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Ridwan Suntoko. A short summary of this paper. Vitamin yang akan diuji adalah vitamin A, vitamin B1, vitamin B6 dan vitamin C. Praktikum kali ini, bertujuan untuk dapat memahami dan mengerti tentang cara-cara mengidentifikasi adanya vitamin dalam suatu bahan secara kualitatif. Tinjauan Pustaka Vitamin merupakan senyawa-senyawa organik tertentu yang memliki bobot molekul kecil dan berfungsi sebagai metabolisme organisme, memelihara kesehatan, mengatur pembentukan tulang, dan mengubah lemak dan karbohidrat menjadi energi.
Kebanyakan vitamin-vitamin tidak dapat disintesis oleh tubuh karena tidak memiliki enzim untuk membentuknya,sehingga harus diperoleh dari makanan atau suplemen. Namun beberapa diantaranya masih dapat dibentuk oleh tubuh yang disebut dengan provitamin, tetapi kecepatan pembentukannya sangat kecil sehingga jumlah yang terbentuk tidak dapat memenuhi kebutuhan hidup. Contoh provitamin adalah vitamin D yang banyak terdapat di jaringan bawah kulit.
Vitamin lain yang disintetis di dalam tubuh adalah vitamin K dan vitamin B Kedua macam vitamin tersebut disintetis di dalam usus oleh bakteri. Tubuh memerlukan vitamin dalam jumlah sedikit, tetapi jika kebutuhan yang sedikit itu diabaikan, akan mengakibatkan terganggunya metabolisme di dalam tubuh kita karena fungsinya tidak dapat digantikan oleh senyawa lain.
Kondisi kekurang vitamin disebut avitaminosis. Bedasarkan kelarutannya vitamin dibagi menjadi dua kelompok, yaitu vitamin yang larut dalam air vitamin C dan semua golongan vitamin B dan yang larut dalam lemak vitamin A, D, E, dan K. Oleh karena sifat kelarutannya tersebut, vitamin yang larut dalam air tidak dapat disimpan dalam tubuh, sedangkan vitamin yang larut dalam lemak dapat disimpan dalam tubuh.
Vitamin A atau retinol merupakan senyawa poliisoprenoid yang mengandung cincin sikloheksinil. Retinol adalah substansi induk dari retinoid yang terdapat pada retinal dan asam retinoat. Retinol terdapat dalam makanan yang berasal dari hewan. Senyawa mirip b-karoten dikenal sebagai karotenoid.
Dalam tubuh, fungsi utama vitamin A dilaksanakan oleh retinol dan kedua derivatnya yaitu retinal dan asam retinoat. Retinol dan retinal dapat melakukan interkonversi dengan adanya enzim dehidrogenase atau reduktase yang memerlukan NAD atau NADP di dalam banyak jaringan.
Sedangkan asam retinoat dapat mendukung pertumbuhan dan diferensiasi, tetapi tidak dapat menggantikan retinal dalam peranannya pada penglihatan ataupun retinol yang berperan dalam sistem reproduksi. Retinal adalah bahan pewarna pigmen penglihatan, yaitu rodopsin. Rodopsin terdapat dalam sel batang retina yang bertanggung jawab atas penglihatan pada saat cahaya kurang terang.
Removal of extracellular glutamate by such a process, would also decrease excitotoxicity caused by activation of cell surface and synaptic glutamate receptors [15,,]. It was hoped that knowledge of the regional distribution of ascorbate throughout the brain would provide vital clues as to its neuromodulatory function.
Areas such as the forebrain that typically show the highest levels of ascorbate are rich in catecholamine innervation []. However, there does not appear to be any clear relationship between extracellular ascorbate levels and any neurotransmitters, and the question as to how such modulation is achieved has yet to be clarified. In the animals with the most severe ascorbate deficiency, neurotransmitter levels never normalized.
However, with only slightly higher brain ascorbate levels, dopamine and norepinephrine contents slowly returned to control levels over the course of eight weeks. This recovery indicates an excellent plasticity of the brain in dealing with a low ascorbate environment, but shows that there are situations in which minimal ascorbate is sufficient to maintain apparently healthy growth, but NIH-PA Author Manuscript in which brain function can be compromised.
