ArticlePDF AvailableLiterature Review

Abstract

Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. 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 of a general collapse. Vitamin C is potentially involved also in cancer and cardiovascular diseases prevention. In addition, vitamin C effects on nervous system and chronically ill patients have been also documented. This review attempts to summarize recent and well established advances in vitamin C research and its clinical implications. Since vitamin C has the potential to counteract inflammation and subsequent oxidative damage that play a major role in the initiation and progression of several chronic and acute diseases, it represents a practical tool to administer for the early prevention of these pathologic conditions.
1
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
Effects of Vitamin C on health: a review of evidence
Giuseppe Grosso
1,2
, Roberto Bei
3
, Antonio Mistretta
1
, Stefano Marventano
1
, Giorgio Calabrese
4
, Laura Masuelli
5
, Maria
Gabriella Giganti
3
, Andrea Modesti
3
, Fabio Galvano
2
, Diego Gazzolo
6,7
.
1
Department of G.F. Ingrassia, Section of Hygiene and Public Health, University of Catania, Catania, Italy,
2
Department of Drug
Sciences, Section of Biochemistry, University of Catania,
3
Department of Clinical Sciences and Translational Medicine, University
of Rome "Tor Vergata", Rome, Italy,
4
Department of Biology, Piemonte Orientale University, Alessandria, Italy,
5
Department of
Experimental Medicine, University of Rome “Sapienza”, Rome, Italy.
6
Department of Maternal, Fetal and Neonatal Medicine,
Cesare Arrigo Children's Hospital, Alessandria, Italy.
7
Department of Pediatric Cardiac Surgery IRCCS, San Donato Milanese
Hospital, San Donato Milanese, Italy.
TABLE OF CONTENTS
1. Abstract
2. Introduction
3. Vitamin C in humans: adsorption, deficiency, excess
4. Mechanisms of action of Vitamin C
4.1. Collagen synthesis
4.2. Regulation of hypoxia-inducible factor 1α
4.3. Antioxidant action
4.4. Pro-oxidant action
5. Anti-carcinogenic effects of vitamin C
6. Vitamin C and cardiovascular diseases
7. The Role of vitamin C in critically ill patients
8. Vitamin C effects on nervous system
9. Vitamin C in ocular diseases
10. Conclusions
11. Acknowledgements
12.References
1. ABSTRACT
Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of
catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. 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 of a general collapse. Vitamin C is potentially involved also in cancer and cardiovascular diseases
prevention. In addition, vitamin C effects on nervous system and chronically ill patients have been also documented. This review
attempts to summarize recent and well established advances in vitamin C research and its clinical implications. Since vitamin C has
the potential to counteract inflammation and subsequent oxidative damage that play a major role in the initiation and progression of
several chronic and acute diseases, it represents a practical tool to administer for the early prevention of these pathologic conditions.
2. INTRODUCTION
Vitamin C, or ascorbic acid, is an essential dietary nutrient for a variety of biological functions. Under physiological
conditions, it is fundamental in the biosynthesis of collagen through facilitating the hydroxylation of proline and lysine residues, thus
allowing proper intracellular folding of pro-collagen for export and deposition as mature collagen (1). Vitamin C serves in humans
also as a co-factor in several important hydroxylation reactions, such as the biosynthesis of catecholamines (through the conversion
of dopamine to norepinephrine), L-carnitine, cholesterol, amino acids, and some peptide hormones (2).
The growing understanding of mechanisms of vitamin C on human health led to calls for continuous updated reappraisals
regarding the dietary requirements for this nutrient. Given the potential involvement of vitamin C in cancer and cardiovascular
diseases (CVD), as well as its effects on nervous system and chronically ill patients, the aim of this review is to address the potential
effects of vitamin C at both experimental and clinical stages focusing on recent evidences supporting a potential role for vitamin C in
degenerative diseases prevention.
2
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
3. VITAMIN C IN HUMANS: ADSORPTION, DEFICIENCY, EXCESS
Though most animals are able to endogenously synthesize large quantities of vitamin C, humans do not have the capability
to synthesize vitamin C due to a series of mutations of the gene encoding gulonolactone oxidase which catalyses the last enzymatic
step in ascorbate synthesis (3, 4). However, the requirement for vitamin C is satisfied by natural sources and vitamin C supplements
existing in the ordinary diet. The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility,
connective tissue damage, fatigue, and, finally, death. In addition to poor dietary intake of vitamin C, alcoholism (5), elderly age,
socioeconomic deprivation (6), mental illness (7), malabsorption disorders, kidney failure, hemodialysis (8), and peritoneal dialysis
(9) have been identified as risk factors for low vitamin C endogen levels and developing clinical symptoms of scurvy (10-12). Intake
of 10 mg per day of vitamin C is appropriate to prevent scurvy. This amount results in plasma concentrations of vitamin below 10
µM, already higher than that necessary to prevent scurvy (13). However, the current recommended dietary allowance (RDA) for
vitamin C for adult men and women, is set at 75 mg/day for women and 90 mg/day for men (14).
The adsorption of vitamin C from the dietary sources depends on the facilitated diffusion and a saturable-substrate transport
mechanism involving the ascorbate-specific transporters, which saturation and low expression (induced by substrate downregulation)
control the effective serum vitamin C concentration. The facilitated diffusion is mediated by the facilitative glucose transporters
(GLUT) whereas the active transport depends on the sodium vitamin C transporters (SVCT). The gradient-driven transport mediates
the absorption of oxidized form of vitamin C, dehydroascorbic acid (DHA), in an energy-independent manner especially in osteoblast
(15), muscle (16), and retinal cells (17). where the GLUT transporters are predominantly expressed. DHA and glucose share the same
GLUT transporters leading to a competitive inhibition particularly secondary to pathologies that alter serum glucose levels and
attenuate the bioavailability of vitamin C, for instance under hyperglycemic conditions caused by diabetes (18-20).
SVCT transporters, present in humans in 2 isoforms (SVCT1 and SVCT2), actively transfer ascorbate directly into the cell.
SVCT1 is subject to substrate feedback inhibition by ascorbate and its expression is attenuated by high concentrations of vitamin C in
vitro (21) and by oral ingestion (22). SVCT2 is sensitive to the changes in intracellular ascorbate levels (23), which may play a
regulatory role in maintaining ascorbate homeostasis inside the cell (22). Furthermore, age-related decline in SVCT1 expression in
rat liver cells has been observed (24), explaining why elderly individuals require higher levels of vitamin C (25). On the contrary,
unlike SVCT1, SVCT2 levels were not observed to decline with age, perhaps as a result of low abundance of this transporter in the
liver (24).
