The Effects of Vitamin C Deficiency - Research Paper

Introduction

The body requires nutritional sufficiency in order to function optimally. Vitamin C is one of the nutritional requirements needed to maintain body functions. Since it was first characterised in 1928, researchers have explored the various biochemical and pharmacokinetic properties of Vitamin C as well as its functions. The compound exists predominantly as an ascorbate anion under physiological pH conditions. Vitamin C is thought to play an important role in the treatment of degenerative diseases, maintenance of the oxidation-reduction balance, autoimmune diseases, and cancer (Ashor et al., 2015; Chen, et al., 2015; Dixit et al., 2015). This paper discusses the role of Vitamin C in disease and its clinical significance.

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Transportation of Ascorbate

According to Richelle and colleagues (2006), the highest concentration of ascorbate is found in the adrenal glands, the brain, the liver, and the skeletal tissue. The function performed by the compound in each cell of these organs will determine the effects of its deficiency. In addition, the transporter used to chaperone the ascorbate into the cells depends on the role the compound performs in the organ. For example, studies show that the cerebrospinal fluid ascorbate diffuses into neurons, where it is captured through the sodium-dependent vitamin C transporter 2 (Gess, Lohmann, Halfter, and Young, 2010). According to Savini et al. (2008), sodium-dependent vitamin C transporter 2 is the main transporter in the adrenal glands where it maintains elevated ascorbate concentrations in the chromaffin cells, which are essential for the synthesis of catecholamines, especially dopamine and norepinephrine. Although sodium-dependent vitamin C transporter 2 is also expressed, sodium-dependent vitamin C transporter 1 is the most abundant transporter in the liver. Another study provides evidence that the rate of uptake of ascorbate in hepatocytes and age may be positively correlated (Michels et al., 2003).

May et al.'s (2009) study show that the transport of Vitamin C across endothelial barriers of tissues takes place primarily via a paracellular mechanism because the transport across the cells is not proportional to the Vitamin C transferred across the endothelium (Ashor, Lara, Mathers, & Siervo, 2014). In other words, the transfer of Vitamin C depends on the distance between endothelial cells suggesting that the transport process may be influenced by the effects of the compound on the cytoskeleton.

The Effects of on Neuronal Differentiation, Maturation, and Survival

Ascorbate has been found to have an effect on the differentiation of embryonic stem cells into neurons. (Harrison and May, 2009). Harrison and May (2009) reported that the differentiation was due to the increased expression of the genes involved. In addition, Lee et al. (2003) identified the increased expression of four genes namely BMP2, BMP7, NeuroD, and Notch as those affected in the differentiation of astrocytic and neuronal cells. Haramoto, Tatemoto, and Muto (2008) also demonstrated the increased neurite formation in response to the potentiating effect of an ascorbate analogue on the nerve growth factor suggesting a different mechanism of Vitamin C's antioxidant properties. Grant, Barber, & Griffiths (2005) also observed an elevated expression of the brain-derived neurotrophic factor because of ascorbate presence in cell culture. According to Grant and associates, brain-derived neurotrophic factor activates the RAS/mitogen-activated protein kinase pathway, which enhances the expression of the enzymes of the endogenous antioxidant system thereby contributing to cell survival.

The Effect of Vitamin C on Catecholamine Biosynthesis and Neurotransmission Modulation

The role of Vitamin C in the biosynthesis of norepinephrine and dopamine has long been established. It has been proposed that ascorbate confers short term and long term modulatory effects of neurotransmission. Ascorbate is a co-substrate for tyrosine hydroxylase and dopamine-v-hydroxylase whereby its modulatory effect is short-term (Berger & Oudemans-van Straaten, 2015). Also, it has been hypothesized that the ascorbate is involved in the increase in intracellular cAMP via the elevated expression of tyrosine hydroxylase (Harrison and May, 2009). According to Yu et al. (2001), Vitamin C plays an integral role in the promotion and maintenance of the differentiation of dopaminergic cells. In another study, Yu et al. (2004) identified observed that ascorbate upregulated and downregulated approximately 92 and 118 genes, respectively during the differentiation of the involved cells. Ascorbate has also been described as a having an induction effect on the liberation of gonadotropins (Karanth et al., 2001). According to Karanth et al. (2001), ascorbate from the gonadotrope cell vesicles is recaptured by the sodium-dependent vitamin C transporter 2 and facilitates the entry of calcium ions into the cell whose interaction with calmodulin increases the neuronal nitric oxide synthase activity. This regulates the downstream activities leading to the release of gonadotropins from the cells.

The Effects of Vitamin C on Learning, and Memory

Laboratory studies have demonstrated that deficiency of ascorbate has adverse effects on learning and memory (Fillenbaum et al., 2005; Parle and Dhingra, 2003). Figueroa-Mendez and Rivas-Arancibia (2015) recently showed that the effects of ascorbate on learning and memory depend on the state of reduction/ oxidation balance. Using healthy mice models, they demonstrated that a low dose of vitamin C has the same effect of decreased retention latency in the passive avoidance test as exposure to an acute dose of ozone without ascorbate. However, when the same dose of ascorbate is given to rats exposed to ozone, the results are similar to that of the control group. This demonstrates that Vitamin C has a protective effect due to the pro-oxidant effect of low dose ascorbate in reduction-oxidation equilibrium and an antioxidant effect at an oxidative stress state.

