity of vitamin C in presence of iron, there is compelling evidence for antioxidant protection of lipids by ascorbic acid both with and without iron co-supplementation in animals and humans. Current evidences also suggest that ascorbic acid protects against atherogenesis by inhibiting LDL oxidation. The data on vitamin C and DNA damage are conflicting and inconsistent. However, more mechanistic and human in vivo studies are warranted to establish the beneficial claims on ascorbic acid. Thus, though ascorbic acid was discovered in 17 th century, the role of this important vitamin in human health and disease still remains a mystery in view of many beneficial claims and contradictions.

Lind J: A treatise of scurvy. Printed by Sands, Murray and Cochran for Kincaid, A and Donaldson, A. Edinburgh. 1753

Google Scholar

Svirbely JL, Szent-Gyorgyi A: The chemical nature of vitamin C. Biochem J. 1932, 26865-870.

Waugh WA, King CG: Isolation and identification of vitamin C. J Biol Chem. 1932, 97: 325-331.

CAS Google Scholar

Haworth WN, Hirst EL: Synthesis of ascorbic acid. J Soc Chem Ind (London). 1933, 52: 645-647.

Moser U, Bendich A: Vitamin C. In: Handbook of Vitamins. Edited by: Machlin LJ. 1990, Marcel Dekker, New York, Ch5-

Sauberlich HE: Bioavailability of vitamins. Prog Food Nutr Sci. 1985, 9: 1-33.

CAS PubMed Google Scholar

Sauberlich HE: Ascorbic acid. In: Present knowledge in Nutrition. Edited by: Brown ML. 1990, Nutrition Foundation, Washington DC

Hellman L, Burns JJ: Metabolism of L-ascorbic acid-1-C 14 in man. J Biol Chem. 1958, 230: 923-930.

Kallner A, Horing D, Hartman D: Kinteics of ascorbic acid in humans. In: Ascorbic acid: Chemistry, metabolism and uses. Edited by: Seib PA, Tolbert BM. 1982, Advances in Chemistry Series No.200, American Chemical Society, Washington, DC, 385-400.

Anderson D, Phillips BJ, Yu T, Edwards AJ, Ayesh R, Butterworth KR: The effect of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with low or high cholesterol levels. Environ Mol Mutagens. 1997, 30: 161-174. 10.1002/(SICI)1098-2280(1997)30:2<161::AID-EM9>3.3.CO;2-J.

Johnson CS: Biomarkers for establishing a tolerable upper intake level for vitamin C. Nutr Rev. 1999, 57: 71-77.

Johnson CS, Steinberg FM, Rucker RB: Ascorbic acid. In: Hand book of Vitamins. Edited by: Rucker RB, Sultie JW, McCormick, DB, Machlin LJ. 1998, Marcel Dekker Inc, New York, 529-585.

Olson RE: Water soluble vitamins. In: Principles of Pharmacology. Edited by: Munson PL, Mueller RA, Bresse GR. 1999, Chapman and Hall, New York, Ch 59-

Frei B, Traber M: The new US dietary reference for vitamins C and E. Redox Rep. 2001, 6: 5-9.

Carr AC, Frei B: Does vitamin C act as pro-oxidant under physiological conditions ?. FASEB J. 1999, 13: 1007-1024.

Frei B, Forte TM, Ames BN, Cross CE: Gas-phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties in human blood plasma: protective effects of ascorbic acid. Biochem J. 1981, 277: 133-138.

Kallner A, Hartmann D, Hornig D: On the requirement of ascorbic acid in man: steady-state turnover and body pool in smokers. Am J Clin Nutr. 1981, 34: 1347-1355.

Carr AC, Frei B: Toward new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999, 69: 1086-1107.

Bendich A: Vitamin C safety in humans. In: Vitamin C in Health and Disease. Edited by: Packer L, Fuchs J. 1997, Marcel Dekker Inc. New York, 369-379.

Food and Nutrition Board: Dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids. National Academy Press, Washington, DC. 2000

Levin M: New concepts in the biology and biochemistry of ascorbic acid. New Engl J Med. 1986, 31: 892-902.

Hulse JD, Ellis SR, Henderson LM: Carnitine biosynthesis-beta hydroxylation of trimethyllysine by an α-keto glutarate dependent mitochondrial dioxygenase. J Biol Chem. 1978, 253: 1654-1659.

Cameron E, Pauling L: Ascorbic acid and the glycosaminoglycans. Oncology. 1973, 27: 181-192.

Ginter E, Bobek P, Jurcovicova M: Role of ascorbic acid in lipid metabolism. In: Ascorbic acid, chemistry, metabolism and uses. Edited by: Seith PA, Toblert, BM. 1982, American Chemical Society, Washington, DC, 381-393.

Hallberg L: Bioavailability of dietary iron in man. Annu Rev Nutr. 1981, 1: 123-127. 10.1146/annurev.nu.01.070181.001011.

Bendich A, Cohen M: Ascorbic acid safety: analysis factors affecting iron absorption. Toxicol Lett. 1990, 51: 189-190. 10.1016/0378-4274(90)90210-D.

Samuni A, Aronovitch J, Godinger D, Chevion M, Czapski G: On the cytotoxicity of vitamin C and metal ions: A site specific Fenton mechanism. Eur J Biochem. 1983, 137: 119-124.

Minetti M, Forte T, Soriani M, Quaresima V, Menditto A, Ferrari M: Iron Induced ascorbate oxidation in plasma as monitored by ascorbate free radical formation: No spin trapping evidence for the hydroxyl radical in iron-over loaded plasmas. Biochem J. 1992, 282: 459-465.

CAS PubMed PubMed Central Google Scholar

Berger TM, Mumby S, Gutteridge JMC: Ferrous ion detected in iron-overloaded cord blood plasma from preterm and term babies: Implication for oxidation stress. Free Rad Res. 1995, 22: 555-559.

Halliwell B: Vitamin C: Antioxidant or pro-oxidant in vivo ?. Free Rad Res. 1996, 25: 439-454.

Herbert V, Shaw S, Jayatileke E: Vitamin C driven free radicals generation from iron. J Nutr. 1996, 126: 1213-1220.

Proteggente AR, Rehman A, Halliwell B, Rice-Evans CA: Potential problems of ascorbic acid and iron supplementation: Pro-oxidant effect in vivo ?. Biochem Biophys Res Commun. 2000, 277: 535-540. 10.1006/bbrc.2000.3711.

Pauling L: Vitamin C and common cold. Freeman, San Francisco, CA. 1970

Douglas RM, Chalker EB, Treacy B: Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev. 2000, 2: CD000980-

PubMed Google Scholar

Campbell JD, Cole M, Bunditrutavorn B, Vell AT: Ascorbic acid is a potent inhibitor of various forms of T cell apoptosis. Cell Immunol. 1999, 194: 1-5. 10.1006/cimm.1999.1485.

Shukla SP: Level of ascorbic acid and its oxidation in the liver of Scorpion. Palamnaeus bengalensis. Experentia. 1969, 25: 602-604.

Steinbrecher UP, Zhang H, Lougheed M: Role of oxidative modified LDL in atherosclerosis. Free Rad Biol Med. 1990, 9: 155-168. 10.1016/0891-5849(90)90119-4.

Frei B: Vitamin C as an antiatherogen: mechanism of action. In Vitamin C in Health and disease. Edited by: Packer L, Fuchs J. 1997, Marcel and Dekker, Inc., New York, 163-182.

Berger TM, Polidori MC, Dabhag A, Evans PJ, Halliwell B, Marrow JD, Roberts LJ, Frei B: Antioxidant activity of viamin C in iron-over loaded human plasma. J Biol Chem. 1992, 272: 15656-15660. 10.1074/jbc.272.25.15656.