Generally, high doses of vitamin C can be toxic (26). Excess ascorbate is normally excreted harmlessly in the urine, but the
excess of formation of oxalate can accumulate in various organs in patients with renal failure or renal insufficiency (such as kidney
transplanted patients) and in patients undergoing dialysis (27, 28). Administration of high doses of vitamin C is contraindicative for
patients with oxalate kidney stones or hyperoxaluria (due to the incapacity of eliminating oxalate) and in patients with a deficiency in
glucose-6-phosphate dehydrogenase (due to the occurring of intravascular haemolysis) (26, 29).
4. MECHANISM OF ACTIONS OF VITAMIN C
4.1. Collagen synthesis
Vitamin C is required for collagen synthesis by acting as a cofactor for non-heme iron α-ketoglutarate-dependent
dioxygenases such as prolyl 4-hydroxylase. Vitamin C stimulates all types of collagen synthesis by donating electrons required for
hydroxylation of proline and lysine in procollagen by specific hydroxylase enzymes (30). In the catalytic cycle, the co-substrate, α-
ketoglutarate, undergoes oxidative decarboxylation to form succinate and a highly reactive iron-oxo (Fe+4) species. In the absence of
a substrate molecule, the enzyme becomes uncoupled and then ascorbate reduces oxo-iron back to Fe+2, restoring the enzyme's
activity. Coordination of ascorbate with enzyme-bound iron would provide the necessary electrons in uncoupled reaction cycles to
reactivate the enzyme, consistent with the observation that the role of ascorbate is to keep the non-heme iron in the catalytically
active, reduced state (31). Collagen synthesis is required for maintaining normal vascular function but also for tumor angiogenesis
(32, 33).
4.2. Regulation of hypoxia-inducible factor 1α
Ascorbate has been shown to assist prolyl and lysyl hydroxylases in the hydroxylation of hypoxia-inducible factor 1α (HIF-
1α), a transcription factor responsible for the cellular response to low oxygen conditions through activation of genes controlling
several cellular transduction pathways by regulating growth and apoptosis, cell migration, energy metabolism, angiogenesis,
vasomotor regulation, extracellular matrix and barrier functions, and transport of metal ions and glucose (34, 35). Under normoxic
3
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
conditions, the HIF-1α subunit is targeted for degradation by HIF-specific prolyl hydroxylases. Under hypoxic conditions, such as
those existing in fast growing tumors, HIF-1α hydroxylation is repressed with the result that HIF-dependent gene transcription
increases, thus promoting angiogenesis and tumor growth. Because HIF-1α prolyl hydroxylase is stimulated by ascorbic acid, low
vitamin C levels would reduce HIF-1α hydroxylation and thus stabilize HIF-1α, thereby promoting HIF-dependent gene transcription
and tumor growth (36).
4.3. Antioxidant action
In all of its known functions, vitamin C functions as a potent reducing agent that efficiently quenches potentially damaging
free radicals produced by normal metabolic respiration of the body (37). At physiological concentrations, vitamin C is a potent free
radical scavenger in the plasma, protecting cells against oxidative damage caused by ROS (38-41). The antioxidant property of
ascorbic acid is attributed to its ability to reduce potentially damaging ROS, forming, instead, resonance-stabilized and relatively
stable ascorbate free radical (AFR) serving as a one-electron donor (42). The AFR is reduced back to ascorbate within cells by
NADH- and NADPH-dependent reductases that have a high affinity for the low concentrations of the radical generated (43, 44). If
the AFR significantly accumulates in areas not accessible to these enzymes, or if its concentration exceeds their capacity, two
molecules of the AFR reactor dismutate to form one molecule each of ascorbate and DHA (45).
This mechanism might explain a number of cytoprotective functions of vitamin C, including prevention of DNA mutation
induced by oxidation (46-49), protection of lipids against peroxidative damage (50, 51), and repair of oxidized amino acid residues to
maintain protein integrity (50, 52, 53). Since oxidative stress is involved in the pathogenesis of many morbid conditions, vitamin C
(frequently administered in combination with other antioxidants) have been often used to prevent or treat several diseases due to its
antioxidant properties (26, 54) .
4.4. Pro-oxidant action
Vitamin C, under certain conditions such as low concentrations and/or in the presence of free transition metals such as
copper and iron, may function as a pro-oxidant (55). Metal ions are indeed reduced by ascorbate and, in turn, may react with
hydrogen peroxide leading to the formation of highly reactive and damaging hydroxyl radicals (56). The pro-oxidant activity of
vitamin C leads to the formation of ROS (57) or glycated proteins (58). On the other hand, in vitro model suggested that certain pro-
oxidant effects of ascorbate such as the capacity to promote protein thiol oxidation in rat liver microsomes (59) can also be
advantageous.
We next discuss the effects of vitamin C in preventing or treating chronic and acute pathologic conditions due to all its
properties listed above.
5. ANTI-CARCINOGENIC EFFECTS OF VITAMIN C
Since the second half of ‘90s, a growing body of literature aimed at demonstrating that vitamin C may reduce the incidence
of most malignancies in humans (60). Indeed, high-dose of intravenous vitamin C has been found to increase the average survival of
advanced cancer patients and for a small group of responders, survival was increased to up to 20 times longer than that of controls
(61-63). Other researchers reported benefits consisting of increased survival, improved well-being and reduced pain (64, 65). The
anti-inflammatory action of ascorbic acid in cellular ambient is evident in a number of cytoprotective functions under physiological
conditions, including prevention of DNA mutation induced by oxidation (39-41, 46-49). Since DNA mutation is likely a major
contributor to the age-related development of cancer, attenuation of oxidation-induced mutations by vitamin C may be considered as
a potential anti-cancer mechanism (66). Plasma vitamin C at normal to high physiological concentrations (60–100 µmol/L)
neutralizes potentially mutagenic ROS thus decreasing oxidative stress-induced DNA damage (46-49). Moreover, in vivo studies
confirmed that consumption of vitamin C-rich foods is inversely related to the level of oxidative DNA damage (67-70).
