PHILOSOPHY OF BENEFITS OF ASCORBIC ACID FOR HUMAN BODY

PRO.BUNDELA JACKSON; PRO.RAMESHWRA DINGRA

(FACULTY OF MEDICINE AND NUETRACUETICAL SCIENCE; UNIVERSITY OF NIGERIA)

VOL.03 Issue 11

ABSTRACT

Vitamin C is a necessary dietary nutrient for the biosynthesis of collagen and a co-factor within the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and a few peptide hormones. the dearth of water-soluble vitamins causes scurvy, a pathological condition resulting in vas fragility and animal tissue damage because of failure in producing collagen, and, finally, to death because of the results of a general collapse. Additionally, vitamin C’s effects on the system nervous and chronically ill patients are also documented. This review attempts to summarize recent and well-established advances in antioxidant research and its clinical implications. Since vitamin C has the potential to counteract inflammation and subsequent oxidative damage that play a significant role within the initiation and progression of several chronic and acute diseases, it represents a practical tool to administer for the first prevention of those pathologic conditions.

INTRODUCTION

Vitamin C, or vitamin C, is an important dietary nutrient for the spread of biological functions. deposition as mature collagen (1). Water-soluble vitamin serves in humans also as a co-factor in several important hydroxylation reactions, like the biosynthesis of catecholamines (through the conversion of dopamine to norepinephrine), L-carnitine, cholesterol, amino acids, and a few peptide hormones (2).

                      The growing understanding of the mechanisms of ascorbic acid on human health led to requires continuously updated reappraisals regarding the dietary requirements for this nutrient. Given the potential involvement of antioxidants in cancer and cardiovascular diseases (CVD), additionally as its effects on the system and chronically ill patients, this review aims to handle the potential effects of vitamin C at both experimental and clinical stages that specialize in recent evidence supporting a possible role for ascorbic acid in degenerative diseases prevention.

 

Keywords:

Vitamin C, ascorbic acid, cardiovascular disease, cancer, anti-inflammation, antioxidant.

ASCORBIC ACID IN HUMANS

ADSORPTION, DEFICIENCY, EXCESS Though most animals can endogenously synthesize large quantities of antioxidants, humans don’t have the aptitude to synthesize ascorbic acid thanks to a series of mutations of the gene encoding gluconolactone oxidase which catalyzes the last enzymatic step in ascorbate synthesis (3, 4). However, the necessity for ascorbic acid is satisfied by natural sources and vitamin C supplements existing within the ordinary diet. the dearth of antioxidants causes scurvy, a pathological condition resulting in vas fragility, animal tissue damage, fatigue, and, finally, death. additionally to poor dietary intake of the water-soluble vitamins, alcoholism (5), elderly age, socioeconomic deprivation (6), psychopathy (7), malabsorption disorders, renal disorder, hemodialysis (8), and peritoneal dialysis (9) are identified as risk factors for low water-soluble vitamin endogen levels and developing clinical symptoms of scurvy (10-12). Intake of 10 mg per day of antioxidants is suitable to stop scurvy. This amount ends up in plasma concentrations of vitamins below 10 μM, already beyond that

necessary to forestall scurvy (13). However, the present recommended dietary allowance (RDA) for water-soluble vitamins for adult men and ladies, is about 75 mg/day for girls and 90 mg/day for men (14).

                          The adsorption of antioxidants 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 transport depends on the sodium ascorbic acid transporters (SVCT). where the GLUT transporters are predominantly expressed. DHA and glucose share identical GLUT transporters, resulting in competitive inhibition, particularly secondary to pathologies that alter serum glucose levels and attenuate the bioavailability of ascorbic acid under hyperglycemic conditions caused by diabetes (18- 20).

           SVCT2 is sensitive to the changes in intracellular ascorbate levels (23), which can play a regulatory role in maintaining ascorbate homeostasis inside the cell (22). Furthermore, an age-related decline in SVCT1 expression in rat liver cells has been observed (24), explaining why elderly individuals require higher levels of water-soluble vitamins (25). On the contrary, unlike SVCT1, SVCT2 levels weren’t observed to say no with age, perhaps as a result of the low abundance of this transporter within the liver (24).

 Generally, high doses of ascorbic acid are often toxic (26). Excess ascorbate is often excreted harmlessly within the urine, but the surplus formation of oxalate can

accumulate in various organs in patients with the renal disorder or kidney disease (such as kidney transplanted patients) and patients undergoing dialysis (27, 28). Administration of high doses of antioxidants 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 hemolysis) (26, 29)

MECHANISM OF ACTIONS OF ASCORBIC ACID

COLLAGEN SYNTHESIS

the water-soluble vitamin stimulates all kinds of collagen synthesis by donating electrons required for the hydroxylation of proline and lysine in procollagen by specific hydroxylase enzymes (30). within the catalytic cycle, the co-substrate, ?- ketoglutarate, undergoes oxidative decarboxylation to create succinate and a highly reactive iron-oxo (Fe+4) species. within the absence of a substrate molecule, the enzyme becomes uncoupled and so ascorbate reduces oxo-iron back to Fe+2, restoring the enzyme’s activity. Coordination of ascorbate with enzyme-bound iron would supply the mandatory electrons in uncoupled reaction cycles to reactivate the enzyme, in keeping with the observation that the role of ascorbate is to stay the non-heme iron within the catalytically active, reduced state (31).