Following an even longer period of ascorbate deficiency, depressed levels of both dopamine and norepinephrine were reported along with increased catecholamine oxidation []. Pharmacological manipulations highlight the strength of the relationship between ascorbate and dopaminergic function. Treatment with amphetamine, which affects dopaminergic, cholinergic and glutamatergic activity, increased levels of both dopamine and ascorbate in the caudate nucleus [].
Apomorphine a dopamine receptor agonist increased striatal dopamine and ascorbate, whereas the inverse is true of haloperidol a dopamine receptor antagonist which decreased both. These results reflect a well-regulated interaction between dopamine and ascorbate function, especially in the striatum [].
The increases in extracellular ascorbate levels that are seen following activity or amphetamine administration are not uniform across brain areas and may implicate the heteroexchange system between ascorbate and glutamate in the control of these changes.
There are rich glutamatergic Free Radic Biol Med. Harrison and May Page 8 projections from the cortex to the neostriatum. When the cortex is damaged, severing these connections, basal ascorbate levels decrease in the neostriatum and activity-induced increases in extracellular release are also diminished [].
A large body of evidence reviewed in Rebec NIH-PA Author Manuscript and Pierce, [15] suggests that the substantia nigra may be critically involved in dopaminergic and ascorbate interactions in the neostriatum which would implicate a highly complex pathway of innervation and synaptic signaling governing the relationship.
There is also evidence that ascorbate is involved in the regulation of both acetylcholine and catecholamine release from synaptic vesicles []. Scopolamine is a muscarinic receptor antagonist that also inhibits the action of acetylcholinesterase to break down acetylcholine in the synaptic cleft. In rats fed an ascorbate-enriched diet, the acetylcholinesterase inhibition caused by scopolamine was reversed [], whereas in a guinea pig vitamin C deficiency model, brain acetylcholinesterase was found to be decreased relative to control animals [].
Conversely, scopolamine treatment decreased ascorbate levels in rat striatum []. In vivo voltammetry studies of amphetamine-induced activity enhancement showed increased levels of ascorbate in the caudate nucleus. Parenteral administration of scopolamine and MK an NMDA receptor blocker both diminished the increase in ascorbate, further supporting relationship between ascorbate release and cholinergic receptor stimulation [].
In addition to the noted effects of ascorbate on neurotransmitters, ascorbate also has been shown to be involved in neuropeptide amidation [] and release in brain [,]. Most of the positive effects of ascorbate follow parenteral administration of the vitamin typically intraperitoneal injection , since much higher effective doses can be given by this route compared to oral administration.
Improvement was not noted in 3 month old mice or when ascorbate was administered alone in that study. It should be noted, however, that these are atypical tests of learning and memory. The first two are variants of tasks more often used to measure anxiety than learning, and the third relies on learned associations between a response and an electric shock. Less agreement has been found in rats using a shock avoidance shuttle-box paradigm. The shock- avoidance test is highly stressful, and in the latter study involved up to electric shocks per day.
Even in the former study, where as few as one or two shocks may have been administered to the rat, the stress response may have been a confounding factor in the results.
Ascorbate provided in drinking water has been shown to reduce the fear response in Japanese quail chicks tested in a less stressful light-dark emergence paradigm [].
If ascorbate altered anxiety levels or the stress response in any of the above tasks, then task motivation, and therefore performance, may have been affected rather than cognitive ability.
Further, different doses of ascorbate and different dosing regimens used within these experiments rarely reflected a clear Free Radic Biol Med. Harrison and May Page 9 pattern of results or obvious dose-response relationships. Notwithstanding the negative results, it seems possible that ascorbate could be a mediator of learning and memory, especially stress- related learning, although the exact circumstances under which it has nootropic cognitive NIH-PA Author Manuscript enhancing abilities are as yet unclear.
As with the effects on neurotransmitter levels noted above, a modulatory role of ascorbate on behavior can be more clearly seen in animals undergoing pharmacological challenge. Treatment with amphetamine increased the number of avoidance responses made in the shuttle box task describe above [,], and this effect was blocked by ascorbate treatment.