Vitamin C may also function as cancer cells killer due to its pro-oxidant capacity (56). The tumor cell-killing action is
dependent upon ascorbate incubation time and extracellular ascorbate concentration (71). The effective concentration of vitamin C
required to mediate cancer killing can be easier achieved by intravenous injection than by per os ingestion (71, 72). Regarding the
modality of cytotoxicity to cancer cells, it remains an unsolved issue. Among the possible mechanisms, stimulatory effects on
apoptotic pathways (73-75), accelerated pro-oxidant damage that cannot be repaired by tumor cells, and increased oxidation of
ascorbate to the unstable metabolite DHA, which in turn can be toxic, have been hypothesized. The killing of cancer cells is
dependent on extracellular H2O2 formation with the ascorbate radical as an intermediate. The H2O2 formed from pharmacological
ascorbate concentrations diffuses into cells (76) and tumor cells are killed by exposure to H2O2 in less than minutes (77-81). The
4
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
H2O2 within the cells may cause breaks in DNA and mitochondria and the mitochondria in some cancer cells may have increased
sensitivity to H2O2 (79, 81-83).
Among other mechanisms of anti-cancer action of vitamin C, it has been earlier hypothesized a possible role of ascorbic
acid in increasing collagen synthesis (84) and inhibiting hyaluronidase (85). These mechanisms are supposed to prevent cancer
spread by increasing extracellular matrix, thus walling in tumors (86-88).
In contrast with these results, other studies have reported no effects after using vitamine C as a therapeutic drug (89, 90).
Another randomized, placebo-controlled clinical study in which a high dose of vitamin C was given orally to advanced cancer
patients led to inconsistent results, ultimately casting doubt over the effectiveness of vitamin C in treating cancer (90). Due to the
controversy of results on the vitamin C-cancer correlation and lack of validated mechanistic basis for its therapeutic action, further
research is needed to determine the feasibility of using vitamin C in clinical treatment or prevention of cancer.
6. VITAMIN C AND CARDIOVASCULAR DISEASES
Reactive oxygen species (ROS) are highly reactive molecules that derive mainly from the mitochondrial electron transport
chain and that are necessary for sever normal cellular functions, ranging from their role as signaling molecules to the more
unexpected role in inducing certain cancers. However most studies have linked the excessive generation of ROS, so-called oxidative
stress, to disease states, such as cancer, insulin resistance, diabetes mellitus, cardiovascular diseases, atherosclerosis, and aging (39-
40, 91-94) and superoxide is the most biologically relevant radical in vasculature, as it is naturally produced by most vascular cells
(95). Vitamin C provides collagens synthesis, hence allowing proper folding into the triple helical collagen molecule that is then
secreted to form the extracellular matrix, or to form part of the basement membrane with regard to type IV collagen (33). By contrast,
lack of ascorbate results in friable vessels and especially capillaries that are more prone to rupture, creating the typical petechial
hemorrhages and ecchymoses observed in scurvy and in the cerebral cortex of SVCT2 knockout mice (96).
Vitamin C has been found to prevent apoptosis by blocking the activity of inflammatory cytokines and oxidized LDL both
in cultured endothelial cells (97-99) and patients with congestive heart failure in which treatment with vitamin C decreased release of
microparticles derived from endothelial cells (98).
Results of a randomized, double-blind, placebo-controlled study conducted on subjects with documented coronary artery
disease have shown that long term oral ascorbate supplements do have persistent effects on endothelial-dependent flow-mediated
brachial artery dilation (100). A possible mechanism of action has been thought to depend on the effect of vitamin C on nitric oxide
(NO) synthase. Indeed, vitamin C enhances the NO synthase activity by maintaining tetrahydrobiopterin, an essential co-factor for
the enzyme, in its reduced and active form (101-103), normally inhibited by ROS that oxidize and thus deplete the co-factor. By
increasing NO production, vitamin C may indirectly protect the vascular endothelium due to its actions, namely smooth muscle cell
relaxation, downstream vasodilatation, and inhibition the effects of pro-inflammatory cytokines and adhesion molecules important in
atherosclerosis (104-107). Moreover, due to its antioxidant properties, vitamin C directly reduces nitrite by releasing NO from
nitrosothiols, and scavenges superoxide, although relatively high ascorbate concentrations (>100 µM) are required to prevent the
reaction of superoxide with NO (108).
The role of ascorbate in preventing uncontrolled vascular smooth muscle cells (VSMC) proliferation and dedifferentiation
after acute arterial injury have been investigated in studies of coronary restenosis in pigs (109, 110) and in humans after angioplasty
showing larger luminal diameters in subjects receiving oral vitamin C supplements compared to matched controls who did not
receive ascorbate (111). The mechanism of action is still unclear, since vitamin C has been shown to paradoxically provide collagen
synthesis, necessary for VSMC migration and proliferation (112, 113) and to prevent VSMC dedifferentiation (114, 115). A possible
explanation of the protective role of vitamin C may depend on its role on protecting VSMCs (116) and mature human macrophages
(117) from apoptosis and necrosis due to injury by oxidized LDL (118). Oxidative modification of LDL by ROS, such as superoxide
and hydroxyl radicals, also initiates a sequence of atherogenic events in the sub-endothelial space. Physiological concentrations of
ascorbic acid in vitro attenuate oxidative modification of LDL induced by transition metals (119, 120), homocysteine (121), and
myeloperoxidase-derived HOCl (122, 123), as well as those naturally produced by human vascular endothelial cells (124). The
mechanisms responsible for these actions include the ascorbate capacity of quenching aqueous ROS and reactive nitrogen species
(RNS), decreasing their bioavailability in the plasma, and of reducing the affinity of LDL-bound apolipoprotein B protein for
transition metal ions, enhancing the resistance of LDL to metal ion-dependent oxidation (125).
Macrophages take up modified LDL to become the foam cells and also mediate the inflammatory response that
accompanies atherosclerosis (126). In recent studies performed on mouse peritoneal macrophages it has been found that ascorbate
loading to intracellular concentrations of 3-10 mM prevented oxidative stress induced by latex beads (127) and stimulated several
5
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
functions such as adherence, chemotaxis, phagocytosis, and superoxide production (128). Results regarding such effects of vitamin C
have not been uniformly observed and controversy is ongoing between studies assessing that ascorbate inhibits macrophage function
by decreasing uptake and degradation of oxidized human LDL (129-131) and others in which such effect has not been observed (81,
132), maybe due to different in vitro conditions (133, 134).