                                                                      Regulation of hypoxia-inducible factor 1α Ascorbate has been shown to help prolyl and lysyl hydroxylases within the hydroxylation of hypoxia-inducible factor 1? (HIF- 1?), a transcription factor answerable for the cellular response to low oxygen metal ions and glucose (34, 35). Under normoxic .Under hypoxic conditions, like those existing in fast-growing tumors, HIF-1? hydroxylation is repressed with the result that HIF-dependent gene transcription increases, thus promoting angiogenesis and tumor growth. Because of HIF-1? prolyl hydroxylase is stimulated by vitamin C, low ascorbic acid levels would cut back HIF-1? hydroxylation and thus stabilize HIF-1?, thereby promoting HIF-dependent gene transcription and tumor growth (36).

                                                                    Antioxidant action In all of its known functions, ascorbic acid functions as a potent chemical agent that efficiently quenches potentially damaging free radicals produced by normal metabolic respiration of the body (37). At physiological concentrations, the water-soluble vitamin may be a potent atom scavenger within the plasma, protecting cells against oxidative damage caused by ROS (38-41). The antioxidant property of vitamin C is attributed to its ability to scale back potentially damaging ROS, forming, instead, resonance-stabilized and comparatively stable ascorbate 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 unconventional generated (43, 44). If the AFR significantly accumulates in areas not accessible to those enzymes, or if its concentration exceeds their capacity, two molecules of the AFR reactor dismutate to create one molecule each of ascorbate and DHA (45).   oxidized aminoalkanoic acid residues to take care of protein integrity (50, 52, 53). Since oxidative stress is involved within the pathogenesis of the many morbid conditions, antioxidant (frequently administered together with other antioxidants) has been often wont to prevent or treat several diseases thanks to its antioxidant properties (26, 54). Pro-oxidant action Vitamin C, under certain conditions like low concentrations and/or within the presence of free transition metals like copper and iron, may function as a pro-oxidant (55). The pro-oxidant activity of ascorbic acid ends up in the formation of ROS (57) or glycated proteins (58).

On the opposite hand, in vitro model suggested that certain pro-oxidant effects of ascorbate like the capacity to market protein thiol oxidation in rat liver microsomes (59) can even be advantageous. We next discuss the results of antioxidants in preventing or treating chronic and acute pathologic conditions because of all its properties listed above.

ANTI-CARCINOGENIC EFFECTS OF ASCORBIC ACID

Since the half of the ‘90s, a growing body of literature aimed toward demonstrating that vitamin C may reduce the incidence of most malignancies in humans (60). Indeed, high-dose of intravenous water-soluble vitamins has been found to extend the typical survival of advanced cancer patients and for a little group of responders, survival was increased to up to twenty 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 water-soluble vitamins in cellular ambient is obvious in several cytoprotective functions under physiological conditions, including prevention of DNA mutation induced by oxidation (39-41, 46-49). Since DNA mutation is probably going a serious contributor to the age-related development of cancer, attenuation of oxidation-induced mutations by vitamin C could also be considered as a possible anticancer mechanism (66). Moreover, in vivo studies confirmed that consumption of

vitamin C-rich foods is inversely associated with the extent of oxidative DNA damage (67-70). Vitamin C may function as a cancer cells killer thanks to its pro-oxidant capacity (56). The tumor cell-killing action relies upon ascorbate incubation time and extracellular ascorbate concentration (71).

                     which successively may be toxic, are hypothesized. The killing of cancer cells relies 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 but minutes (77-81) Among other mechanisms of anti-cancer action of water-soluble vitamin, it’s been earlier hypothesized a possible role of an antioxidant in increasing collagen synthesis (84) and inhibiting hyaluronidase (85). These mechanisms are purported to prevent cancer spread by increasing the extracellular matrix, thus walling in tumors (86-88). In contrast with these results, other studies have reported no effects after using antioxidants as a therapeutic drug (89, 90). Another randomized, placebo-controlled clinical study within 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 antioxidants in

treating cancer (90). because of the controversy of results on the vitamin C-cancer correlation and lack of validated mechanistic basis for its therapeutic action, further research is required to work out the feasibility of using ascorbic acid in clinical treatment or prevention of cancer.

 

VITAMIN C AND CARDIOVASCULAR DISEASES

Reactive oxygen species (ROS) are highly reactive molecules that derive mainly from

the mitochondrial electron transport chain which is necessary for severe normal cellular functions, starting from their role as. However, most studies have linked the excessive generation of ROS, so-called oxidative stress, to disease states, like cancer, insulin resistance, diabetes, cardiovascular diseases, atherosclerosis, and aging (39- 40, 91-94) and superoxide is that the most biologically relevant radical within the vasculature because it is of course produced by most vascular cells (95). vitamin C provides collagen synthesis, hence allowing proper folding into the triple-helical collagen molecule that’s then secreted to make the extracellular matrix or to create a part of the basement membrane concerning type IV collagen (33). in contrast, lack of ascorbate leads to friable vessels and particularly capillaries that are more liable to rupture, creating the everyday petechial hemorrhages and ecchymoses observed in scurvy and also the neural structure of SVCT2 knockout mice (96).