The Effects of Vitamin C on the Central Nervous System Structure

Vitamin C also plays an important role in the elastin and collagen synthesis (Harrison and May, 2009). Also, ascorbate plays an important role in inducing myelination mediated by Schwann cells. One study reported that basal lamina, which is integral to the induction of myelination was triggered by adding Vitamin C to cultures of Schwann cells with ganglion neurons (Fernandez-Valle et al., 1993). Fragoso et al. (2003) described a member of the family of mitogen-activated protein kinases or p38 plays an important role during the early stages of ascorbate-induced myelination. They concluded that the main role of Vitamin C on myelination may be associated with the lamina structural integrity.

Antioxidant Role of Vitamin C in Central Nervous System

The brain has a high metabolic rate and consumes a fifth of the total body oxygen (Erecinska and Silver, 2001). As such, the brain is readily oxidised; thus, antioxidants play a crucial role in the brain to maintain the reduction-oxidation balance. Differential distribution of ascorbate has been noted in the brain with a heavy presence in the neurons and astrocytes. Probably due to the protective mechanism against ischemic oxidative stress, increased expression of translation of sodium-dependent vitamin C transporter 2 in both neurons and astrocytes has been observed (Berger et al., 2003).

The Role of Vitamin C in Redox Balance

Valko et al. (2007) suggest that the constant balance between oxidants and antioxidants in the body plays an important role in maintaining homeostasis. As such, the endogenous antioxidant system's activities increase when the production of reactive oxygen species increases through a mechanism of reduction-oxidation signalling. Exogenous sources of antioxidants also play an important role in maintaining the reduction-oxidation balance. Whereas the endogenous antioxidant consists of the various antioxidant enzymes and molecules, the exogenous sources include Vitamins C and E as well as flavonoids obtained from the diet. Valko also reported a number of molecules that chelate metals and prevents the production of the hydroxyl radical. An oxidative stress state is obtained when reactive oxygen and nitrogen species increases beyond the ability of the antioxidant system. Vitamin C has the ability to donate electrons which makes it effective in preventing lipid peroxidation in plasma.

The Effects of Vitamin C Deficiency

Scurvy is the state of deficiency of Vitamin C or ascorbic acid in the body. Since Vitamin C is needed to synthesise collagencollagen, which is an important component of the connective tissue (Maxfield & Crane, 2018). Connective tissues play a central role in the body structure including the structural integrity of blood vasculature. The effects of Vitamin C deficiency are related to the differentiation of stem cells, biosynthesis and of catecholamines and modulation of neurotransmission, learning and memory, synthesis of elastin and collagen, and redox balance. As such, the symptoms of ascorbate deficiency include muscular and joint pains, tiredness and weakness, easy bruising of the skin, red-bluish spots on the skin, dry skin, nose bleeding, weak gums, splitting of hair, tooth loss, problems fighting infections and wound healing, changes in bones as well as loss of tooth and weight. In addition, the deficiency of the compound in the body compromises the immune system, metabolism of cholesterol, iron absorption just to mention but a few.

As mentioned earlier, scurvy is a clinical manifestation of severe deficiency of ascorbate caused by the role of the compound in collagen synthesis (especially, Collagen type IV). This collagen is the main component of skin and walls of blood vessels. Vitamin C is influential on the hydroxylase enzyme responsible for the hydroxylation and crosslinking of pro-collagen. Therefore, the deficiency of the vitamin reduces the pro-collagen transcription. Furthermore, it has been reported that the lack of vitamin C leads to the epigenetic DNA hypermethylation as well as inhibition of the transcription of collagen in tissues, skin, and blood vessels.

The symptoms of Vitamin C deficiency manifest between 8 and 12 weeks after inadequate intake. The patient suffers from the initial symptoms of irritation and anorexia. Dermatologic investigation after these symptoms generally finds ecchymosis, gum swelling with loss of teeth, hyperkeratosis, mucocutaneous petechiae, and poor wound healing (Maxfield & Crane, 2018). The swan-neck and corkscrew hairs appear in response to the disruption of the formation of disulfide bonds. Because of the resulting capillary fragility and its inability to withstand the hydrostatic pressure, perifollicular hemorrhages usually occur in the lower extremities sometimes resulting in oedema. Examination of the nails often reveals koilonychia and splinter hemorrhages. Manifestations also occur in multiple other organs. For example, the patient suffers from rheumatologic problems such as subperiosteal hemorrhage and painful hemarthrosis. The impaired formation of collagen is responsible for the vascular fragility which leads to bleeding. The patient also suffers from bone problems which present as fractures because of the disruption of the formation of the endochondral bones. Symptoms of flame and retrobulbar haemorrhages into optic nerves may occur leading to atrophy and papilledema. Chronic deficiency of vitamin C may be life-threating because of the resulting anasarca, convulsions, haemolysis, and jaundice.

The diagnosis of scurvy begins with the physical examination as well as evaluation of the risk factors. As such, dermoscopic techniques play an important role in the diagnosis and confirmation of the...