Dasgupta A, Zdunek T: In vitro lipid peroxidation of human serum catalyzed by copper ion: antioxidant rather than pro-oxidant role of ascorbate. Life Sci. 1992, 50: 2875-2882. 10.1016/0024-3205(92)90206-5.

Frei B, England L, Ames BN: Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA. 1989, 86: 6377-6381.

Martin A, Frei B: Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells. Atheroscler Thromb Vasc Biol. 1997, 17: 1583-1590.

Lehr HA, Frei B, Arfors KE: Vitamin C prevents cigarette smoke-induced leukocyte aggregation and adhesion to endothelium in vivo. Proc Natl Acd Sci USA. 1994, 91: 7688-7692.

Lehr HA, Weyrich AS, Saetzler RK, Jurek A, Arfors KE, Zimmerman GA, Prescott SM, McIntyre TM: Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking. J Clin Invest. 1997, 99: 2358-2364.

Lehr HA, Frei B, Olofsson AM, Carew TE, Arfors KE: Protection from oxidized LDL induced leukocyte adhesion to microvascular and macrovascular endothelium in vivo by vitamin C but not by vitamin E. Circulation. 1995, 91: 1552-1532.

Kaneko T, Kaji K, Mastuo M: Protective effect of lipophilic derivatives of ascorbic acid on lipid peroxide-induced endothelial injury. Arch Biochem Biophys. 1993, 304: 176-180. 10.1006/abbi.1993.1336.

Fuller CJ, Grundy SM, Norkus EP, Jialal I: Effect ascorbate supplementation on low density lipoprotein oxidation in smokers. Atherosclerosis. 1996, 119: 139-150. 10.1016/0021-9150(95)05659-9.

Nyyssonen K, Poulsen HE, Hayn M, Agerbo P, Porkkalo Sarataho E, Kaikkonen J, Salonen R, Salonen JT: Effect of supplementation of smoking men with plain or slow release ascorbic acid on lipoprotein oxidation. Eur J Clin Nutr. 1997, 51: 154-163. 10.1038/sj.ejcn.1600376.

Samman S, Brown AJ, Beltran C, Singh S: The effect of ascrobic acid on plasma lipids and oxidisability of LDL in male smokers. Eur J Clin Nutr. 1997, 51: 472-477. 10.1038/sj.ejcn.1600431.

Wen Y, Cooke T, Feely J: The effect of pharmacological supplemen-tation with vitamin C on low density lipoprotein oxidation. Br J Clin Pharma. 1997, 44: 94-97. 10.1046/j.1365-2125.1997.00623.x.

Kapsokefalou M, Miller DD: Iron loading and large doses of intravenous ascorbic acid promote lipid peroxidation in whole serum in guinea pigs. Br J Nutr. 85: 681-687.

Chen K, Suh J, Carr AC, Marrow JD, Zeind J, Frei B: Vitamin C suppresses lipid damage in vivo even in the presence of iron over-load. Am J Physiol Endocrinol Metab. 2000, 279: E1406-1212.

Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A: Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994, 139: 1180-1189.

Manson JE, Stampfer MJ, Willett WC, et al: A prospective study of vitamin C and incidence of coronary heart disease in women. Circulation. 1982, 85: 865-875.

Rimm EB, Stampfer MJ, Ascherio A, Giovanno E, Colditz GA, Willettt WC: Vitamin E consumption and risk of coronary heart disease in men. N Engl J Med. 1993, 328: 1450-1456. 10.1056/NEJM199305203282004.

Enstrom JE, Kanim LE, Klein MA: Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992, 3: 194-202.

Gale CR, Martyn CN, Winter PD, Cooper C: Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people. Br Med J. 1995, 310: 1563-1566.

Ness A, Egger M, Davey-Smith G: Role of antioxidant vitamins in prevention of cardiovascular disease. Br Med J. 1999, 319: 577-579.

Cameron E, Pauling L: In: Cancer and Vitamin C. 1979, W.W.Norton &; Company, Inc, New York, 132-

Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 1976, 73: 3685-3689.

Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci USA. 1978, 75: 4538-4542.

Murata A, Morsige F, Yamaguchi H: Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vit Nutr Res Suppl. 1982, 23: 103-113.

Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM: High dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemothrerapy : A randomized double blind comparison. N Engl J Med. 1985, 312: 137-141.

Block G: Vitamin C and cancer prevention: the epidemiological evidence. Am J Clin Nutr. 1991, 53: 270S-282S.

Frei B: Reactive oxygen species and antioxidant vitamins: Mechanism of action. Am J Med. 1994, 97: 5S-13S.

Uddin S, Ahmad S: Antioxidant protection against cancer and other human diseases. Comprehen Therap. 1995, 21: 41-45.

Tsao CS: Inhibiting effect of ascorbic acid on growth of human mammary tumor xenografts. Am J Clin Nutr. 1991, 54: 1274S-1280S.

Liehr JG: Vitamin C reduces the incidence and severity of renal tumors induced by estradiol or diethylstibesterol. Am J Clin Nutr. 1991, 54: 1256S-1260S.

Park CH, Kimler BF: Growth modulation of human leukemic, pre-leukemic and myeloma progenitor cell by L-ascorbic acid. Am J Clin Nutr. 1991, 54: 1241S-1246S.

Eckert-Maksic M, Kovacek I, Maksic ZB, Osmak M, Paveli K: Effect of ascorbic acid and its derivatives on different tumors in vivo and in vitro. In: Molecules in Natural Science and Medicine. An Encomium for Linus Pauling. Edited by: Maksic ZB, Eckert-Maksic M. 1991, Ellis Horwood, New York, 509-524.

Murakami K, Muto N, Fukasawa GK, Yamamoto I: Comparison of ascorbic acid and ascorbic acid 2-O-L-glucosidase on the cytotoxicity and bioavailability to low density culture of fibroblast. Biochem Pharmacol. 1992, 44: 2191-2197. 10.1016/0006-2952(92)90034-G.

Roomi MW, House D, Eckert_Maksic M, Maksic ZB, Tsao CS: Growth suppression of malignant leukemia cell line in vitro by ascorbic acid (Vitamin C) and its derivatives. Cancer Lett. 1998, 122: 93-99. 10.1016/S0304-3835(97)00376-5.

Pavelic K: L-ascorbic acid induced DNA strand breaks and cross links in human neuroblastoma cell. Brain Res. 1985, 342: 369-373. 10.1016/0006-8993(85)91139-4.

Medina MA, de Veas RG, Schweigerer L: Ascorbic acid is cytotoxic for peidoatric tumor cells cultured in vitro. Biochem Mol Biol Inter. 1994, 34: 871-874.

Roomi MW, House D, Tsao CS: Cytotoxic effect of substitution at 2-, 6-, and 2,6-positions in ascorbic acid on malignant cell line. Cancer Biochem Biophys. 1998, 16: 295-300.

Banks WA, Kastin AJ: Peptides and blood brain barrier: lipophilicity as predictor of permeability. Brain Res Bull. 1985, 15: 287-292. 10.1016/0361-9230(85)90153-4.

Naidu AK, Wiranowska M, Kori SH, Prockop LD, Kulkarni AP: Inhibition of human glioma cell proliferation and glutathione-S-transferase by ascorbyl esters and interferon. Anticancer Res. 1993, 13: 1469-1471.

Naidu AK, Wiranowska M, Kori SH, Prockop LD, Kulkarni AP: Inhibition of cell proliferation and glutathione-S-transferase by ascorbyl esters and interferon in mouse glioma. J Neuro-Oncol. 1993, 16: 1-10.