The testing procedure itself led to decreased dopamine concentrations in the striatum, hippocampus and hypothalamus. These decreases were not seen in amphetamine-treated animals. Following ascorbate treatment, striatal dopamine was further decreased, although it remained unchanged relative to untested controls in hypothalamus and hippocampus.
Amphetamine also increases locomotor activity and stereotypic behaviors e. The behavioral effects of amphetamine were also attenuated either by intraventricular or striatal infusions of ascorbate. The results following ascorbate administration were similar to those of haloperidol a dopamine receptor antagonist and larger effects were found when both agents were combined [,].
Scopolamine had almost identical results to apomorphine a dopamine receptor agonist in that both lead to increases in motor activity and NIH-PA Author Manuscript stereotypy []. They also inhibit ascorbate turnover and increase ascorbate catabolism in the striatum []. In rats with nigrostriatal lesions, treatment with amphetamine led to dopamine release contralateral to the lesioned area and results in circling behaviors.
Although there is clearly a complex relationship between ascorbate and the cholinergic and dopaminergic systems, available data suggests that ascorbate can behave as a dopamine receptor antagonist.
Mice deficient in the ascorbate transporter SVCT2 have undetectable levels of ascorbate in brain; they die with capillary hemorrhage in penetrating vessels of the brain [].
Milder variants of this defect in humans have been associated with small vessel disease and hemorrhagic stroke []. Ascorbate- NIH-PA Author Manuscript dependent collagen synthesis has also been linked to formation of the myelin sheath that surrounds many neuronal processes: ascorbate added to a mixed culture of rat Schwann cells and dorsal root ganglion neurons promoted myelin formation and differentiation by Schwann cells during formation of the basal lamina of the myelin sheath [].
The latter process was considered linked to the ability of the Schwann cells to generate collagen. Importance of Vitamin C in the brain: neuroprotective functions of ascorbate 4. Although the disease has been associated with paraparesis in humans, death appears to be due more to complications of systemic collagen dysfunction rather than to a distinct neurologic syndrome [].
This likely Free Radic Biol Med. Harrison and May Page 10 relates to the fact that ascorbate is avidly retained by the CNS during ascorbate deficiency []. Whereas this suggests that decreases in CNS ascorbate do not play a major role in the signs and symptoms of generalized scurvy, it also suggests that the strong retention of ascorbate in the CNS reflects its importance to neuronal function.
This hypothesis is supported by studies in guinea pigs with moderate vitamin E deficiency in which an acute deficiency of ascorbate was superimposed []. These animals gained weight and appeared completely normal. However, within days of removing vitamin C from their diet, most of the animals developed a progressive ascending paralysis and died within 24 hours. No neurologic signs were apparent in animals with single deficiencies of vitamins C or E. These animals had no signs of scurvy no skin or hair changes, no hemarthroses , and only small increases in liver and brain F2- isoprostanes a marker of oxidant stress.
Standard hematoxylin and eosin staining of the brains and spinal cords showed no abnormalities. However, Nissl and silver degeneration stains revealed widespread neuronal loss and degeneration in the pons and long motor tracts of the NIH-PA Author Manuscript spinal cord []. Thus, even a modest decrease in CNS ascorbate accelerated signs of vitamin E deficiency in this model and led to significant neuronal loss.
If the SVCT2 transporter is responsible for maintaining high CSF and neuronal ascorbate concentrations, what happens when the protein is knocked out in the mouse? Targeted deletion of the SVCT2 protein results in homozygotes that die shortly after birth: they never take a breath and have diffuse cerebral hemorrhage []. Whereas the latter could reflect increased capillary fragility, the late-stage embryos do not show hemorrhage elsewhere and lack signs of generalized scurvy.
The proximal cause of death is unclear. Catecholamine synthesis is an ascorbate-dependent function and ascorbate levels are known to be in the millimolar range in adrenal gland Fig.
Although catecholamine synthesis in the SVCT2 knockout mouse is decreased, but this does not appear to be the cause of death []. Although the lungs failed to expand, their architecture was normal, as were surfactant levels [].
