PRO.BUNDELA JACKSON; PRO.RAMESHWRA DINGRA
(FACULTY OF MEDICINE AND NUETRACUETICAL SCIENCE; UNIVERSITY OF NIGERIA)
VOL.03 Issue 11
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.
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.
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
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).
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.
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