Regarding the hypothesis that ascorbate is required for synthesis of the collagenous framework of atherosclerotic plaques, a
study performed on apolipoprotein E (ApoE) knockout mice revealed no effect of ascorbate diet on either plaque size or lipid
content. However, plaque collagen content was found to be decreased in animals on marginal ascorbate diet, thus demonstrating that
it plays a role on stability of atherosclerotic plaques becoming capable of rupture with associated thrombosis and infarction (135).
These findings, in light of the several benefits of ascorbate on endothelial cell proliferation, function, and viability, make it plausible
that increased plasma and cell ascorbate concentration might have a preventive effect on potential endothelial dysfunction.
Recently, several studies observed a decrease in plasma vitamin C levels in both type I and type II diabetes, and the effects
of vitamin C administered in different ways, in addition to various combinations of different anti-diabetic drugs and other
antioxidants, have been assessed (136-142). However, at present, no comprehensive agreement regarding its therapeutic effectiveness
for these conditions has been reached.
7. THE ROLE OF VITAMIN C IN CRITICALLY ILL PATIENTS
Vitamin C concentrations in plasma and leukocytes have been reported to be commonly subnormal in critically ill patients
(143), inversely correlating with multiple organs failure (144) and directly with survival (145). Since sepsis is associated with
increased production of ROS and peroxynitrite that deplete antioxidant molecules and oxidize proteins and lipids, potential
therapeutic implication of vitamin C in the treatment of various infections has been studied for a long time. Indeed, enteral
administration of vitamin C and other antioxidants in patients with sepsis has been shown to affect faster recovery (146) whereas
parenteral administration decreased morbidity and mortality (147-149). In vitro and in animal experimental sepsis vitamin C
prevented hypotension and edema in LPS-injected animals (150-152) and improved capillary blood flow, arteriolar responsiveness,
arterial blood pressure, liver function, and survival (153-158). A possible mechanism of such effects may depend on the role of
ascorbate in both inhibiting apoptosis in endothelial cells and stimulating their proliferation preventing the loss of barrier function in
sepsis condition (97-99, 159). Moreover, vitamin C improves arteriolar responsiveness to vasoconstrictors (norepinephrine,
angiotensin, vasopressin) (160, 161) and prevents inhibition of endothelium- dependent vasodilation responses to acetylcholine (162,
163) in human subjects who have inflammatory disease or have been injected with LPS, thus preventing hypotension in sepsis and,
consequently, edema. Another action of ascorbate on endothelial permeability may involve its scavenging action on superoxide and
inhibition of nitric oxide and peroxynitrite formation, as well as its property of reducing the oxidation products formed by reaction of
peroxynitrite with cell proteins (164). These actions of ascorbate may account for its effectiveness in preventing edema in critically
ill patients and experimental models.
8. VITAMIN C EFFECTS ON NERVOUS SYSTEM
Several effects produced by ascorbate have been explored on nervous system (165). Vitamin C can in fact efflux from
various types of cells (166, 167), including neurons (168), because of its hydrophilic nature and negative charge at physiologic pH.
Vitamin C appears to be allowed to enter into several brain cell lines, improving neurotransmission (169) and leading to a number of
effects on behaviors such as learning, memory and locomotion. Experimental animal models have been shown that intraperitoneal
administration of ascorbate reversed memory deficits in mice (170, 171) whereas oral administration, in conjunction with vitamin E,
improved performance on a passive avoidance task in 15 months mice but not in 3-month old mice or when ascorbate was
administered alone (172). In addiction, ascorbate treatments either intraperitoneally for 14 days or orally for 30 days improved both
acquisition and retention in this passive avoidance task (173), contrasting an earlier study in which five days of acute pre-test
ascorbate dosing led to poorer performance (174).
Oral intake of vitamin C has been shown to reduce the fear response in Japanese quail chicks tested in a less stressful light-dark
emergence paradigm (175). Moreover, long-term low levels of dietary ascorbate did not lead to impairments in learning and memory
or anxiety in knockout mice unable to synthesize their own vitamin C (176). However, due to lack of agreement between results
within these experiments and lack of correlation between different dosing regimens used and a clear pattern of results, it’s hard to
identify the exact mechanism through which vitamin C influence memory, although it appears reasonable to consider it a mediator
especially of stress-related learning.
6
Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
Copyright © 2013 Frontiers in Bioscience. All rights reserved.
Regarding neurodegenerative diseases, a positive relationships has been shown between ascorbate supplement use and
reduced incidence of Alzheimer's disease (177, 178) that is known to be caused by a combination of genetic and lifestyle factors and
in part by oxidative stress (179), although these beneficial results are not universal (180, 181). Orally administered ascorbate
protected the CA1 area of the hippocampus in rats against oxidative stress and cytokine release induced by injection of fibrillar β-
amyloid (182). It also protected SH-SY5Y neuroblastoma cells from β-amyloid induced apoptosis (183).
Finally, it has been observed that intake of ascorbate as a pharmacological agent may be of benefit in protecting against
Parkinson's disease improving the bioavailability of levodopa (184) although population studies revealed no effects of ascorbate
intake in preventing the development of the disease (185).
9. VITAMIN C IN OCULAR DISEASES
The role of Vitamin C in preventing ocular disease has been evaluated, demonstrating that the development of cataract is
influenced by ascorbate (186) and that a combination of ascorbate with other antioxidant vitamins and minerals slows down the
progression of advanced age-related macular degeneration and loss of visual acuity in people with signs of this disease (187, 188).
The effectiveness of vitamin C as a treatment of diabetic retinopathy has also been examined, but further studies are required to prove
that it has a significant impact on its progress (189).
10. CONCLUSIONS
This review attempts to summarize recent and well established advances in vitamin C research and its clinical implications.
Since vitamin C has the potential to counteract inflammation and subsequent oxidative damage that play a major role in the initiation
and progression of several chronic and acute diseases, it represents a practical tool to administer in humans for the early prevention
of such pathologic conditions. However, many of such well-known beneficial effects of vitamin C intake are still only understood at
the phenomenological level and further research is needed to explore the precise effects of ascorbate in physiological systems and in
the pathology of diseases at the molecular level. A better understanding of the mechanisms of its action is of major importance in
order to define novel potential therapeutic implications regarding vitamin C.
11. ACKNOWLEDGEMENTS
This study was supported by a grant from PRIN 2009 (R.B).