Makino Y, Sakagami H, Takeda M: Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. Anticancer Res. 1999, 19: 3125-3132.

Naidu KA, Tang JL, Naidu KA, Prockop LD, Nicosia SV, Coppola D: Antiproliferative and apoptotic effect of ascorbyl stearate in human glioblastoma multiforme cell: Modulation of insulin-like growth factor-I receptor (IGF-IR) expression. J Neuro-Oncol. 2001, 54: 15-22. 10.1023/A:1012545311054.

Liu JW, Nago N, Kageyama K, Miwa N: Anti-metastatic effect of an autooxidation-resistant and lipophilic ascorbic acid derivative through inhibition of tumor invasion. Anticancer Res. 2000, 20: 113-118.

Naidu AK, Karl RC, Naidu KA, Coppola D: The antiproliferative and pro-apoptotic effect of Ascorbyl Stearate in Human pancreatic cancer cells : Association with decreased expression of insulin-like growth factor receptor-1. Digest Dis Sci. 2003, 48: 230-237. 10.1023/A:1021779624971.

Naidu AK, Naidu KA, Sun M, Dan HC, Nicosia SV, Cheng JQ, Coppola D: Ascorbyl stearate inhibits proliferation and induces apoptosis of human ovarian carcinoma cells by targeting PI3k/akt pathway. Communicated to J Biol Chem. 2003

Sauberlich HE: Vitamin C and Cancer. In: Nutrition and disease update cancer. Edited by: Carroll KK, Kritchevsky D. 1994, AOCS Press, Champaign, Ilinois, 111-157.

Schorah CJ, Sobala M, Collis N, Primrose JN: Gastric juice ascorbic acid: effects of disease and implications for gastric carcinogenesis. Am J Clin Nutr. 1991, 53: 287S-293S.

Sobala GM, Pignaetelli B, Schorah CJ, Bartsch H, Sanderson M, Dixon MF, Shires S, King RFG, Axon ATR: Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid in gastric juice of patients with and without precancerous conditions of the stomach. Carcinogenesis. 1991, 12: 193-198.

Drake IM, Davies MJ, Mapstone NP, Dixon MF, Schorah CJ, White KL, Chamers DM, Axon AT: Ascorbic acid may protect against human gastric cancer by scavenging mucosal oxygen radicals. Carcinogenesis. 1996, 17: 559-562.

Brock KE, Berry G, Mock PA, MacLennan R, Truswell AS, Brinton LA: Nutrients in diet and plasma and risk in situ cervical cancer. J Natl Cancer Inst. 1988, 80: 580-585.

Verreault R, Chu J, Mandelson M, Shy K: A case study of diet and invasive cancer. Int J Cancer. 1989, 43: 1050-1054.

Potischman N, Brinton LA: Nutrition and cervical neoplasia. Cancer Causes Control. 1996, 7: 113-126.

Rock CL, Michael CW, Reynolds RK, Ruffin MT: Prevention of cervix cancer. Crit Rev Oncol Hematol. 2000, 33: 169-183. 10.1016/S1040-8428(99)00073-6.

Huang J, Agus DB, Winfree CJ, Kiss S, Mack WJ, McTaggart RA, Choudhri TF, Kim LJ, Mocco J, Pinsky DJ, Fox WD, Israel RJ, Boyd TA, Golde DW, Connolly ES: Dehydroascorbic acid, a blood-brain barrier transportable form of vitamin C, mediates potent cerebroprotection in experimental stroke. Proc Natl Acad Sci U S A. 2001, 98: 11720-11724. 10.1073/pnas.171325998.

Halliwell B, Gutteridge JMC: Free radicals in Biology and Medicine. Oxford University Press, Oxford. 1999

Halliwell B, Gutteridge JMC: Oxygen free radicals and iron in relation to biology and medicine: some problem and concepts. Arch Biochem Biophys. 1986, 246: 501-514.

Neuzil J, Thomas SR, Stocker R: Requirement for promotion or inhibition by α-tocopheroxyl radical induced plasma lipoprotein lipid peroxidation. Free Rad Biol Med. 1997, 22: 57-71. 10.1016/S0891-5849(96)00224-9.

Buettner GR, Jurkiewicz BA: Catalytic metals, ascorbate and free radicals: combinations to avoid. Rad Res. 1996, 145: 532-541.

Berger TM, Poldori MC, Dabbagh A, Evans PJ, Halliwell B, Morrow JD, Roberts II J, Frei B: Antioxidant activity of vitamin C in iron-overloaded human plasma. J Biol Chem. 1997, 279: 15636-15660.

Agus DB, Vera JC, Golde DW: Stromal cell oxidation: A mechanism by which tumors obtain vitamin C. Cancer Res. 1999, 59: 4555-4558.

Lee SH, Oe T, Bliar IA: Vitamin C induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 2001, 292: 2083-2086. 10.1126/science.1059501.

Marnett LJ: Oxyradicals and DNA damage. Carcinogenesis. 2000, 21: 361-370. 10.1093/carcin/21.3.361.

Johnson TM, Yu ZX, Ferrans VJ, Lowenstein T, Finkel T: Reactive oxygen species are downstream mediators of p53 dependent apotposis. Proc Natl Acd Sci USA. 1996, 93: 11848-11852. 10.1073/pnas.93.21.11848.

Lutsenko EA, Carcamo JM, Golde DW: Vitamin C prevents DNA mutation induced by oxidative stress. J Biol Chem. 2002, 277: 16895-16899. 10.1074/jbc.M201151200.

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Acknowledgements

Author gratefully acknowledges Dr.S.G.Bhat, Head, Department of Biochemistry and Nutrition and Dr.V.Prakash, Director, CFTRI, Mysore for their encouragement in preparing this review. The author also acknowledges Dr.Santo V.Nicosia and Dr. D.Coppola, Moffitt Cancer Research Center, University of South Florida, Tampa, FL, USA for supporting the work on ascorbyl stearate in his laboratory.

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Naidu, K.A. Vitamin C in human health and disease is still a mystery? An overview. Nutr J 2 , 7 (2003). https://doi.org/10.1186/1475-2891-2-7

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Li N , Zhao G , Wu W, et al. The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia : A Randomized Clinical Trial . JAMA Netw Open. 2020;3(11):e2023644. doi:10.1001/jamanetworkopen.2020.23644

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The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia : A Randomized Clinical Trial

1 Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China

Question Are the effects of oral iron supplements alone equivalent to a regimen of oral iron supplements plus vitamin C in the treatment of iron deficiency anemia?

Findings In this randomized clinical trial that included 440 adults with iron deficiency anemia, the mean change in hemoglobin level after 2 weeks was 2.00 g/dL in the oral iron supplements plus vitamin C group, compared with 1.84 g/dL in the oral iron supplements–only group. This difference met prespecified criteria for equivalence.

Meaning The use of oral iron supplements alone is comparable to a regimen of vitamin C supplemented with oral iron for patients with iron deficiency anemia.

Importance It remains uncertain whether vitamin C routinely used with oral iron supplements is essential for patients with iron deficiency anemia (IDA).

Objective To compare the equivalence and assess the safety of oral iron supplements plus vitamin C or oral iron supplements alone in patients with IDA.

Design, Setting, and Participants This single-center, open-label, equivalence randomized clinical trial was conducted from January 1, 2016, to December 30, 2017, in Huashan Hospital, Fudan University. Adult patients with newly diagnosed IDA were enrolled. Participants were randomly assigned (1:1) to the oral iron supplements plus vitamin C group or the oral iron supplements–only group. Data analysis was performed from March to December 2018.