As noted earlier, ascorbate levels in brain and pituitary of the homozygous knockout embryos were undetectable. This observation provides strong evidence that uptake on the SVCT2 is the only route for ascorbate entry into neural tissues.
Ischemia initially depletes intracellular GSH [] and ascorbate [] in brain. If reperfusion with oxygen rich blood occurs, the ROS generated due to abnormal mitochondrial metabolism will extend tissue damage to areas with decreased oxidant defenses [].
Parenteral ascorbate injections decreased infarct size in both primate and rodent models of middle cerebral artery ischemia-reperfusion. Harrison and May Page 11 above levels in the treated compared to the non-treated monkeys []. Thus, relatively modest increases in brain ascorbate content due to several days of parenteral administration were associated with neuroprotection against ischemia-reperfusion injury. This dramatic decrease in infarct size with acute dosing was surprising, given that ascorbate normally enters the CNS slowly through the choroid plexus, as discussed above.
Indeed, in a subsequent study in mice with middle cerebral artery occlusion, high dose DHA given by intra-luminal infusion injection just before, 15 min after, or 3 h after occlusion markedly decreased infarct volume, mortality, and neurological deficits in mice []. It is important to note that improvement occurred despite the fact that such high DHA doses may be toxic to some cell types, such as insulin-secreting cells of islets []. In contrast to results with DHA, no effects were observed for comparable injections of ascorbate.
Protection by DHA infusion was observed in both ischemia alone and ischemia-reperfusion models. Why ascorbate infusion decreased lesion size in the primate study but not in the mouse studies is unclear, but it could relate to breakdown of the blood-brain barrier in ischemic regions, thus allowing entry of both ascorbate and DHA, or to differences in the ability of ascorbate to gain access to the CNS in the two species.
That NIH-PA Author Manuscript is, loss of the ability to synthesize ascorbate may have favored development of alternate routes or of more rapid transit of ascorbate into the CNS in primates.
They also allay to some extent the concern raised by a human study of acute parenteral ascorbate prophylaxis before ischemia-reperfusion related to abdominal vascular surgery [].
In that study intravenous ascorbate infusion 2 g given 2 h before ischemia was induced increased tissue release of ROS, possibly due to a Fenton-type reaction of ascorbate with free iron in ischemic areas. This was thought in turn to account for the increased generation of lipid peroxides and inflammatory cytokines observed. That opposite results were seen following middle cerebral artery occlusion suggests that ascorbate did not encounter significant amounts of free iron in the brain.
Such iron would likely be outside living cells, where it would encounter only non-reactive DHA in the DHA infusion studies. This DHA would be taken up and to ascorbate intracellularly, where it would not have exposure to free iron. As alluded to above, a consistent factor in these pathologies is the need to maintain intracellular, as opposed to extracellular, ascorbate. The concept that intracellular ascorbate is crucial for protection against oxidant stress is also supported by results of several in vivo studies.
For example, an increase in intracellular but not extracellular ascorbate content of rat brain slices decreased the swelling induced by oxidant stress []. Finally, the neuroprotective role of intracellular ascorbate highlights a crucial role for the SVCT2 in preserving intracellular ascorbate. This was evident in recent studies using in Free Radic Biol Med. Harrison and May Page 12 primary cultures prepared from hippocampal neurons derived from embryos that either lacked the SVCT2 or expressed normal levels of the protein [].
Excitotoxic challenge with NMDA or direct addition of the oxidant hydrogen peroxide markedly enhanced death of the cells lacking the SVCT2 compared to cells from wild-type mice. Moreover, following middle cerebral artery occlusion in rats, SVCT2 mRNA increased over several hours in the peri-infarct penumbra, both in neurons and in glia [].
Together, the results of these studies strongly support a protective role for ascorbate and for the SVCT2 in brain during acute ROS generation. Potential therapeutic functions of vitamin C in neurodegenerative disorders Oxidative stress in the brain with focus on neurodegenerative diseases has been extensively reviewed [], so only aspects relevant to ascorbate will be considered here.