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Post-print version, please cite this article as:
Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
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Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
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Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
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Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
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Grosso G, Bei R, Mistretta A, Marventano S, Calabrese G, Masuelli L, Giganti MG, Modesti A, Galvano F, Gazzolo D. Effects of
Vitamin C on health: a review of evidence. Front Biosci. 2013 Jun 1;18:1017-29.
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Key Words: vitamin C, ascorbic acid, cardiovascular disease, cancer, anti-inflammation, antioxidant
Send correspondence to: Roberto Bei, MD PhD Associate Professor of General Pathology, Department of Clinical Sciences and
Translational Medicine, Faculty of Medicine, University of Rome "Tor Vergata" Via Montpellier 1, 00133 Rome, Building F Sud,
2nd floor, Room 222 phone: + 39 06-72596522, Fax: + 39 06-72596506, E-mail: bei@med.uniroma2.it
Running title: Vitamin C effects on health
... The oxidation process which is essential for our aerobic life and metabolism involve electron transfer between two atoms. Problems may occur when DZN oxidizes inside the body by cytochrome P450 enzymes, more potent toxic metabolite may be formed in the liver such as diazoxon which may cause an unpaired electron flow, generating free radicals and reactive oxygen species 6 ,which cause lipid peroxidation and phospholipid degeneration, and subsequently lead to cellular damage 7&8 . The screening of natural flavonoids for their bioactivity as antioxidants is usually carried out by determining of their ability to act as chain breaking antioxidants, though their direct free radical-scavenging activity as hydrogen-or electron-donating compounds 9 . ...
... Citrus fruits, red and green peppers, berries, tomatoes, spinach, and broccoli are rich in vitamin C. Humans, unlike most mammals, cannot synthesize vitamin C and hence derive it from their diet 15 .At physiological concentrations, vitamin C is a potent free radical scavenger that protect the cells against oxidative damage caused by ROS. The vitamin C antioxidant effect reduces the formation of potentially damaging ROS; instead, resonance-stabilized and relatively stable ascorbate free radical serves as a oneelectron donor 6 . Recent studies have shown that vitamin C protects against memory deficits associated with several medical condition, such as Alzheimer's disease 16 . ...
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Insecticides have come to be used in a wrong way and uncontrollably, leading to an increase in the incidence of chronic diseases such as chronic nephropathies, diabetes, and other metabolic disorders. Objective: To evaluate the protective effect of Taxifolin and/or vitamin C against Diazinon-induced renal dysfunction. Methods: Thirty-six female rats were divided into six groups gavaged orally for 30 days. Group 1 received 20 mg/kg DZN. Group 2 received 25 mg/kg Taxifolin, 100 mg/kg vitamin C, and then 20 mg/kg DZN. Group 3 received 25 mg/kg Taxifolin and then 20 mg/kg DZN. Group 4 received 100 mg/kg vitamin C and then 20 mg/kg DZN. Group 5 received 25 mg/kg Taxifolin and then 100 mg/kg vitamin C. Finally, group 6 received distilled water. In the end, the rats were sacrificed and their blood and kidneys were collected for biochemical analysis and histopathology. Conclusion: Sub-acute administration of Taxifolin and vitamin C provides a renoprotective effect against oxidative stress induced by DZN.
... Peel and seeds of Phlregrean mandarin are also a source of ascorbic acid. Vitamin C is one of the main compounds in citrus fruit and an essential dietary nutrient to prevent scurvy, cancer, cardiovascular and chronic nervous system diseases [64]. Many factors influence vitamin C content, namely species and cultivar and rootstock, climate, maturity stage, fruit position on the tree, harvest, and storage conditions [41]. ...
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In this work, we assess the potential of waste products of Phlegrean mandarin (Citrus reticulata Blanco), namely seeds and peel, to be reutilized as a source of bioactive compounds beneficial for the human diet. Starting from the evidence that the by-products of this specific cultivar are the most powerful sources of antioxidants compared to pulp, we have investigated if and how the bioactive compounds in peel and seeds may be affected by fruit ripening. Three stages of fruit ripening have been considered in our study: unripe fruits = UF, semi-ripe fruits = SRF, ripe fruits = RF. The overall results indicated that RF showed the highest concentration of antioxidants. Among fruit components, peel was the richest in total antioxidant capacity, total polyphenol content, total flavonoids, total chlorophylls and carotenoids, while seeds exhibited the highest concentration of total condensed tannins and ascorbic acid. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay indicates the occurrence, in peel extracts, of 28 phenolic compounds, mainly flavonoids (FLs); in seeds, 34 derivatives were present in the first stage (UF), which diminish to 24 during the ripening process. Our data indicated that the content of phytochemicals in citrus strongly varies among the fruit components and depends on the ripening stage. The higher antioxidant activity of peel and seeds, especially in RF, encourage a potential use of by-products of this specific citrus cultivar for industrial or pharmacological applications. However, to maximize the occurrence of desired bioactive compounds, it is important also to consider the ripening stage at which fruits must be collected.
... An ordinary diet of natural and synthetic ascorbic acid is the only way to maintain the physiological requirements. The well-known symptom of ascorbic acid deficiency is associated with connective tissue damage, such as scurvy, which is characterized by fragile tissues and poor wound healing [3]. The currently recommended dietary allowances (RDA) for ascorbic acid are 90 mg/day and 75 mg/day for men and women, respectively [4]. ...
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The L-enantiomer of ascorbic acid is commonly known as vitamin C. It is an indispensable nutrient and plays a key role in retaining the physiological process of humans and animals. L-gulonolactone oxidase, the key enzyme for the de novo synthesis of ascorbic acid, is lacking in some mammals including humans. The functionality of ascorbic acid has prompted the development of foods fortified with this vitamin. As a natural antioxidant, it is expected to protect the sensory and nutritional characteristics of the food. It is thus important to know the degradation of ascorbic acid in the food matrix and its interaction with coexisting components. The biggest challenge in the utilization of ascorbic acid is maintaining its stability and improving its delivery to the active site. The review also includes the current strategies for stabilizing ascorbic acid and the commercial applications of ascorbic acid.
... In any case, in the US general population, the amount of vitamin C intake from foods and supplements has decreased over time (29,39) with the mean intake of vitamin C from foods in the current US population (estimation from NHANES 2017-2018 (35) ) estimated to be approximately 70 % of that in the NHANES-III (1988-1994) population (40) . Considering the higher likely prevalence of vitamin C deficiency expected in the current US population as well as the other known health benefits of vitamin C (41) , recommending higher intake of vitamin C-rich foods or dietary supplementation could be a good strategy for lowering population-wide risks of disease severity in future viral epidemics, especially for those with nutritional deficiencies. In addition, given previous epidemiologic and experimental evidence on the protective effects of carotene against influenza or pneumonia (42,43) , further studies to confirm the possible role of carotene supplementation on influenza/pneumonia mortality are warranted. ...