    Vitamin C has been found to forestall apoptosis by blocking the activity of inflammatory cytokines and oxidized LDL both in cultured endothelial cells (97-99) and patients with congestive cardiopathy within which treatment with ascorbic acid decreased the discharge of microparticles derived from endothelial cells (98).

             Results of a randomized, double-blind, placebo-controlled study conducted on subjects with documented arteria disease have shown that long-term oral ascorbate supplements do have persistent effects on endothelial-dependent flow-mediated arterial blood vessel dilation (100). A possible mechanism of action has been thought to depend upon the effect of vitamin C on gas (NO) synthase. Indeed, vitamin C enhances the NO synthase activity by maintaining tetrahydrobiopterin, a vital co-factor for the enzyme, in its reduced and active form (101- 103), normally inhibited by ROS that oxidizes and thus deplete the co-factor. By increasing NO production, ascorbic acid may indirectly protect the vascular endothelium thanks to its actions, namely smooth muscle fiber relaxation, downstream vasodilatation, and inhibition of the consequences, Moreover, thanks to its

antioxidant properties, antioxidant directly reduces nitrite by releasing NO from nitrosothiols, and scavenges superoxide, although relatively high ascorbate concentrations (>100 μM) are required to forestall the reaction of superoxide with NO (108). The role of ascorbate in preventing uncontrolled vascular smooth muscle cells (VSMC) proliferation and dedifferentiation after an acute arterial injury are investigated in studies of coronary restenosis in pigs (109,  The mechanism of action

continues to be unclear since ascorbic acid has been shown to paradoxically provide collagen synthesis, necessary for VSMC migration and proliferation (112, 113) and to stop VSMC dedifferentiation (114, 115) (117) from apoptosis and necrosis because of injury by oxidized LDL (118). Oxidative modification of LDL by ROS, like superoxide and hydroxyl radicals, also initiates a sequence of atherogenic events within the sub-endothelial space. Physiological concentrations of water-soluble vitamin in vitro attenuate oxidative modification of LDL induced by transition metals (119, 120), homocysteine (121), and myeloperoxidase-derived HOCl (122, 123), furthermore as those naturally produced by human vascular endothelial cells (124). The mechanisms liable for these actions include the ascorbate capacity of quenching aqueous ROS and reactive nitrogen species (RNS), decreasing their bioavailability within the plasma, and of reducing the Macrophages take up modified LDL to become the froth cells and also mediate the inflammatory response that accompanies atherosclerosis (126). In recent studies performed on mouse peritoneal macrophages, it’s been found that ascorbate loading to intracellular concentrations of 3-10 mM prevented oxidative stress induced by latex beads (127) and stimulated several functions like adherence, chemotaxis, phagocytosis, and superoxide production (128). Results regarding such effects of the water-soluble vitamin haven’t 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) et al. within which such effect has not been observed (81, 132), maybe thanks to differences.

             In vitro conditions (133, 134). Regarding the hypothesis that ascorbate is required for the synthesis of the collagenous framework of atherosclerotic plaques, a study performed on apolipoprotein E (ApoE) knockout mice revealed no effect. However, plaque collagen content was found to be decreased in animals on a marginal ascorbate diet, thus demonstrating that it plays a job within the stability of atherosclerotic plaques. 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 may need a preventive effect on potential endothelial dysfunction.

                  Recently, several studies observed a decrease in plasma ascorbic acid levels in both type I and sort II diabetes, and also the effects of ascorbic acid administered in several ways, additionally to numerous combinations of various anti-diabetic drugs and other antioxidants, are Assessed (136-142).

THE ROLE OF ANTIOXIDANTS IN CRITICALLY ILL PATIENTS

Vitamin C concentrations in plasma and leukocytes are 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 related to the increased production of ROS and peroxynitrite that deplete antioxidant molecules and oxidize proteins and lipids, the potential therapeutic implication of ascorbic acid within the treatment of varied infections has been studied for a protracted time. Indeed, enteral administration of antioxidants 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 animal experimental sepsis vitamin C prevented hypotension and edema in LPS-injected animals (150-152) and improved capillary blood flow, arteriolar responsiveness, blood pressure, liver function, and survival (153-158). A possible mechanism of such effects may rely on the role of ascorbate in both inhibiting apoptoses in endothelial cells and stimulating their proliferation preventing the loss of barrier function in sepsis

conditions (97-99, 159). Moreover, antioxidant 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 a disease or are injected with LPS, thus preventing hypotension in sepsis and, consequently, edema.   Products are formed by the reaction of peroxynitrite with cell proteins (164)

 

ASCORBIC ACID EFFECTS ON

 systema nervosum Several effects produced by ascorbate are explored on the system (165). ascorbic acid can of course efflux from various styles of cells (166, 167), including neurons (168), thanks to its hydrophilic nature and an electric charge at physiologic pH. water-soluble vitamin appears to be allowed to enter into several neuron lines, improving neurotransmission (169) and resulting in several effects on behaviors like learning, memory, and locomotion. Experimental animal models are shown that intraperitoneal administration of ascorbate reversed memory deficits in mice (170, 171) whereas oral administration, in conjunction with tocopherol, 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). additionally, ascorbate treatments either intraperitoneally for 14 days or orally for 30 days improved both acquisition and retention during this passive avoidance task (173), contrasting an earlier study.