Neurons appear to be especially sensitive to ascorbate deficiency, perhaps because they have fold higher rates of oxidative metabolism than supporting glia [,]. This neuronal sensitivity is most apparent when ascorbate supply is low in conditions in which there is excess oxidant stress.
The involvement of reactive oxygen species in neurodegenerative disorders explains the enthusiasm for ascorbate as an antioxidant therapeutic approach, although its complicated interactions with neurotransmitter systems as described above make it difficult to discern the NIH-PA Author Manuscript specific mechanisms involved.
Alzheimer's disease patients have been found to have lower plasma [] and CSF [] ascorbate levels despite adequate nutritional intake. Positive relationships have been shown between ascorbate supplement use and reduced disease incidence [,] and also with disease-related markers of oxidative stress [], although these beneficial results are not universal [,].
Interpretation of the data is hindered by the nature of the studies as population or epidemiological studies have high levels of variability inherent in their design. Despite the large amount of information that can be collected from participants, and complicated statistical techniques that can be used to control for variability in the data, individual differences can still have a significant influence on results.
The most important contributors to variability are education and career, diet, exercise, alcohol consumption, cigarette smoking and general health and illness across the lifetime. Any combination of the NIH-PA Author Manuscript above factors may contribute to the lack of consistency in findings among these studies. Nevertheless, there is further evidence to support the potential for vitamin C as a therapeutic avenue for Alzheimer's disease.
Scopolamine which impairs memory in rodents is often used as a pharmacological model for Alzheimer's disease. As noted earlier, ascorbate blocked or attenuated the effects of scopolamine in several different types of studies.
Furthermore, ascorbate has been shown to be an effective acetylcholinesterase inhibitor [], the most common form of treatment used for Alzheimer's disease. These results may seem contradictory, since scopolamine can also inhibit acetylcholinesterase, however, the net effect of vitamin C appears to be a boost to cholinergic system functioning, although this relationship needs further investigation.
Harrison and May Page 13 5. Given the range of data presented above concerning the relationship between ascorbate and dopaminergic function it is understandable that ascorbate is being investigated for its therapeutic potential in this disease. Although population studies concerning ascorbate intake show no protection against development of Parkinson's disease [], there are a number of lines of evidence that suggest that ascorbate as a pharmacological agent may be of more benefit.
Ascorbate has been shown to improve bioavailability of levodopa which can then be converted into dopamine in members of an elderly Parkinson's disease population with low baseline bioavailability for levodopa []. MPTP 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine causes massive decreases in dopamine in striatum and leads to Parkinsonian like symptoms in humans if ingested []. As such it is often used to model Parkinsonian symptoms in animals. Mice that express the gene for Huntington's disease show a deficit in striatal ascorbate release during periods of behavioral activity [].
This deficit was reversed with ascorbate injections which also improved the behavioral phenotype of repetitive movements [].
Conclusions That ascorbate is important for neuronal maturation and function, as well as for protection of the brain against oxidant stress is well supported by the evidence presented in this review. The vitamin is maintained at high concentrations in brain and in neurons in particular relative to other organs. In addition, strong homeostatic mechanisms maintain brain and neuronal ascorbate concentrations within very tight limits. Thus, not only is it difficult to deplete brain ascorbate, but it is also difficult if not impossible to increase levels for more than a short period above those set by uptake and recycling mechanisms.
Study of the role of ascorbate in human brain function has been limited, but with the availability of suitable mouse models, ascorbate deficiency or excess can be studied in more detail, particularly with regard to effects of the vitamin on brain development, neurotransmitter function and responses to inflammatory or oxidant stresses, such as might exist in cerebral atherosclerosis or in several neurodegenerative diseases. References 1. Synthesis and some major functions of vitamin C in animals.
Ann N Y Acad Sci ;— Harrison and May Page 14 2. Semenza GL. Cell ;—3. Chishti A. Neutrophil chemotaxis and receptor expression in clinical septic shock. Intensive Care Med. Tavares-Murta B. Failure of neutrophil chemotactic function in septic patients.