Interventions Patients were randomized to receive a 100-mg oral iron tablet plus 200 mg of vitamin C or a 100-mg iron tablet alone every 8 hours daily for 3 months.

Main Outcomes and Measures The primary outcome was the change in hemoglobin level from baseline to 2 weeks of treatment, and an equivalence margin of 1 g/dL in hemoglobin was chosen for the demonstration of comparable efficacy. Secondary outcomes included the change in the reticulocyte percentage after 2 weeks of treatment, the increase in hemoglobin level after 4 weeks of treatment, the increase in serum ferritin level after 8 weeks of treatment, and adverse events.

Results Among the 440 randomized patients (220 each in the oral iron supplements plus vitamin C group and iron-only group; 426 women [96.8%]; mean [SD] age, 38.3 [11.7] years), all were assessed for the primary outcome, and 432 (98.2%) completed the trial. From baseline to the 2-week follow-up, the mean (SD) change in hemoglobin level was 2.00 (1.08) g/dL in the oral iron supplements plus vitamin C group and 1.84 (0.97) g/dL in the oral iron supplements–only group (between-group difference, 0.16 g/dL; 95% CI, −0.03 to 0.35 g/dL), thus meeting the criteria for equivalence. The mean (SD) change in serum ferritin level from baseline to 8-week follow-up was 35.75 (11.52) ng/mL in the vitamin C plus iron group and 34.48 (9.50) ng/mL in the iron-only group (between-group difference, 1.27 ng/mL; 95% CI, −0.70 to 3.24 ng/mL; P = .21). There were no significant differences between the 2 groups regarding the rates of adverse events (46 [20.9%] vs 45 [20.5%]; difference, 0.4%; 95% CI, −6.7% to 8.5%; P = .82). No patient withdrew because of adverse events.

Conclusions and Relevance Among patients with IDA, oral iron supplements alone were equivalent to oral iron supplements plus vitamin C in improving hemoglobin recovery and iron absorption. These findings suggest that on-demand vitamin C supplements are not essential to take along with oral iron supplements for patients with IDA.

Trial Registration ClinicalTrials.gov Identifier: NCT02631668

Iron deficiency anemia (IDA) is associated with a decrease in erythropoiesis caused by a deficit in total body iron. 1 Iron deficiency is the leading cause of anemia worldwide. According to the World Health Organization guideline, 2 IDA affects 30% of the world’s population, indicating that it is a problem requiring attention.

Iron deficiency can be divided into 3 stages: prelatent iron deficiency, latent iron deficiency (also called iron-deficient erythropoiesis), and iron deficiency anemia (IDA). 2 , 3 At the first stage, iron intake lower than the required amount causes progressive depletion of iron storage primarily in the liver and muscle cells. Patients at this stage generally have no symptoms, and the diagnosis of iron deficiency is made when levels of serum ferritin (the storage form of iron) decrease below 20 ng/mL (to convert to micrograms per liter, multiply by 1.0). Sustained iron storage depletion leads to the second stage of iron deficiency, iron-deficient erythropoiesis, in which iron deficiencies progress and begin to affect erythropoiesis. Despite an increased transferrin level, serum iron level decreases along with transferrin saturation. Erythropoiesis impairment appears when the serum iron level decreases to less than 50.3 μg/dL (to convert to micromoles per liter, multiply by 0.179) and transferrin saturation is less than 16%. 4 Hemoglobin level is still within the normal range until the development of the IDA stage. Iron storage levels deplete to the point that they can no longer support the hemoglobin production and generate enough red blood cells (RBCs). Iron deficiency impairs RBC synthesis and hemoglobin production, leading to anemia. 5

During the prelatent iron deficiency phase, an iron-rich diet can treat most cases. However, patients with IDA require iron supplements to replenish storage iron, restore normal hematopoiesis, treat anemia, and relieve symptoms. 3

Oral iron supplementation is the primary approach to restore iron levels for patients with IDA. Numerous nonheme iron supplements are available, and ferrous sulfate and ferric succinate supplements are the most commonly used. Vitamin C is the only dietary constituent other than animal tissue that has been shown to promote iron absorption. 6 - 9 Iron absorption occurs predominantly in the duodenum and upper jejunum, where ferrous iron can be transported into small intestine mucosal epithelial cells. When taken orally, iron is always oxidized to the Fe 3+ state from its original form. It requires an acidic gastrointestinal environment to be dissolved adequately for absorption. Vitamin C can create a more acidic environment in the stomach and prevent the oxidization of ferrous iron to ferric iron. 10 However, in a series of 12 individuals treated with iron during intake of a regular or vitamin C–supplemented diet, 8 the effect of vitamin C on promoting iron absorption from a complete diet was far less pronounced than that from a single meal. The facilitating impact of vitamin C with food on iron status is minimal. 8 , 11 Therefore, whether vitamin C has additional advantages, such as improving the efficacy of iron tablets and, thus, speeding up the recovery of anemia, remains poorly understood. Whether iron tablets with vitamin C supplements should be recommended is controversial.

To our knowledge, until now there has not been a randomized clinical trial (RCT) to assess whether vitamin C supplements are necessary for patients with IDA taking iron tablets. Therefore, it is necessary to conduct a rigorous RCT to assess the efficacy and safety of oral iron supplements alone or combined with vitamin C in patients with IDA. We designed a single-center, equivalence RCT to evaluate whether oral iron supplements alone were comparable with oral iron supplements plus vitamin C and to verify whether vitamin C routinely used with iron supplements can improve iron absorption.

This 2-year, open-label, single-center, RCT was conducted at Huashan Hospital, Fudan University, Shanghai, China. All patients provided written informed consent before the commencement of the study. The institutional review board of Huashan Hospital, Fudan University, approved this research. This study follows the Consolidated Standards of Reporting Trials ( CONSORT ) reporting guideline.

Randomization of participants at a 1:1 ratio was performed using Stata statistical software version 11.0 (StataCorp) by a randomization procedure ( Figure 1 ). Sequentially numbered, opaque, sealed envelopes ensured the concealment of randomization. The serial numbers on the outside of the envelopes were consistent with the patients’ visit numbers. After baseline measurements, the physician provided the sealed envelope marked with the eligible patient’s consulting number. Then the patient opened the sealed envelope, which contained the information on the assigned randomization group.

The intervention group received a 100-mg oral iron tablet (ferrous succinate, 100 mg/tablet) plus 200 mg of vitamin C (vitamin C, 100 mg/tablet) every 8 hours daily; the control group received a 100-mg iron tablet (ferrous succinate, 100 mg/tablet) every 8 hours daily. All patients took the supplements with warm water half an hour after a meal. Compliance was addressed by determining the actual number of iron and vitamin C tablets returned by the participants. The complete trial protocol can be seen in Supplement 1 .

We screened patients newly diagnosed with IDA who had not received any iron supplement therapy in Huashan Hospital, Fudan University, from January 1, 2016, to December 30, 2017. Some of these patients were found to have anemia during a routine checkup. Most patients presented because of symptoms such as dizziness and palpitation. The nurse prechecked first. If the patients were found to have anemia, the nurse would recommend them to the anemia clinic to receive examination and treatment. Then our team screened these patients for enrollment.