Oral intake of ascorbic acid has been shown to cut back the fear response in Japanese quail chicks tested in an exceedingly less stressful light-dark emergence paradigm (175).

However, thanks to lack of agreement between results within these experiments and lack of correlation between different dosing regimens used and a transparent pattern of results, it’s hard to spot the precise mechanism through which water-soluble vitamin influences memory, although it appears reasonable to contemplate, it a mediator, especially of stress-related learning. Regarding neurodegenerative diseases, a positive relationship has been shown between ascorbate supplement use and reduced incidence of Alzheimer’s disease (177, 178) that’s known to be caused by a mix of genetic and lifestyle factors and partly by oxidative stress (179), although these beneficial results aren’t universal (180, 181). Finally, it’s been observed that intake of ascorbate as a pharmacological agent could also be of benefit in protecting against brain disorder improving the bioavailability of levodopa (184) although population studies revealed no effects of ascorbate intake in preventing the event of the disease (185).

ASCORBIC ACID IN OCULAR

vitamins and minerals slow down the progression of advanced age-related degeneration and loss of visual sense in people with signs of this disease (187, 188). The effectiveness of water-soluble vitamins as a treatment of diabetic retinopathy has also been examined, but further studies are required to prove that it’s a major impact on its progress (189).

CONCLUSIONS

This review attempts to summarize recent and well-established advances in antioxidant research and its clinical implications. Since ascorbic acid has the potential to counteract inflammation and subsequent oxidative damage that play a significant role within the initiation and progression of several chronic and acute diseases, it represents a practical tool to administer in humans for the first prevention of such pathologic conditions. However, many of such well-known beneficial effects of antioxidant intake are still only understood at the phenomenological level and further research is required to explore the precise effects of ascorbate in physiological systems and therefore the pathology of diseases at the molecular level. a much better understanding of the mechanisms of its action is of major importance to define novel potential therapeutic implications regarding antioxidant.

 

REFERENCE

 

  1. J. Rebouche: Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr 54, 1147S-1152S (1991)

 

  1. B. Chatterjee, A.K. Majumder, B.K. Nandi, N. Subramanian: Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci 258, 24-47 (1975)

 

  1. Nishikimi, T. Koshizaka, T. Ozawa, K. Yagi: Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase. Arch Biochem Biophys 267, 842-846 (1988)
  2. Nishikimi, R. Fukuyama, S. Minoshima, N. Shimizu, K. Yagi: Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J Biol Chem 269, 13685-13688 (1994)
  3. S. Gropper, J.L. Smith, J.L. Groff. Advanced Nutrition and Human Metabolism. Eds: T Wadsworth, Belmont CA (2009)
  4. Talwar, A. McConnachie, P. Welsh, M. Upton, D. O’Reilly, S.G. Davey, G. Watt, N. Sattar: Which circulating antioxidant vitamins are confounded by socioeconomic deprivation? The MIDSPAN family study. PLoS One 5, e11312 (2010)
  5. Michiels, M. Mellema, F.P. Peters: [Haemorrhages due to vitamin C deficiency. Scurvy in the 21st century]. Ned Tijdschr Geneeskd 154, A1638 (2010),K.L. Retsky, M.W. Freeman, B. Frei: Ascorbic acid oxidation product(s) protect                        
  1. M. Rivers: Safety of high-level vitamin C ingestion. Ann N Y Acad Sci 498, 445-454 (1987)

 

  1. Libby, M. Aikawa: Vitamin C, collagen, and cracks in the plaque. Circulation 105, 1396-1398 (2002)
  2. Myllyla, K. Majamaa, V. Gunzler, H.M. Hanauske-Abel, K.I. Kivirikko: Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. J Biol Chem 259, 5403-5405 (1984)
  3. Telang, A.L. Clem, J.W. Eaton, J. Chesney: Depletion of ascorbic acid restricts angiogenesis and retards tumor growth in a mouse model. Neoplasia 9, 47-56 (2007)
  4. Bei, L. Masuelli, C. Palumbo, I. Tresoldi, A. Scardino, A. Modesti: Long-lasting tissue inflammatory processes trigger autoimmune responses to extracellular matrix molecules. Int Rev Immunol 27, 137-175 (2008)
  5. L. Semenza: HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell 107, 1-3 (2001)
  6. J. Schofield, P.J. Ratcliffe: Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5, 343-354 (2004)
  7. Flashman, S.L. Davies, K.K. Yeoh, C.J. Schofield: Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. Biochem J 427, 135-142 (2010
  8. M. Gaziano, R.J. Glynn, W.G. Christen, T. Kurth, C. Belanger, J. MacFadyen, V. Bubes, J.E. Manson, H.D. Sesso, J.E. Buring: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 301, 52-62 (2009)