Care Med. Hotchkiss R. Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy. Vohra K. Improvement of neutrophil migration by systemic vitamin C in neonates. Roos D. Chronic granulomatous disease. Introne W. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome.
Effects of ascorbate on leucocytes: Part IV. Increased neutrophil function and clinical improvement after oral ascorbate in 2 patients with chronic granulomatous disease. Assessment of oral ascorbate in three children with chronic granulomatous disease and defective neutrophil motility over a 2-year period.
Effects of ascorbate on normal and abnormal leucocyte functions. Gallin J. Boxer L. Correction of leukocyte function in Chediak-Higashi syndrome by ascorbate. Yegin O. Defective lymphocyte locomotion in Chediak-Higashi syndrome. Weening R. Effect of ascorbate on abnormal neutrophil, platelet and lymphocytic function in a patient with the Chediak-Higashi syndrome. Enhancement of chemotactic response and microtubule assembly in human leukocytes by ascorbic acid.
Impaired microtubule assembly and polymorphonuclear leucocyte function in the Chediak-Higashi syndrome correctable by ascorbic acid. Parker W. Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton.
Cell Physiol. Bozonet S. Enhanced human neutrophil vitamin C status, chemotaxis and oxidant generation following dietary supplementation with vitamin C-rich SunGold kiwifruit. De la Fuente M. Immune function in aged women is improved by ingestion of vitamins C and E.
Reactive oxygen species and neutrophil function. Effects of ascorbic acid on neutrophil function. Studies on normal and chronic granulomatous disease neutrophils. Acta Vitaminol. Foroozanfar N. Hampton M. Inside the neutrophil phagosome: Oxidants, myeloperoxidase, and bacterial killing. Wenisch C. Are soluble factors relevant for polymorphonuclear leukocyte dysregulation in septicemia?
Danikas D. Prognostic value of phagocytic activity of neutrophils and monocytes in sepsis. Correlation to CD64 and CD14 antigen expression. Stephan F. Impairment of polymorphonuclear neutrophil functions precedes nosocomial infections in critically ill patients. McGovern N. Hypoxia selectively inhibits respiratory burst activity and killing of Staphylococcus aureus in human neutrophils. Drifte G. Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome.
Bass D. Subpopulations of neutrophils with increased oxidative product formation in blood of patients with infection. Pillay J.
Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia. Assessment of neutrophil function in patients with septic shock: Comparison of methods. Fox S. Neutrophil apoptosis: Relevance to the innate immune response and inflammatory disease. Innate Immun. Redox regulation of the caspases during apoptosis.
Fadeel B. Involvement of caspases in neutrophil apoptosis: Regulation by reactive oxygen species. Wilkie R. Keel M. Interleukin counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. Jimenez M. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome.
Harter L. Mcl-1 correlates with reduced apoptosis in neutrophils from patients with sepsis. Taneja R. Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity.
Fotouhi-Ardakani N. Role for myeloid nuclear differentiation antigen in the regulation of neutrophil apoptosis during sepsis. Paunel-Gorgulu A. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis. Tamayo E. Evolution of neutrophil apoptosis in septic shock survivors and nonsurvivors. Fialkow L. Neutrophil apoptosis: A marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome.
Ertel W. Circulating mediators in serum of injured patients with septic complications inhibit neutrophil apoptosis through up-regulation of protein-tyrosine phosphorylation. Parlato M.
CDtriggered caspase-dependent apoptosis via mitochondrial membrane depolarization and reactive oxygen species production of human neutrophils is impaired in sepsis. Colotta F. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Mikirova N. Ferron-Celma I. Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery.
Pechous R. Zawrotniak M. Neutrophil extracellular traps NETs —Formation and implications. Acta Biochim. Fuchs T. Novel cell death program leads to neutrophil extracellular traps.
Brinkmann V. Neutrophil extracellular traps kill bacteria. Parker H. Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide. Czaikoski P. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. Camicia G. Neutrophil extracellular traps in sepsis. Silk E. The role of extracellular histone in organ injury. Cell Death Dis. Margraf S.