The inclusion criteria were age 18 years or older, voluntarily signing the informed consent form, and meeting the diagnostic criteria for IDA, which include a hemoglobin level less than 13 g/dL for men or less than 12 g/dL for women (to convert hemoglobin to grams per liter, multiply by 10.0), mean corpuscular volume (MCV) less than 80 μm 3 (to convert MCV to femtoliters, multiply by 1.0), mean corpuscular hemoglobin (MCH) less than 27 pg/cell, mean corpuscular hemoglobin concentration (MCHC) less than 32 g/dL (to convert MCHC to grams per liter, multiply by 10), serum ferritin level less than 14 ng/mL for women or 30 ng/mL for men, serum iron less than 39 μg/dL for women or 56 μg/dL for men, transferring saturation less than 20%, and total iron-binding capacity (TIBC) exceeding 428 μg/dL (to convert TIBC to micromoles per liter, multiply by 0.179). Exclusion criteria were pregnancy, severe uncorrectable bleeding, identified stomachache or intestinal ulcers, any inflammatory diseases, or identified gastrointestinal tumors.

Patients were treated for 3 months and assessed with a complete blood count every 2 weeks for 2 months; iron metabolism was measured at week 8. The primary outcome was the change in hemoglobin level from baseline to the 2-week follow-up. The secondary outcomes included the change in the reticulocyte percentage after 2 weeks of treatment, the increase in hemoglobin after 4 weeks of treatment, the increase in serum ferritin after 8 weeks of treatment, and adverse events. Exploratory outcomes included MCV, MCH, and MCHC levels every 2 weeks at all time points and serum iron level, transferring saturation, and TIBC at 8 weeks. The Department of Laboratory Medicine in Huashan Hospital, Fudan University, conducted the measurements and biochemical analyses.

Sample size calculations were performed for the change in hemoglobin level from baseline using an equivalence design; with bounds of 1 g/dL for the mean difference and a significance level of .05, a total sample size of 392 participants (assuming no difference between groups), a common SD of 1.5 g/dL, an allowable error of 0.5 g/dL, and an allocation ratio of 1:1 would correspond to a power of 90%. Considering a dropout rate of 10%, 440 patients in total were enrolled in the study.

Results with normal distributions were confirmed by a normal distribution test and were presented as mean (SD) values. Comparison of ages, the baseline of complete blood count, and iron metabolism parameters between the 2 groups was performed with the t test. Comparison of sexes and the incidence of adverse reactions between the 2 groups were based on 2-sided Pearson χ 2 test. The 95% CIs for the difference of the changes of hemoglobin level between the 2 groups were calculated at each time point, and the equivalence was evaluated using the predefined margins of equivalence (±1 g/dL). Efficacy variables were analyzed on an intention-to-treat basis. If patients dropped out, missing data were imputed by the last observation carried forward method. For analysis of adverse events, patients who received at least 1 dose of study drug were included in the safety population. The threshold of a statistical significance was set as a P < .05. All tests were performed using Stata statistical software version 11.0 (StataCorp) from March to December 2018. The full statistical analysis plan is available in Supplement 2 .

Of 530 patients assessed for eligibility, 90 were excluded. The remaining 440 patients (mean [SD] age, 38.3 [11.7] years) underwent randomization. All patients completed the follow-up until 5 patients in the vitamin C plus iron group and 4 patients in the iron-only group dropped out after 2 weeks. The proportion of compliance was 98.2% (432 participants). Figure 1 shows the flow of participants in this trial.

Of the 440 patients, 426 (96.8%) were women with a mean age of 38.1 years (range, 18-90 years). The most common cause of IDA in women was menorrhagia due to uterine fibroids or endometriosis, which was found in 389 women (91.3%) in this study. Other reasons included hemorrhoidal hemorrhage (9 patients [2.1%]), vegetarian diet (7 patients [1.6%]), fecal occult blood positive due to gastrointestinal bleeding (4 patients [0.9%]), repeated hematuria (1 patients [0.2%]), and unknown (16 patients [3.8%]). Fourteen of the patients (3.2%) were men with a mean age of 61.4 years (range, 24-80 years), with causes of IDA including hemorrhoidal hemorrhage (5 patients [35.7%]), bleeding ulcer (4 patients [28.6%]), gastric cancer after surgery (3 patients [21.4%]), intestinal inflammation (1 patient [7.1%]), and colon cancer after surgery (1 patient [7.1%]). There were no significant differences between the 2 groups in terms of baseline characteristics ( Table 1 ).

From baseline to 2-week follow-up, the mean (SD) change in hemoglobin level was 2.00 (1.08) g/dL in the vitamin C plus iron group and 1.84 (0.97) g/dL in the iron-only group (mean between-group difference, 0.16 g/dL; 95% CI, −0.03 to 0.35 g/dL). For the primary outcome, the change in hemoglobin level from baseline to 2-week follow-up was contained within the equivalence margin of 1 g/dL ( Figure 2 ); thus, there was no significant difference in hemoglobin level increase between the 2 groups. Similarly, there was no significant difference in the change in hemoglobin level at weeks 4, 6, and 8 ( Table 2 ).

The median (interquartile range) change in reticulocyte percentage after a 2-week follow-up was 1.03% (0.74%-1.20%) in the vitamin C plus iron group and 1.04% (0.50%-1.20%) in the iron-only group (between-group difference, 0.11%; 95% CI, 0.10% to 0.32%); the difference was not significant. Similar results were obtained at week 4, 6, and 8 showing no significant differences between the 2 groups ( Table 2 ).

MCV and MCH levels increased slightly (all 95% CIs were positive) in the vitamin C plus iron group at all follow-up points ( Table 2 ). The increase in MCHC level was higher in the vitamin C plus iron group at 6 weeks, with mean (SD) changes in MCHC of 3.10 (1.33) g/dL in vitamin C plus iron group and 2.82 (1.41) g/dL in the iron-only group (between-group difference, 0.28 g/dL; 95% CI, 0.02-0.53 g/dL). Changes of RBC distribution width coefficient of variation showed no significant difference between the 2 groups at all follow-up points ( Table 2 ).

Likewise, no difference was observed between groups for the change in serum ferritin level from baseline to 8-week follow-up. The mean (SD) change was 35.75 (11.52) ng/mL in the vitamin C plus iron group and 34.48 (9.50) ng/mL in the iron-only group (mean between-group difference, 1.27 ng/mL; 95% CI, −0.70 to 3.24 ng/mL; P = .21). The mean changes in serum iron, transferring saturation, and TIBC were also comparable between the 2 groups ( Table 2 ).

The treatment was similarly well tolerated during 8 weeks of follow-up. The most frequent adverse events were stomach upset, nausea, and acid reflux ( Table 3 ). The proportion of patients with adverse events was comparable between the 2 groups, 46 (20.9%) in the vitamin C plus iron group and 45 (20.5%) in the iron-only group after 2 weeks of follow-up (difference, 0.4%; 95% CI, −6.7% to 8.5%; P = .82). After 2 weeks of treatment, 68 patients with adverse events felt better and another 23 patients could tolerate the adverse events. No patients opted out because of adverse events ( Table 3 ).

These findings demonstrate that oral iron supplements alone provide hemoglobin level and iron storage recovery efficacy equivalent to that of oral iron supplemented with vitamin C in patients with IDA. To our knowledge, this RCT is the first to evaluate the efficacy and safety of vitamin C supplements combined with oral iron in patients with IDA.