 

  1. Carr, B. Frei: Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 13, 1007-1024 (1999)
  2. Izzi, L. Masuelli, I. Tresoldi, P. Sacchetti, A. Modesti, F. Galvano, R. Bei: The effects of dietary flavonoids on the regulation of redox inflammatory networks. Front Biosci 17, 2396-2418 (2012)
  3. Izzi, L. Masuelli, I. Tresoldi, C. Foti, A. Modesti, R. Bei: Immunity and malignant mesothelioma: from mesothelial cell damage to tumor development and immune response-based therapies. Cancer Lett 322, 18-34 (2012)
  4. Marzocchella, M. Fantini, M. Benvenuto, L. Masuelli, I. Tresoldi, A. Modesti, R. Bei: Dietary flavonoids: molecular mechanisms of action as anti-inflammatory agents. Recent Pat Inflamm Allergy Drug Discov 5, 200-220 (2011)
  5. R. Buettner: The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch Biochem Biophys 300, 535-543 (1993)
  6. M. Wakefield, A.E. Cass, G.K. Radda: Electron transfer across the chromaffin granule membrane. Use of EPR to demonstrate reduction of intravesicular ascorbate radical by the extravesicular mitochondrial NADH:ascorbate radical oxidoreductase. J Biol Chem 261, 9746-9752 (1986)
  7. R. Schulze, H. Gallenkamp, H. Staudinger: [Microsomal NADH-dependent electron transport]. Hoppe Seylers Z Physiol Chem 351, 809-817 (1970)
  8. H. Bielski, A.O. Allen, H.A. Schwarz: Mechanism of disproportionation of
  9. V. Khan, D.G. Harrison, M.T. Olbrych, R.W. Alexander, R.M. Medford: Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci U S A 93, 9114-9119 (1996)

 

  1. Kubes, M. Suzuki, D.N. Granger: Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 88, 4651-4655 (1991)

 

  1. Signore, M. Chianelli, R. Bei, W. Oyen, A. Modesti: Targeting cytokine/chemokine receptors: a challenge for molecular nuclear medicine. Eur J Nucl Med Mol Imaging 30, 149-156 (2003)

 

  1. S. Jackson, A. Xu, J.A. Vita, J.F. Keaney, Jr.: Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res 83, 916-922 (1998)

 

  1. L. Nunes, D.S. Sgoutas, R.A. Redden, S.R. Sigman, M.B. Gravanis, S.B. King, III, B.C. Berk: Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol 15, 156-165 (1995)

 

  1. Orbe, J.A. Rodriguez, R. Arias, M. Belzunce, B. Nespereira, M. Perez-Ilzarbe, C. Roncal, J.A. Paramo: Antioxidant vitamins increase the collagen content and reduce MMP-1 in a porcine model of atherosclerosis: implications for plaque stabilization. Atherosclerosis 167, 45-53 (2003)

 

  1. Tomoda, M. Yoshitake, K. Morimoto, N. Aoki: Possible prevention of postangioplasty restenosis by ascorbic acid. Am J Cardiol 78, 1284-1286 (1996)

 

  1. O. Ivanov, S.V. Ivanova, A. Niedzwiecki: Ascorbate affects proliferation of guinea-pig vascular smooth muscle cells by direct and extracellular matrix-mediated effects. J Mol Cell Cardiol 29, 3293-3303 (1997)
  2. F. Rocnik, B.M. Chan, J.G. Pickering: Evidence for a role of collagen synthesis in arterial smooth muscle cell migration.J Clin Invest 101, 1889-1898 (1998)
  3. Arakawa, K. Hasegawa, N. Yanai, M. Obinata, Y. Matsuda: A mouse bone marrow stromal cell line, TBR-B, shows an inducible expression of smooth muscle-specific genes. FEBS Lett 481, 193-196 (2000)

 

  1. Arakawa, K. Hasegawa, J. Irie, S. Ide, J. Ushiki, K. Yamaguchi, S. Oda, Y. Matsuda: L-ascorbic acid stimulates expression of smooth muscle-specific markers in smooth muscle cells both in vitro and in vivo. J Cardiovasc Pharmacol 42, 745-751 (2003)

 

  1. C. Siow, J.P. Richards, K.C. Pedley, D.S. Leake, G.E. Mann: Vitamin C protects human vascular smooth muscle cells against apoptosis induced by moderately oxidized LDL containing high levels of lipid hydroperoxides. Arterioscler Thromb Vasc Biol 19, 2387-2394 (1999)

 

  1. Asmis, E.S. Wintergerst: Dehydroascorbic acid prevents apoptosis induced by oxidized low-density lipoprotein in human monocyte-derived macrophages. Eur J Biochem 255, 147-155 (1998)

 

  1. Jimi, K. Saku, N. Uesugi, N. Sakata, S. Takebayashi: Oxidized low-density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells. Atherosclerosis 116, 15-26 (1995)

 