Natarajan R. Impact of intravenous ascorbic acid infusion on novel biomarkers in patients with severe sepsis. Elks P. Activation of hypoxia-inducible factor-1alpha Hif-1alpha delays inflammation resolution by reducing neutrophil apoptosis and reverse migration in a zebrafish inflammation model. Hirota K. Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases.
McInturff A. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Hong J. Vitamin C is taken up by human T cells via sodium-dependent vitamin C transporter 2 SVCT2 and exerts inhibitory effects on the activation of these cells in vitro. Ascorbic acid transport and distribution in human B lymphocytes.
Lenton K. Glutathione and ascorbate are negatively correlated with oxidative DNA damage in human lymphocytes. Campbell J. Ascorbic acid is a potent inhibitor of various forms of T cell apoptosis. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Penn N. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized controlled trial.
Age Ageing. Heuser G. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: The role of protein kinase-C. Sasidharan Nair V. Nikolouli E. Monfort A. Breathing-in epigenetic change with vitamin C. EMBO Rep. Song C. Potential functional roles of DNA demethylation intermediates. Trends Biochem. Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: A randomized controlled trial.
Haryanto B. Multivitamin supplementation supports immune function and ameliorates conditions triggered by reduced air quality. Romieu I. Air pollution, oxidative stress and dietary supplementation: A review. Kelly F. Marmot A. Pozzer A. Effects of business-as-usual anthropogenic emissions on air quality. Sram R. Vitamin C for DNA damage prevention. Tribble D. Reduced plasma ascorbic acid concentrations in nonsmokers regularly exposed to environmental tobacco smoke.
Valkonen M. Passive smoking induces atherogenic changes in low-density lipoprotein. Schectman G. Ascorbic acid requirements for smokers: Analysis of a population survey. Preston A. Influence of environmental tobacco smoke on vitamin C status in children. Strauss R. Environmental tobacco smoke and serum vitamin C levels in children. Panda K. Vitamin C prevents cigarette smoke-induced oxidative damage in vivo.
Dietrich M. Vitamin C supplementation decreases oxidative stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke. Bagaitkar J.
Tobacco use increases susceptibility to bacterial infection. Arcavi L. Cigarette smoking and infection. Sargeant L. European Prospective Investigation into Cancer and Nutrition.
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Wilson R. Inadequate vitamin C status in prediabetes and type 2 diabetes mellitus: Associations with glycaemic control, obesity, and smoking. Essential role of vitamin C and zinc in child immunity and health. Wintergerst E.
Immune-enhancing role of vitamin C and zinc and effect on clinical conditions. Harding A. Plasma vitamin C level, fruit and vegetable consumption, and the risk of new-onset type 2 diabetes mellitus: The European prospective investigation of cancer—Norfolk prospective study. Kositsawat J. This was thought in turn to account for the increased generation of lipid peroxides and inflammatory cytokines observed. That opposite results were seen following middle cerebral artery occlusion suggests that ascorbate did not encounter significant amounts of free iron in the brain.
Such iron would likely be outside living cells, where it would encounter only non-reactive DHA in the DHA infusion studies. This DHA would be taken up and to ascorbate intracellularly, where it would not have exposure to free iron. As alluded to above, a consistent factor in these pathologies is the need to maintain intracellular, as opposed to extracellular, ascorbate.
The concept that intracellular ascorbate is crucial for protection against oxidant stress is also supported by results of several in vivo studies. For example, an increase in intracellular but not extracellular ascorbate content of rat brain slices decreased the swelling induced by oxidant stress [].
Finally, the neuroprotective role of intracellular ascorbate highlights a crucial role for the SVCT2 in preserving intracellular ascorbate. This was evident in recent studies using in Free Radic Biol Med.
Harrison and May Page 12 primary cultures prepared from hippocampal neurons derived from embryos that either lacked the SVCT2 or expressed normal levels of the protein []. Excitotoxic challenge with NMDA or direct addition of the oxidant hydrogen peroxide markedly enhanced death of the cells lacking the SVCT2 compared to cells from wild-type mice.