Oral iron provides an inexpensive and effective means of restoring iron balance in patients with IDA. Vitamin C is the only dietary constituent other than animal tissue that has been shown to promote the absorption of nonheme iron in humans. 9 Thus, some clinicians, who believe that vitamin C can improve the efficacy of oral iron and speed up the treatment of anemia, recommend taking vitamin C supplements combined with oral iron tablets. However, the absolute dose of vitamin C did not appear to be associated with iron absorption with a complete diet, and the improvement in iron status was not noticeable, 8 , 11 which was consistent with our findings that oral iron alone provides efficacy equivalent to that of oral iron with vitamin C. The changes in hemoglobin level were similar between the 2 groups at weeks 2, 4, 6, and 8. The mean difference in hemoglobin level change was within the equivalence margin of ±1 g/dL, which is the threshold for clinically significant change recommended by hematologists. Notably, the changes in MCV from baseline to all time points were slightly greater in the vitamin C plus iron group. MCV is a measure of the mean size of RBCs, and patients with IDA typically have lower than normal values. The RBC parameters MCH, MCV, and MCHC are more sensitive and helpful to monitor the response to a treatment. 12 However, the aim of treatment was restoring hemoglobin levels and replenishing iron stores, neither of which was sensitive to the treatment. Iron metabolism parameters such as serum ferritin, serum iron, iron saturation, and TIBC at week 8 were comparable between the 2 groups. Adverse events were also equivalent between the 2 groups.

These results challenge the recommendation to take vitamin C supplements with oral iron to improve the efficacy and speed up the recovery from anemia. Iron is absorbed as the ferrous salt (Fe ++ ) in a mildly acidic medium. In theory, vitamin C is helpful in its absorption. However, in light of the results of this RCT, vitamin C may be less beneficial than reported and expected.

This study has some limitations. First, 426 of the included patients were women and 19 were men, which was an imbalance. Second, the overall follow-up period was not long enough. We found that iron deficiency anemia relapsed easily if the underlying causes, such as iron-absorption defects and bleeding, were not investigated and addressed. Some patients came back to our clinic approximately 1 year after the trial ended because of relapse. The time when iron deficiency reappeared again and whether the proportion of relapse was comparable for the 2 groups were both unknown. Future research should extend the observation period to obtain more accurate and reliable results.

The findings of this equivalence RCT demonstrate that in patients with IDA, taking oral iron alone was equivalent to taking oral iron supplemented with vitamin C in improving hemoglobin level and iron stores. Our results suggest that vitamin C is not essential for patients with IDA.

Accepted for Publication: August 31, 2020.

Published: November 2, 2020. doi:10.1001/jamanetworkopen.2020.23644

Corresponding Author: Xiaoqin Wang, MD, PhD, Department of Hematology, Huashan Hospital, Fudan University, 12 Wulumuqi Rd, Shanghai 200024, China ( [email protected] ).

Author Contributions: Dr Wang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Li and Zhao are co–first authors.

Concept and design: Li, Zhao, Chen, Wang.

Acquisition, analysis, or interpretation of data: Wu, Zhang, Liu.

Drafting of the manuscript: Li, Zhao.

Critical revision of the manuscript for important intellectual content: Wu, Zhang, Liu, Chen, Wang.

Statistical analysis: Li, Zhao, Wang.

Obtained funding: Wang.

Administrative, technical, or material support: Li, Wu, Zhang, Liu, Chen, Wang.

Supervision: Zhao, Wang.

Conflict of Interest Disclosures: None reported.

Data Sharing Statement: See Supplement 3 .

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v.5(1); 2014 Jan

Vitamin C 1

Vitamin C (ascorbic acid) is a simple low-molecular-weight carbohydrate with an ene-diol structure that has made it a ubiquitous and essential water-soluble electron donor in nature. It is synthesized by all species except for higher-order primates, guinea pigs, and some bat, fish, and bird species. In all of the latter, the gene encoding for i-gulonolactone oxidase—the enzyme catalyzing the final step in the biosynthesis of ascorbic acid—has evolved into a nonfunctional state due to accumulation of mutations and/or deletions; consequently, these species rely on an adequate supply of vitamin C from their diet.

In all its known biologic functions, vitamin C acts as a reductant, i.e., it donates an electron to a substrate while itself being oxidized to an ascorbyl radical, a relatively stable free radical. Two molecules of ascorbyl free radical can dismutate into 1 molecule of ascorbate and 1 molecule of dehydroascorbic acid, the fully reduced and oxidized forms of vitamin C, respectively. To minimize the loss of vitamin C through metabolism and excretion, efficient retaining mechanisms have evolved, including ascorbate recycling, in which dehydroascorbic acid is rapidly reduced to ascorbate intracellularly by glutathione (another cellular reductant) or the selenoenzyme, thioredoxin reductase, and active renal reabsorption by the sodium-dependent vitamin C transporter (SVCT) 2 1. Vitamin C absorption, tissue distribution, and excretion are tightly controlled by tissue-specific, active transport through SVCT1 and SVCT2. If vitamin C intake in humans is in excess of ∼400 mg/d, a homeostatic state is reached with maximal plasma steady-state concentrations of ∼60 to 90 μ mol/L and intracellular concentrations ranging from 0.5 to 10 mmol/L, depending on the tissue. The highest concentrations of vitamin C are found in the brain, eye, and adrenal gland.

The biologic role of vitamin C is related to its reduced form, ascorbate, and can be separated into enzymatic and nonenzymatic functions. The best-known enzymatic function of vitamin C is probably as cofactor for the ferrous [Fe(II)] and 2-oxoglutarate dependent dioxygenases in collagen synthesis. These enzymes catalyze the hydroxylation of lysine and proline residues in unfolded procollagen chains, which are the building blocks of the triple-helical structure of mature, functional collagen. Ascorbate also serves as an electron donor for various enzymes catalyzing carnitine and norepinephrine biosynthesis, peptide hormone amidation, and tyrosine metabolism. Ascorbate-mediated hydroxylation of hypoxia inducible factor 1 α (HIF-1 α ) regulates the transcription of several genes encoding proteins involved in iron homeostasis, angiogenesis, and cell proliferation.

More recently, several studies have shown that vitamin C plays an important role in vascular function. Ascorbate modulates vasorelaxation by increasing NO synthesis or bioavailability in a number of ways ( 1 ). Endothelial NO synthase (eNOS) generates NO, which diffuses to the smooth muscle cell layer of the vascular wall and mediates dilation through its interaction with soluble guanylyl cyclase. Tetrahydrobiopterin is a cofactor for eNOS activity, and vitamin C appears to recycle tetrahydrobiopterin from its oxidized form(s), thereby sustaining the enzyme’s activity. Moreover, vitamin C may affect NO bioavailability through ascorbate-mediated denitrosylation and phosphorylation of eNOS. Other roles of vitamin C in vascular function include modulating the endothelial cell barrier and regulating the activity of NADPH oxidases (NOXs) involved in inflammatory gene response.

In addition to its roles in the above enzymatic processes, ascorbate is a powerful antioxidant with the ability to reduce or “scavenge” many (patho)physiologically relevant free radicals and reactive oxygen species. In addition, vitamin C can regenerate vitamin E ( α -tocopherol) from its oxidized form ( α -tocopheroxyl radical), allowing vitamin C to indirectly inhibit lipid peroxidation. Ascorbate can also reduce urate and glutathione radicals as part of the antioxidant network in cells and extracellular fluids. Although the clinical importance of ascorbate’s antioxidant action is difficult to assess, a considerable experimental literature has shown that vitamin C effectively protects biologic macromolecules from oxidative damage that might otherwise causally contribute to the initiation and progression of several chronic and acute diseases ( 2 ).