  1. L. Retsky, B. Frei: Vitamin C prevents metal ion-dependent initiation and propagation of lipid peroxidation in human low-density lipoprotein. Biochim Biophys Acta 1257, 279-287 (1995)
  2. L. Retsky, K. Chen, J. Zeind, B. Frei: Inhibition of copper-induced LDL oxidation by vitamin C is associated with decreased copper-binding to LDL and 2-oxo-histidine formation. Free Radic Biol Med 26, 90-98 (1999)
  3. H. Alul, M. Wood, J. Longo, A.L. Marcotte, A.L. Campione, M.K. Moore, S.M. Lynch: Vitamin C protects low-density lipoprotein from homocysteine-mediated oxidation. Free Radic Biol Med 34, 881-891 (2003)
  4. C. Carr, T. Tijerina, B. Frei: Vitamin C protects against and reverses specific hypochlorous acid- and chloramine- dependent modifications of low-density lipoprotein. Biochem J 346 Pt 2, 491-499 (2000)
  5. Martin, B. Frei: Both intracellular and extracellular vitamin C inhibit atherogenic modification of LDL by human vascular endothelial cells. Arterioscler Thromb Vasc Biol 17, 1583-1590 (1997)
  6. L. Retsky, M.W. Freeman, B. Frei: Ascorbic acid oxidation product(s) protect human low density lipoprotein against atherogenic modification. Anti- rather than prooxidant activity of vitamin C in the presence of transition metal ions. J Biol Chem 268, 1304-1309 (1993)
  7. Kanters, M.J. Gijbels, d.M. van, I, M.N. Vergouwe, P. Heeringa, G. Kraal, M.H. Hofker, M.P. de Winther: Hematopoietic NF-kappaB1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype. Blood 103, 934-940 (2004)
  8. M. May, Z.C. Qu, J. Huang: Ascorbate uptake and antioxidant function in peritoneal macrophages. Archives of Biochemistry and Biophysics 440, 172 (2005)
  9. M. Del, G. Ruedas, S. Medina, V.M. Victor, M. De la Fuente: Improvement by several antioxidants of macrophage function in vitro. Life Sci 63, 871-881 (1998)
  10. Jialal, G.L. Vega, S.M. Grundy: Physiologic levels of ascorbate inhibit the oxidative modification of low-density lipoprotein. Atherosclerosis 82, 185-191 (1990)

 

  1. H. Kang, S.H. Park, Y.J. Lee, J.S. Kang, I.J. Kang, H.K. Shin, J.H. Park, R. Bunger: Antioxidant alpha-keto-carboxylate pyruvate protects low-density lipoprotein and atherogenic macrophages. Free Radic Res 36, 905-914 (2002)

 

  1. C. Carr, B. Frei: Human neutrophils oxidize low-density lipoprotein by a hypochlorous acid-dependent mechanism: the role of vitamin C. Biol Chem 383, 627-636 (2002)
  2. human low-density lipoprotein against atherogenic modification. Anti- rather than prooxidant activity of vitamin C in the presence of transition metal ions. J Biol Chem 268, 1304-1309 (1993)
  3. Ashidate, M. Kawamura, H. Tohda, S. Miyazaki, H. Hayashi, T. Teramoto, Y. Hirata: Ascorbic acid augments cytotoxicity induced by oxidized low-density lipoprotein. J Atheroscler Thromb 10, 7-12 (2003)
  4. E. Stait, D.S. Leake: The effects of ascorbate and dehydroascorbate on the oxidation of low-density lipoprotein. Biochem J 320 ( Pt 2), 373-381 (1996)
  5. E. Stait, D.S. Leake: Ascorbic acid can either increase or decrease low-density lipoprotein modification. FEBS Lett 341, 263-267 (1994)
  6. Nakata, N. Maeda: Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic acid. Circulation 105, 1485-1490 (2002)
  7. Bonnefont-Rousselot: The role of antioxidant micronutrients in the prevention of diabetic complications. Treat Endocrinol 3, 41-52 (2004)
  8. Dorchy: Screening for subclinical complications in young type 1 diabetic patients: experience acquired in Brussels.Pediatr Endocrinol Rev 1, 380-403 (2004)
  9. V. Ratnam, D.D. Ankola, V. Bhardwaj, D.K. Sahana, M.N. Kumar: Role of antioxidants in prophylaxis and therapy: A pharmaceutical perspective. J Control Release 113, 189-207 (2006)
  10. H. Alamdari, K. Paletas, T. Pegiou, M. Sarigianni, C. Befani, G. Koliakos: A novel assay for the evaluation of the prooxidant-antioxidant balance, before and after antioxidant vitamin administration in type II diabetes patients. Clin Biochem 40, 248-254 (2007)
  11. Chen, R.J. Karne, G. Hall, U. Campia, J.A. Panza, R.O. Cannon, III, Y. Wang, A. Katz, M. Levine, M.J. Quon: High- dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol 290, H137-H145 (2006)
  12. Ceriello, S. Kumar, L. Piconi, K. Esposito, D. Giugliano: Simultaneous control of hyperglycemia and oxidative stress normalizes endothelial function in type 1 diabetes. Diabetes Care 30, 649-654 (2007)
  13. Ceriello, L. Piconi, K. Esposito, D. Giugliano: Telmisartan shows an equivalent effect of vitamin C in further improving endothelial dysfunction after glycemia normalization in type 1 diabetes. Diabetes Care 30, 1694-1698 (2007)
  14. X. Wilson: Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors 35, 5-13 (2009)
  15. Borrelli, P. Roux-Lombard, G.E. Grau, E. Girardin, B. Ricou, J. Dayer, P.M. Suter: Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med 24, 392-397 (1996)
  16. F. Galley, M.J. Davies, N.R. Webster: Ascorbyl radical formation in patients with sepsis: effect of ascorbate loading. Free Radic Biol Med 20, 139-143 (1996)
  17. J. Beale, T. Sherry, K. Lei, L. Campbell-Stephen, J. McCook, J. Smith, W. Venetz, B. Alteheld, P. Stehle, H. Schneider: Early enteral supplementation with key pharmaco nutrients improves Sequential Organ Failure Assessment score in critically ill patients with sepsis: outcome of a randomized, controlled, double-blind trial. Crit Care Med 36, 131-144 (2008)