Moreover, following middle cerebral artery occlusion in rats, SVCT2 mRNA increased over several hours in the peri-infarct penumbra, both in neurons and in glia [].
Together, the results of these studies strongly support a protective role for ascorbate and for the SVCT2 in brain during acute ROS generation. Potential therapeutic functions of vitamin C in neurodegenerative disorders Oxidative stress in the brain with focus on neurodegenerative diseases has been extensively reviewed [], so only aspects relevant to ascorbate will be considered here.
Neurons appear to be especially sensitive to ascorbate deficiency, perhaps because they have fold higher rates of oxidative metabolism than supporting glia [,]. This neuronal sensitivity is most apparent when ascorbate supply is low in conditions in which there is excess oxidant stress. The involvement of reactive oxygen species in neurodegenerative disorders explains the enthusiasm for ascorbate as an antioxidant therapeutic approach, although its complicated interactions with neurotransmitter systems as described above make it difficult to discern the NIH-PA Author Manuscript specific mechanisms involved.
Alzheimer's disease patients have been found to have lower plasma [] and CSF [] ascorbate levels despite adequate nutritional intake. Positive relationships have been shown between ascorbate supplement use and reduced disease incidence [,] and also with disease-related markers of oxidative stress [], although these beneficial results are not universal [,]. Interpretation of the data is hindered by the nature of the studies as population or epidemiological studies have high levels of variability inherent in their design.
Despite the large amount of information that can be collected from participants, and complicated statistical techniques that can be used to control for variability in the data, individual differences can still have a significant influence on results.
The most important contributors to variability are education and career, diet, exercise, alcohol consumption, cigarette smoking and general health and illness across the lifetime. Any combination of the NIH-PA Author Manuscript above factors may contribute to the lack of consistency in findings among these studies.
Nevertheless, there is further evidence to support the potential for vitamin C as a therapeutic avenue for Alzheimer's disease. Scopolamine which impairs memory in rodents is often used as a pharmacological model for Alzheimer's disease. As noted earlier, ascorbate blocked or attenuated the effects of scopolamine in several different types of studies.
Furthermore, ascorbate has been shown to be an effective acetylcholinesterase inhibitor [], the most common form of treatment used for Alzheimer's disease. These results may seem contradictory, since scopolamine can also inhibit acetylcholinesterase, however, the net effect of vitamin C appears to be a boost to cholinergic system functioning, although this relationship needs further investigation.
Harrison and May Page 13 5. Given the range of data presented above concerning the relationship between ascorbate and dopaminergic function it is understandable that ascorbate is being investigated for its therapeutic potential in this disease. Although population studies concerning ascorbate intake show no protection against development of Parkinson's disease [], there are a number of lines of evidence that suggest that ascorbate as a pharmacological agent may be of more benefit.
Ascorbate has been shown to improve bioavailability of levodopa which can then be converted into dopamine in members of an elderly Parkinson's disease population with low baseline bioavailability for levodopa []. MPTP 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine causes massive decreases in dopamine in striatum and leads to Parkinsonian like symptoms in humans if ingested [].
As such it is often used to model Parkinsonian symptoms in animals. Mice that express the gene for Huntington's disease show a deficit in striatal ascorbate release during periods of behavioral activity []. This deficit was reversed with ascorbate injections which also improved the behavioral phenotype of repetitive movements []. Conclusions That ascorbate is important for neuronal maturation and function, as well as for protection of the brain against oxidant stress is well supported by the evidence presented in this review.
The vitamin is maintained at high concentrations in brain and in neurons in particular relative to other organs. In addition, strong homeostatic mechanisms maintain brain and neuronal ascorbate concentrations within very tight limits. Thus, not only is it difficult to deplete brain ascorbate, but it is also difficult if not impossible to increase levels for more than a short period above those set by uptake and recycling mechanisms.
Study of the role of ascorbate in human brain function has been limited, but with the availability of suitable mouse models, ascorbate deficiency or excess can be studied in more detail, particularly with regard to effects of the vitamin on brain development, neurotransmitter function and responses to inflammatory or oxidant stresses, such as might exist in cerebral atherosclerosis or in several neurodegenerative diseases.
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