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Objective We examined the association between serum antioxidant status and mortality from influenza and pneumonia in US adults. Design Serum concentrations of antioxidants included vitamin C, vitamin A, vitamin E, sum of α- and β-carotene, β-cryptoxanthin, lutein+zeaxanthin, and lycopene. We computed total antioxidant capacity (TAC) as a measure of composite antioxidant status in serum. Survey-weighted Cox proportional hazard models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) comparing quartiles of each antioxidant and TAC. Setting Data from the US National Health and Nutrition Examination Survey (NHANES)-III. Participants A total of 7428 NHANES-III participants ≥45 years of age. Results With a weighted-median follow-up of 16.8 years, 154 participants died from influenza/pneumonia. After adjustment for covariates, serum vitamin C, the sum of α- and β-carotene, and TAC were non-linearly associated with influenza/pneumonia mortality, with the statistically significant smallest HRs at the third quartile vs the first quartile [HRs=0.38 (95% CI: 0.19–0.77), 0.29 (0.16–0.51), and 0.30 (0.15–0.59), respectively]. HRs comparing the fourth vs the first quartiles were weaker and non-significant: 0.57 (95% CI: 0.27–1.17), 0.70 (0.41–1.19), and 0.65 (0.31–1.35), respectively. Serum lycopene had a monotonic association with influenza/pneumonia mortality [HR=0.43 (95% CI: 0.23–0.83) comparing the fourth vs the first quartile, P -for-trend=0.01]. Conclusions The present study suggests that antioxidant intake as reflected by serum concentrations may reduce mortality risk from influenza or pneumonia in the US general population. These findings warrant further confirmation in other populations with different settings (e.g., a shorter-term association with influenza infection).
... L-ascorbic acid (AsA), also known as vitamin C, is an essential component of the human diet, and fruits and vegetables are the main sources of this compound [1]. Moreover, AsA is a powerful antioxidant that may also decrease the incidence of several illnesses such as cancer or cardiovascular diseases [2]. Hence, the elucidation of AsA accumulation and the factors regulating its concentration in horticultural crops has been a topic of interest, and many studies have focused on assessing AsA concentrations in the edible parts of plants [3,4]. ...
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Citrus fruit is one of the most important contributors to the ascorbic acid (AsA) intake in humans. Here, we report a comparative analysis of AsA content and transcriptional changes of genes related to its metabolism during development of petals, leaves and fruits of Valencia Late oranges (Citrus sinensis). Petals of close flowers and at anthesis contained the highest concentration of AsA. In fruits, AsA content in the flavedo reached a maximum at color break, whereas the pulp accumulated lower levels and experienced minor fluctuations during development. AsA levels in leaves were similar to those in the flavedo at breaker stage. The transcriptional profiling of AsA biosynthetic, degradation, and recycling genes revealed a complex and specific interplay of the different pathways for each tissue. The D-galacturonic acid pathway appeared to be relevant in petals, whereas in leaves the L-galactose pathway (GGP and GME) also contributed to AsA accumulation. In the flavedo, AsA content was positively correlated with the expression of GGP of the L-galactose pathway and negatively with DHAR1 gene of the recycling pathway. In the pulp, AsA appeared to be mainly controlled by the coordination among the D-galacturonic acid pathway and the MIOX and GalDH genes. Analysis of the promoters of AsA metabolism genes revealed a number of cis-acting elements related to developmental signals, but their functionalities remain to be investigated.
... Vitamin C (VC) or ascorbic acid is a vital watersoluble micronutrient that is essential for physiological functions in animals, including aquatic animals (Fracalossi et al. 2001;Grosso et al. 2013). Adel and Khara (2016) reported that adding vitamin C and iron to the basic diet of rainbow trout could improve the growth rate and health status. ...
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Copper and vitamin C are micronutrients needed for the living organism’s functions. Vitamin C has a great effect on the immune system of fish. The present study aimed to evaluate the effects of dietary copper nanoparticles (Cu-NPs) and vitamin C (VC) supplementations on rainbow trout (Oncorhynchus mykiss) juveniles. So, 216 rainbow trout juveniles were randomly assigned to six groups with trial diets supplemented with Cu-NPs and VC including 0/0 (T1, control diet), 0/250 (T2), 0/500 (T3), 2/250 (T4), 2/500 (T5), and 2/0 (T6) mg Cu-NPs/VC per kg diet. After the feeding trial for 60 days, the fish were challenged with Yersinia ruckeri, and the survival rate was calculated for 15 days. Based on the data analysis, weight gain (WG), specific growth rate (SGR), protein efficiency ratio (PER), lysozyme, alternative complement activity (ACH50), hematocrit (Hct), hemoglobin (Hb), and mean corpuscular volume (MCV) were significantly (p < 0.05) increased in the fish fed on T4 and T5 diets compared with the control group. Catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) were significantly (p < 0.05) decreased in the fish fed with diets contain Cu-NPs and VC (T4 and T5). The expressions of TNF-α, IL-1ß, IL-10, SOD, CAT, and GPX genes were significantly (p < 0.05) decreased in the fish fed on T3, T4, and T5 diets versus the control. In addition, the dietary Cu-NPs and VC supplementations significantly enhanced resistance against pathogens and led to the control of infection in rainbow trout. In conclusion, Cu-NPs and VC administered as feed additives at 2/250–500 mg/kg elevated the growth performance, antioxidant capacity, and health of rainbow trout.
... Since it possesses antioxidant properties, and it acts as a cofactor in various enzymatic and hormonal procedures, it is a major compound for the growth and repair of all tissues. It participates in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, collagen and some peptide hormones [19]. Vitamin C serves as a reducing agent that efficiently scavenges potentially damaging free radicals, protecting cells against oxidative damage caused by ROS. ...