 

  1. Crimi, A. Liguori, M. Condorelli, M. Cioffi, M. Astuto, P. Bontempo, O. Pignalosa, M.T. Vietri, A.M. Molinari, V. Sica, C.F. Della, C. Napoli: The beneficial effects of antioxidant supplementation in enteral feeding in critically ill patients: a prospective, randomized, double-blind, table (2004)
  2. B. Nathens, M.J. Neff, G.J. Jurkovich, P. Klotz, K. Farver, J.T. Ruzinski, F. Radella, I. Garcia, R.V. Maier: Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg 236, 814-822 (2002)

 

  1. Tanaka, T. Matsuda, Y. Miyagantani, T. Yukioka, H. Matsuda, S. Shimazaki: Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 135, 326-331 (2000)

 

  1. Dwenger, H.C. Pape, C. Bantel, G. Schweitzer, K. Krumm, M. Grotz, B. Lueken, M. Funck, G. Regel: Ascorbic acid reduces the endotoxin-induced lung injury in awake sheep. Eur J Clin Invest 24, 229-235 (1994)
  2. H. Feng, S.J. Chu, D. Wang, K. Hsu, C.H. Lin, H.I. Lin: Effects of various antioxidants on endotoxin-induced lung injury and gene expression: mRNA expressions of MnSOD, interleukin-1beta and iNOS. Chin J Physiol 47, 111-120 (2004)
  3. P. Shen, Y.C. Lo, R.C. Yang, H.W. Liu, I.J. Chen, B.N. Wu: Antioxidant eugenosedin-A protects against lipopolysaccharide-induced hypotension, hyper glycaemia, and cytokine immunoreactivity in rats and mice. J Pharm Pharmacol 57, 117-125 (2005)
  4. Armour, K. Tyml, D. Lidington, J.X. Wilson: Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol 90, 795-803 (2001)
  5. Tyml, F. Li, J.X. Wilson: Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med 33, 1823-1828 (2005)
  6. Wu, J.X. Wilson, K. Tyml: Ascorbate protects against impaired arteriolar constriction in sepsis by inhibiting inducible nitric oxide synthase expression. Free Radic Biol Med 37, 1282-1289 (2004)
  7. Y. Kim, S.M. Lee: Vitamins C and E protect hepatic cytochrome P450 dysfunction induced by polymicrobial sepsis. Eur J Pharmacol 534, 202-209 (2006)
  8. Tyml, F. Li, J.X. Wilson: Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 36, 2355-2362 (2008)
  9. Wu, J.X. Wilson, K. Tyml: Ascorbate inhibits iNOS expression and preserves vasoconstrictor responsiveness in skeletal muscle of septic mice. Am J Physiol Regul Integr Comp Physiol 285, R50-R56 (2003)
  10. M. Schor, S.L. Schor, T.D. Allen: Effects of culture conditions on the proliferation, morphology and migration of bovine aortic endothelial cells. J Cell Sci 62, 267-285 (1983)
  11. Ferlitsch, J. Pleiner, F. Mittermayer, G. Schaller, M. Homoncik, M. Peck-Radosavljevic, M. Wolzt: Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites. Crit Care Med 33, 2028-2033 (2005)
  12. Pleiner, F. Mittermayer, G. Schaller, C. Marsik, R.J. Macallister, M. Wolzt: Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress. J Am Coll Cardiol 42, 1656-1662 (2003)
  13. Mittermayer, J. Pleiner, G. Schaller, S. Zorn, K. Namiranian, S. Kapiotis, G. Bartel, M. Wolfrum, M. Brugel, J. Thiery,
  14. Pleiner, F. Mittermayer, G. Schaller, R.J. Macallister, M. Wolzt: High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm. Circulation 106, 1460-1464 (2002)
  15. Kirsch, G.H. de: Ascorbate is a potent antioxidant against peroxynitrite-induced oxidation reactions. Evidence that ascorbate acts by re-reducing substrate radicals produced by peroxynitrite. J Biol Chem 275, 16702-16708 (2000)
  16. E. Harrison, J.M. May: Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med 46, 719-730 (2009)