The clinical hallmark of severe and prolonged vitamin C deficiency is scurvy, which is fatal if left untreated. The symptoms of impaired wound healing, gingivitis, perifollicular hemorrhages, ecchymoses, and petechiae have been known for centuries and are largely related to impaired collagen biosynthesis and perhaps HIF-1 α hydroxylation. Other symptoms of severe vitamin C deficiency are malaise and fatigue or lethargy, which may be difficult to diagnose clinically. These symptoms can be explained by impaired carnitine biosynthesis resulting in decreased fatty acid transport and subsequent β -oxidation in mitochondria required for ATP production and decreased synthesis of the neurotransmitter norepinephrine. The enzymatic synthesis of both carnitine and norepinephrine involves hydroxylation steps that depend on vitamin C for full enzyme activity ( 2 ). Whereas vitamin C deficiency is mainly caused by poor diet, several additional risk factors have been identified, including smoking, pregnancy, low socioeconomic status, genetic predisposition, old or young age, strenuous exercise, and clinical conditions associated with metabolic syndrome, such as hypertension, diabetes, and obesity.

Dietary Recommendations

Based on the vitamin C intake required to achieve near-saturation of plasma and leukocytes with minimal urinary excretion, and adjusted for body mass, an RDA of 75 and 90 mg/d for women and men, respectively, was established by the U.S. Institute of Medicine (IOM) in 2000. In addition, the RDA for pregnant and breastfeeding women (≥19 y) was set at 85 and 120 mg/d, respectively. No RDA was established for infants; instead, the Adequate Intake of vitamin C was set at 40 mg/d for infants up to 6 mo of age, and 50 mg/d for infants up to 12 mo. For older children, the recommendation is based on estimated body mass in relation to an adult: 15 mg/d for children up to 3 y of age, 25 mg/d for children up to 8 y, and 45 mg/d for children up to 13 y. The RDA for teenagers is based on gender: 75 and 65 mg/d for boys and girls 13–17 y of age, respectively ( 3 ).

It has long been recognized that smokers and individuals exposed to environmental tobacco smoke (“passive” smokers) have a lower vitamin C status than nonsmokers. This is believed to be partly due to poor dietary habits but also due to the oxidizing properties of tobacco smoke per se, resulting in an increased turnover of vitamin C. Consequently, the IOM recommends that smokers get an additional 35 mg/d of vitamin C. No increased RDA has been established for passive smokers, but they are strongly encouraged to ensure that they meet the standard RDA.

Recent data suggest that the current RDA for vitamin C set by the IOM for men and women may be too low. On the basis of a comprehensive review of the scientific evidence from human metabolic, pharmacokinetic, and observational studies as well as phase 2 randomized controlled trials, it was concluded that 200 mg/d is the optimum intake of vitamin C for the majority of the adult population to maximize the vitamin’s potential health benefits with the least risk of inadequacy or adverse health effects ( 4 ).

Food Sources

Fruit and vegetables are good sources of vitamin C, and ~90% of the daily intake in the general population comes from these sources. The content varies between species, but citrus fruit, kiwi, mango, and vegetables such as broccoli, tomatoes, and peppers are all rich sources of vitamin C. Because vitamin C degrades when heated and during storage, the processing and preparation procedures should be considered when estimating dietary intake of vitamin C. A total of 5–9 servings of fresh, minimally processed, or frozen fruit and vegetables per day is estimated to equal ~200 mg of vitamin C. The presence of vitamin C in dietary products other than fruit and vegetables is typically due to its addition as a preservative to processed foods to protect against oxidation. In areas where vegetation is sparse, such as the arctic regions, people have traditionally relied on alternative sources of vitamin C, such as medicinal herbs (herbal teas and tinctures from rose hips, pine needles, and tree barks) and animal organs, such as raw liver and whale skin.

Clinical Uses

The current RDA for vitamin C largely exceeds the amount necessary to prevent scurvy (~10 mg/d). However, given the possible severity of events associated with scurvy, urgent replacement therapy is suggested when clinical signs or symptoms of vitamin C deficiency are identified. Oral supplementation with 500 mg/d will be adequate in milder cases, but parenteral therapy may be required in severe cases and in cases of impaired intestinal function or lack of compliance. Subclinical vitamin C deficiency is difficult to detect because the typical symptoms, fatigue and lassitude, are nonspecific. Overt vitamin C deficiency can be seen in malnourished populations, including those with chronic conditions, poor dietary habits, malabsorption, or chemical dependencies.

A considerable epidemiologic literature has found associations between poor vitamin C status and increased risk of developing cardiovascular diseases (CVDs), including coronary heart disease, ischemic stroke, and hypertension ( 5 ). Those with near-saturated plasma vitamin C concentrations appear to have the lowest CVD risk, suggesting that intakes greater than the RDA are required to achieve these health benefits. However, properly designed randomized controlled trials have not yet been conducted to either confirm or reject a causal link between vitamin C status and CVD. Thus, prophylactic supplementation of high-risk individuals is not currently recommended by the medical community. In contrast, a considerable number of large intervention studies have confirmed that supplementation of already well-nourished individuals has no additional health benefits.

Another clinical use of vitamin C is to increase nonheme-iron absorption. In the small intestine, vitamin C reduces dietary iron and allows for efficient transport across the intestinal epithelium. Food sources of vitamin C or supplements, when consumed with iron, may lead to increased hemoglobin production in anemic patients. Recent work at the NIH and the University of Iowa has suggested that gram-doses of intravenously administered vitamin C may have merit in cancer therapy in conjunction with standard chemotherapy. This beneficial effect of intravenous vitamin C may be due to ascorbate autooxidation and the generation of hydrogen peroxide, which is selectively toxic to cancer cells.

Vitamin C is generally safe and well tolerated, even in large doses. The IOM set the Tolerable Upper Intake Level for oral vitamin C ingestion at 2 g daily for adults based on gastrointestinal disturbances observed in some individuals at higher doses. High amounts of vitamin C intake have been associated with an increased risk of kidney stones, although the evidence is mixed and inconsistent. The current recommendation is to avoid vitamin C supplementation in those susceptible to kidney stone formation. Vitamin C consumed with iron could increase the risk of iron overload in susceptible individuals. Patients with these conditions should not avoid eating fruit and vegetables but limit their intake of iron instead. Vitamin C has been reported to cause hemolysis in individuals with glucose-6-phosphate dehydrogenase deficiency, but these reports have not been substantiated.

Recent Research

The so-called antioxidant hypothesis of the 1980s promising a long and healthy life from an abundant intake of antioxidants, including vitamin C, has long been replaced by the view that the health benefits of vitamin C are derived from its role in a number of key reactions within immune function, metabolism, and other enzymatic and nonenzymatic reactions (see above). Thus, emerging evidence indicates that even marginal vitamin C deficiency may impair normal perinatal neurogenesis, affect fetal programming of adult disease risk, and increase the risk of cardiovascular and all-cause mortality. Several genetic variants have been identified in SVCTs, haptoglobin, and glutathione S -transferases that may influence plasma vitamin C status or uptake into tissues. More recent studies have investigated how these polymorphisms may interact with low dietary vitamin C concentrations to increase chronic disease risk ( 6 ).