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Trong nghiên cứu này, chúng tôi đã phân tích hàm lượng thành phần hữu cơ, một số loại chất khoáng và vitamin có trong lá non và ngọn của cây rau Sứng (Strophioblachia fimbricalyx Boerl.) thu hái ở Cù Lao Chàm, thành phố Hội An, tỉnh Quảng Nam. Trong lá non và ngọn của cây rau Sứng có hàm lượng protein (6,13 g/100g tươi) và chất xơ (2,07 g/100g tươi) cao nhất. Lipid có hàm lượng thấp nhất (0,10 g/100g tươi). Ngoài ra, lá non và ngọn cây rau Sứng có các chất khoáng như: sắt (Fe), kẽm (Zn), đồng (Cu), selen (Se), mangan (Mn). Chất khoáng có hàm lượng cao nhất là sắt (5,32 mg/100g tươi), selen (14,80 µg/100g tươi) và kẽm (1,37 mg/100g tươi). Hàm lượng vitamin C trong rau Sứng thấp, chỉ có 1,54 mg vitamin C trong 100g tươi. Ngoài ra, trong rau Sứng còn có beta caroten với hàm lượng 0,51 mg/100g tươi, là nguồn vitamin A cho thể người.
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Anthocyans (ACNs), i.e. anthocyanins and anthocyanidins, belong to a widespread group of plant constituents, collectively known as flavonoids, which occur in the western diet at relatively high concentrations. ACNs display a variety of pharmacological properties which make them potential anti-inflammatory and anti-cancer agents. In addition to their ability to scavenge reactive oxygen species, ACNs can affect the functions of enzymes involved in DNA damage and in cancer-related signaling pathways. The antiproliferative, proapoptotic and antiangiogenic effects of ACNs rely on the inhibition of signaling by tyrosine kinase growth factor receptors (EGFR/ErBs, c-Met, VEGFRs, PDGFRs) as well as on the impairment of cAMP phosphodiesterase, proteasome chymotrypsin-like, ornithine decarboxylase and glyoxalase I activity. ACNs interfere also with cancer cell invasion by lowering the expression of the urokinase-type plasminogen activator and matrix metalloproteinases. Further, these compounds have been found to affect the transcriptional activity of NF-κB by inhibiting the IκB kinase complex and histone acetyltransferases, the inhibition of NF-κB being closely linked with the downregulation of COX-2 expression. Finally, ACNs are regarded as multi-target kinase inhibitors due to their ability to bind and inhibit a number of signaling kinases, such as Raf, MEK, MAPKK4, PI3K and Fyn. This review will provide an update on the effects of ACNs on the expression and function of enzymes involved in cancer development and progression, and will discuss the preventive/therapeutic potential of these compounds against human cancers.
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Patients with sepsis have low concentrations of antioxidants, including ascorbic acid, and also have increased concentrations of markers of free radical damage. Although ascorbic acid is a potent antioxidant, it can act as a prooxidant by promoting iron-catalysed reactions. We measured baseline total vitamin C and bleomycin-detectable “free” iron levels and ascorbyl radical concentrations before and after intravenous infusion of 1 g ascorbic acid in patients with sepsis and healthy control subjects. Vitamin C concentrations were decreased in patients compared to healthy subjects (p<0.0001), and “free” iron was increased (p < 0.002). Preinfusion ascorbyl radical concentrations were not different in patients and controls. Postinfusion ascorbyl radical levels increased in both controls and patients, with larger increases in healthy subjects (p < 0.0001), suggesting suboptimal basal vitamin C levels and increased scavenging of a constant oxidant pool by ascorbate in the controls. In the patients, who were all vitamin C deficient, infused ascorbate was rapidly consumed, either via the promotion of redox cycling of iron or as a result of radical scavenging. This study demonstrates markedly different handling of infused ascorbate in patients with sepsis and healthy subjects, and further studies are needed to elucidate the relative anti- and pro-antioxidant mechanisms of ascorbate in patients with raised “free” iron levels.
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Hypothesis High-dose ascorbic acid (vitamin C) therapy (66 mg/kg per hour) attenuates postburn lipid peroxidation, resuscitation fluid volume requirements, and edema generation in severely burned patients.Study Design and Setting A prospective, randomized study at a university trauma and critical care center in Japan.Subjects and Methods Thirty-seven patients with burns over more than 30% of their total body surface area (TBSA) hospitalized within 2 hours after injury were randomly divided into ascorbic acid and control groups. Fluid resuscitation was performed using Ringer lactate solution to maintain stable hemodynamic measurements and adequate urine output (0.5-1.0 mL/kg per hour). In the ascorbic acid group (n=19; mean burn size, 63% ± 26% TBSA; mean burn index, 57 ± 26; inhalation injury, 15/19), ascorbic acid was infused during the initial 24-hour study period. In the control group (n=18; mean burn size, 53% ± 17% TBSA; mean burn index, 47 ± 13; inhalation injury, 12/18), no ascorbic acid was infused. We compared hemodynamic and respiratory measurements, lipid peroxidation, and fluid balance for 96 hours after injury. Two-way analysis of variance and Tukey test were used to analyze the data.Results Heart rate, mean arterial pressure, central venous pressure, arterial pH, base deficit, and urine outputs were equivalent in both groups. The 24-hour total fluid infusion volumes in the control and ascorbic acid groups were 5.5 ± 3.1 and 3.0 ± 1.7 mL/kg per percentage of burn area, respectively (P<.01). In the first 24 hours, the ascorbic acid group gained 9.2% ± 8.2% of pretreatment weight; controls, 17.8% ± 6.9%. Burned tissue water content was 6.1 ± 1.8 vs 2.6 ± 1.7 mL/g of dry weight in the control and ascorbic acid groups, respectively (P<.01). Fluid retention in the second 24 hours was also significantly reduced in the ascorbic acid group. In the control group, the ratio of PaO2 to fraction of inspired oxygen at 18, 24, 36, 48, and 72 hours after injury was less than that of the ascorbic acid group (P<.01). The length of mechanical ventilation in the control and ascorbic acid groups was 21.3 ± 15.6 and 12.1 ± 8.8 days, respectively (P<.05). Serum malondialdehyde levels were lower in the ascorbic acid group at 18, 24, and 36 hours after injury (P<.05).Conclusions Adjuvant administration of high-dose ascorbic acid during the first 24 hours after thermal injury significantly reduces resuscitation fluid volume requirements, body weight gain, and wound edema. A reduction in the severity of respiratory dysfunction was also apparent in these patients.