 

  1. M. Upston, A. Karjalainen, F.L. Bygrave, R. Stocker: Efflux of hepatic ascorbate: a potential contributor to the maintenance of plasma vitamin C. Biochem J 342 ( Pt 1), 49-56 (1999)
  2. A. Davis, S.E. Samson, K. Best, K.K. Mallhi, M. Szewczyk, J.X. Wilson, C.Y. Kwan, A.K. Grover: Ca2+-mediated ascorbate release from coronary artery endothelial cells. Br J Pharmacol 147, 131-139 (2006)
  3. V. Rebec, R.C. Pierce: A vitamin as a neuromodulator: ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission. Prog Neurobiol 43, 537-565 (1994)
  4. A. Grunewald: Ascorbic acid in the brain. Brain Res Brain Res Rev 18, 123-133 (1993)
  5. Parle, D. Dhingra: Ascorbic Acid: a promising memory-enhancer in mice. J Pharmacol Sci 93, 129-135 (2003)

 

  1. L. de, C. Furlan: The effects of ascorbic acid and oxiracetam on scopolamine-induced amnesia in a habituation test in aged mice. Neurobiol Learn Mem 64, 119-124 (1995)

 

  1. Arzi, A.A. Hemmati, A. Razian: Effect of vitamins C and E on cognitive function in the mouse. Pharmacol Res 49, 249- 252 (2004)
  2. Shahidi, A. Komaki, M. Mahmoodi, N. Atrvash, M. Ghodrati: Ascorbic acid supplementation could affect passive avoidance learning and memory in rat. Brain Res Bull 76, 109-113 (2008)
  3. S. Desole, V. Anania, G. Esposito, F. Carboni, A. Senini, E. Miele: Neurochemical and behavioral changes induced by ascorbic acid and d-amphetamine in the rat. Pharmacol Res Commun 19, 441-450 (1987)
  4. B. Jones, D.G. Satterlee, G.G. Cadd: Timidity in Japanese quail: effects of vitamin C and divergent selection for an adrenocortical response. Physiol Behav 67, 117-120 (1999)
  5. E. Harrison, S.S. Yu, K.L. Van Den Bossche, L. Li, J.M. May, M.P. McDonald: Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. J Neurochem 106, 1198-1208 (2008)
  6. C. Morris, L.A. Beckett, P.A. Scherr, L.E. Hebert, D.A. Bennett, T.S. Field, D.A. Evans: Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord 12, 121-126 (1998)
  7. J. Engelhart, M.I. Geerlings, A. Ruitenberg, J.C. van Swieten, A. Hofman, J.C. Witteman, M.M. Breteler: Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223-3229 (2002)
  8. F. Quinn, K.S. Montine, M. Moore, J.D. Morrow, J.A. Kaye, T.J. Montine: Suppression of longitudinal increase in CSF F2-isoprostanes in Alzheimer’s disease. J Alzheimers Dis 6, 93-97 (2004)
  9. A. Luchsinger, M.X. Tang, S. Shea, R. Mayeux: Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol60, 203-208 (2003)
  10. G. Fillenbaum, M.N. Kuchibhatla, J.T. Hanlon, M.B. Artz, C.F. Pieper, K.E. Schmader, M.W. Dysken, S.L. Gray: Dementia and Alzheimer’s disease in community-dwelling elders taking vitamin C and/or vitamin E. Ann Pharmacother 39, 2009-2014 (2005)
  11. Rosales-Corral, D.X. Tan, R.J. Reiter, M. Valdivia-Velazquez, G. Martinez-Barboza, J.P. Acosta-Martinez, G.G. Ortiz: Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. J Pineal Res 35, 80-84 (2003)
  12. Huang, J.M. May: Ascorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by beta- amyloid. Brain Res 1097, 52-58 (2006)
  13. Nagayama, M. Hamamoto, M. Ueda, C. Nito, H. Yamaguchi, Y. Katayama: The effect of ascorbic acid on the pharmacokinetics of levodopa in elderly patients with Parkinson disease. Clin Neuropharmacol 27, 270-273 (2004)
  14. M. Zhang, M.A. Hernan, H. Chen, D. Spiegelman, W.C. Willett, A. Ascherio: Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology 59, 1161-1169 (2002)
  15. Fan, L.W. Reneker, M.E. Obrenovich, C. Strauch, R. Cheng, S.M. Jarvis, B.J. Ortwerth, V.M. Monnier: Vitamin C mediates chemical aging of lens crystallins by the Maillard reaction in a humanized mouse model. Proc Natl Acad Sci U S A 103, 16912-16917 (2006)
  16. Evans: Antioxidant supplements to prevent or slow down the progression of AMD: a systematic review and meta-analysis. Eye (Lond) 22, 751-760 (2008)
  17. R. Evans, K. Henshaw: Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Syst Rev , CD000253 (2008)
  18. C. Lopes de Jesus, A.N. Atallah, O. Valente, V.F. Moca Trevisani: Vitamin C and superoxide dismutase (SOD) for diabetic retinopathy. Cochrane Database Syst Rev , CD006695 (2008)
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