Literature Cited

IMAGES

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COMMENTS

Vitamin C—Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination
Vitamin C has been undergoing extensive research and we know many processes in which it is involved. ... Ascorbate is recovered from the ascorbyl radical (3) by several pathways discussed in this article. Under the lack of vitamin C and under oxidative stress, BH 4 is oxidized by reactive oxygen species (ROS).
On the effect of vitamin C intake on human health: How to (mis
2. Pharmacokinetics of vitamin C. The pharmacokinetics of vitamin C has recently been reviewed in detail [] and only a brief overview is provided here.The intestinal absorption of orally ingested vitamin C—that being from food sources or supplements alike—occurs through transporter proteins rather than by passive diffusion [8,9].Several decades ago, it was observed by independent ...
Vitamin C in Disease Prevention and Cure: An Overview
The recognition of vitamin C is associated with a history of an unrelenting search for the cause of the ancient haemorrhagic disease scurvy. Isolated in 1928, vitamin C is essential for the development and maintenance of connective tissues. ... Research has also refocused on the implications and applicability of high i.v. dose of vitamin C in ...
On the effect of vitamin C intake on human health: How to (mis
Metabolism of vitamin C is intimately linked to its redox status. Ascorbate is an efficient chain-breaking antioxidant both capable of quenching free radicals and specifically donating electrons to a considerable number of mono- and dioxygenase enzymes [32].Moreover, a whole range of mechanisms has evolved to ensure that oxidized vitamin C is almost quantitatively salvaged by intracellular ...
A comprehensive review and recent advances of vitamin C: Overview
To date, the price of the standard 99% vitamin C is in the range of USD 2.00/kg to USD 10.00/kg (FIC, 2023, TJHB, 2023) which has reduced after the COVID-19 peak in global, Asia, and Southeast Asia markets as shown in Fig. 1, as well as Figs. S1 and S2 in the supplementary material.In the market trend of vitamin C 99% based on the selling price, it can be seen that there is a price decline ...
Frontiers
Introduction. Vitamin C (ascorbic acid) plays an important role in the normal functioning of the immune system (1-4) and its use in preventing and/or treating infections has strongly attracted the interest of physicians and investigators for almost a century.A plethora of papers have been published on this topic, but, although it is well known that a deficiency of vitamin C due to a low ...
Parenteral Vitamin C in Patients with Severe Infection: A Systematic
Introduction. Severe infections manifest with inflammation and oxidative damage. 1 Vitamin C (ascorbic acid) deficiency has been reported in patients with severe infection. 2-4 Preclinical evidence suggests that vitamin C supplementation may reduce endothelial injury in the pulmonary and systemic vasculature, oxidative damage, and harmful ...
The effects of vitamin C supplementation in the critically... : Medicine
Research has shown that vitamin C deficiency is one of the independent risk factors in death in intensive care unit (ICU) patients, closely related to the severity and prognosis of the disease. [10, 11] The current published research results are inconsistent, [10, 12, 13] so we must conduct this study. We aim to conduct the meta-analysis of all ...
Vitamin C and Immune Function
Vitamin C is an essential micronutrient for humans, with pleiotropic functions related to its ability to donate electrons. It is a potent antioxidant and a cofactor for a family of biosynthetic and gene regulatory enzymes. Vitamin C contributes to immune defense by supporting various cellular functi …
Vitamin C
Vitamin C and Health . There is interest in the antioxidant role of vitamin C, as research has found the vitamin to neutralize free radical molecules, which in excess can damage cells. Vitamin C is also involved in the body's immune system by stimulating the activity of white blood cells. Does this translate to protection from certain diseases?
High-dose vitamin C enhances cancer immunotherapy
Vitamin C (VitC) is an essential dietary nutrient, and its chronic deficiency contributes to impaired immunity ().Immune cells accumulate high intracellular concentrations of VitC, suggesting that this cofactor is crucial for the function of these cells (12, 13).A possible effect of VitC on innate and adaptive immune responses in infectious diseases has been reported (13, 14).
Vitamin C in Human Health and Disease
The Special Issue "Vitamin C in Human Health and Disease" includes 10 peer-reviewed papers (nine review articles and one original research article) which mainly focus on the broadly defined role of vitamin C in osteoporosis, sleep quality, exercise performance, oxidative stress and inflammatory response in hemodialyzed patients, the ...
Nutrients
Dear Colleagues, Vitamin C is a pivotal water soluble electron donor in nature and an essential nutrient in man. Despite its many years as a research focus, new and increasingly regulatory functions of vitamin C in human health are continually being unravelled.
Vitamin C: One compound, several uses. Advances for delivery
Vitamin C (Vit C) or Ascorbic acid (AA) is a hydrophilic molecule, composed of six carbons, similar to glucose. 1 In the organisms, Vit C can be found in its reduced form (ascorbic acid or ascorbate) or in its oxidized form called dehydroascorbic acid (DHA), which is a product of two-electron oxidation of ascorbic acid. 2 It has essential physiological and metabolic activities in humans, but ...
Effects of vitamin C on health: A review of evidence
The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility and connective tissue damage due to failure in producing collagen, and, finally, to death as result ...
Vitamin C
Introduction. Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component [ 1 ].
Assessment of Human Vitamin C Status
Since no reliable functional markers of human vitamin C status have been demonstrated, determination of vitamin C levels in blood plasma and/or leukocytes remains the current choice for individual and population assessments. Newer analytical techniques, especially high-performance liquid chromatography, allow determination of reduced (ascorbic acid), oxidized (dehydroascorbic acid), or total ...
The effects of vitamin C on respiratory, allergic and ...
Vitamin C is used in modern medicine supplements for treatment of various disorders associated with oxidative stress, inflammation and immune dysregulation. In this review article, experimental and clinical results regarding the effects of vitamin C on respiratory immunologic, and allergic diseases are reviewed. Various databases and appropriate keywords are used to search the effect of ...
The Role of Vitamin C in Cancer Prevention and Therapy: A Literature
Abstract. Vitamin C is a water-soluble antioxidant associated with the prevention of the common cold and is also a cofactor of hydrolases that participate in the synthesis of collagen and catecholamines, and in the regulation of gene expression. In cancer, vitamin C is associated with prevention, progression, and treatment, due to its general ...
Vitamin C in human health and disease is still a mystery? An overview
Ascorbic acid is one of the important water soluble vitamins. It is essential for collagen, carnitine and neurotransmitters biosynthesis. Most plants and animals synthesize ascorbic acid for their own requirement. However, apes and humans can not synthesize ascorbic acid due to lack of an enzyme gulonolactone oxidase. Hence, ascorbic acid has to be supplemented mainly through fruits ...
Vitamin C: Why we need it, sources, and how much is too much
Summary. Vitamin C is a vital nutrient for health. Vitamin C benefits include helping form and maintain bones, cartilage, skin, and blood vessels. As an antioxidant, it also supports the immune ...
Vitamin C deficiency: Causes, treatment, and prevention
A prolonged vitamin C deficiency can cause severe and potentially life threatening symptoms. Eating a variety of fruits and vegetables can help maintain optimal levels of this important nutrient.
Vitamin C Intake and Cancers: An Umbrella Review
It was shown by dose-response analysis that every 50 mg/day increment of VC intake was related to a 13% decrease in esophageal cancer risk (95% CI 0.80-0.93) ( 22 ), and every 100 mg/day increment of VC intake was associated with a 26% reduce in gastric cancer risk (95% CI 0.69-0.79) ( 23 ).
Efficacy and Safety of Vitamin C for Iron Supplementation in Adults
The facilitating impact of vitamin C with food on iron status is minimal. 8,11 Therefore, whether vitamin C has additional advantages, such as improving the efficacy of iron tablets and, thus, speeding up the recovery of anemia, remains poorly understood. Whether iron tablets with vitamin C supplements should be recommended is controversial.
The Best Costco Finds This Week
The Olay Pro Advanced Vitamin C Complex, at just $36.99, offers spa-like skin treatment for a radiant summer glow. Sink into the Novaform 14" Serafina Pearl Gel Memory Foam Mattress for cool ...
Vitamin C
Vitamin C (ascorbic acid) is a simple low-molecular-weight carbohydrate with an ene-diol structure that has made it a ubiquitous and essential water-soluble electron donor in nature. It is synthesized by all species except for higher-order primates, guinea pigs, and some bat, fish, and bird species. In all of the latter, the gene encoding for i ...

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Vitamin C in human health and disease is still a mystery? An overview

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