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purpose. To elucidate the mechanisms of vitamin C transport across the blood–retinal barrier (BRB) in vivo and in vitro. methods. [¹⁴C]Dehydroascorbic acid (DHA) and [¹⁴C]ascorbic acid (AA) transport in the retina across the BRB were examined using in vivo integration plot analysis in rats, and the transport mechanism was characterized using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2) as an in vitro model of the inner BRB. results. The apparent influx permeability clearance (K in) per gram of retina of [¹⁴C]DHA and [¹⁴C]AA was found to be 2.44 × 10³ μL/(min · g retina) and 65.4 μL/(min · g retina), respectively. In the retina and brain, the K in of [¹⁴C]DHA was approximately 38 times greater than that of [¹⁴C]AA, whereas there was no major difference in the heart. The K in of [¹⁴C]DHA in the retina was eight times greater than that in the brain. HPLC analysis revealed that most of the vitamin C accumulated in AA form in the retina. These results suggest that vitamin C is mainly transported in DHA form across the BRB and accumulates in AA form in the rat retina. In an in vitro uptake study in TR-iBRB2 cells, the initial uptake rate of [¹⁴C]DHA was 37 times greater than that of [¹⁴C]AA, which is in agreement with the results of the in vivo study. [¹⁴C]DHA uptake by TR-iBRB2 cells took place in an Na⁺-independent and concentration-dependent manner with a K m of 93.4 μM. This process was inhibited by substrates and inhibitors of glucose transporters. [¹⁴C]DHA uptake was inhibited by d-glucose in a concentration-dependent manner with a 50% inhibition concentration of 5.56 mM. Quantitative real-time PCR and immunostaining analyses revealed that expression of GLUT1 and -3 was greater than that of the Na⁺-dependent l-ascorbic acid transporter (SVCT)-2 in TR-iBRB2 cells. conclusions. Vitamin C is mainly transported across the BRB as DHA mediated through facilitative glucose transporters and accumulates as AA in the rat retina.
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The development of head and neck squamous cell carcinomas (HNSCCs) is a multistep process progressing from precancerous lesions to highly malignant tumors. A critical role in HNSCCs development and progression is played by EGFR family members including EGFR and ErbB2. The aim of this study was to investigate the effect of apigenin, a low molecular weight flavonoid contained in fruits and vegetables, on growth and survival and on EGFR/ErbB2 signaling in cell lines derived from HNSCCs of the tongue (CAL-27, SCC-15) or pharynx (FaDu). Using sulforhodamine B assay, FACS analysis and activated caspase-3 detection by immunofluorescence, we here demonstrate that apigenin dose-dependently inhibits survival and induces apoptosis of HNSCC cells. Further, by performing western blotting with antibodies specific for phosphorylated EGFR, ErbB2, Erk1/2 and Akt we demonstrate that apigenin reduces ligand-induced phosphorylation of EGFR and ErbB2 and impairs their downstream signaling. On the whole, our results suggest that apigenin properties might be exploited for chemoprevention and/or therapy of head and neck carcinomas.
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Malignant tumors of mesenchimal origin such as rhabdomyosarcoma and osteosarcoma are highly aggressive pedriatic malignancies with a poor prognosis. Indeed, the initial response to chemotherapy is followed by chemoresistance. Diallyl disulfide (DADS), resveratrol (RES) and curcumin (CUR) are dietary chemopreventive phytochemicals which have been reported to have antineoplastic activity on rhabdomyosarcoma and osteosarcoma cells as single drugs. In this study we evaluated whether, as compared to the single compounds, the combination of DADS+RES, DADS+CUR and RES+CUR resulted in an enhancement of their antitumor potential on malignant rhabdoid (SJ-RH4, RD/18) or osteosarcoma (Saos-2) cell lines. Through FACS analysis and activated caspase-3 labeling we demonstrate that CUR induces apoptosis of rabdomyosarcoma and osteosarcoma cells and that this effect is potentiated when CUR is combined with RES or DADS. Further, we explored the effects of the compounds, alone or in combination, on signal transduction pathways involved in apoptosis and growth of cancer cells and show that in rhabdomyosarcoma cells the apoptotic effect of CUR, either alone or in combination, is independent of p53 activity. Our findings suggest that CUR and CUR-based combinations may have relevance for the treatment of p53-deficient cancers, which are often unaffected by conventional chemotherapies or radiotherapy.
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Dietary flavonoids are a large family of polyphenols ubiquitously expressed in plants. Recent evidence show that flavonoids possess several anti-inflammatory activities due to their ability to scavenge reactive oxygen and nitrogen species (ROS and RNS), to inhibit the pro-inflammatory activity of ROS-generating enzymes including cyclooxygenase (COX), lipoxygenase (LOX) and inducible nitric oxide synthase (iNOS) and to modulate different intracellular signaling pathways from NF-kB to mitogen-activated protein kinases (MAPKs) through perturbation of redox-sensible networks in immune cells. This report will review current knowledge on the anti-inflammatory effects of flavonoids on immune cells focusing on their ability to modulate multiple redox-sensible pathways involved in inflammation.
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Existing data on the kinetics of ascorbate radical decay, together with some new data on the effects of temperature, ionic strength, and presence of phosphate buffers, suggest a mechanism in which the ascorbate radical ion is in equilibrium with a dimer. This dimer reacts with hydrogen ion, or with other proton donors present including water and buffers (at rates depending upon their acid strengths), to form the disproportionation products ascorbate ion and dehydroascorbate acid.
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Male Japanese quail chicks of two genetic lines selected for low (LS) or high (HS) adrenocortical responses to mechanical restraint were housed in mixed-line groups of 24 in four compartments of a multitier brooder battery at 20 days of age. Quail in two of the four compartments were given vitamin C (ascorbyl-2-polyphosphate, APP, 1 g l-ascorbic acid/L) solution for 48 h, whereas the other birds received untreated tap water as usual before they were tested at 23 days of age. At test, each quail was placed individually in a dark, sheltered compartment of an emergence box and allowed 1 min to acclimatise before a door was raised allowing access to an illuminated and exposed area. Vocalisation and the latencies to head and full emergence were then recorded to measure its fear levels. More LS quail vocalised than did HS ones. They also emerged more rapidly from the sheltered compartment into the illuminated one than HS birds. These findings further support our hypothesis that decreased fearfulness has accompanied genetic selection for reduced adrenocortical responsiveness. Treatment with APP reduced the latency to emerge fully into the exposed compartment, and there were no line × treatment interactions. These results suggest that vitamin C supplementation alleviated fearfulness, regardless of existing line differences in this behavioural trait.