Ascorbate Bioavailability Research Articles

Surface-engineered liposomal particles of calcium ascorbate with fenugreek galactomannan enhanced the oral bioavailability of ascorbic acid: a randomized, double-blinded, 3-sequence, crossover study.

The antioxidant, anti-inflammatory, immunomodulating, anti-thrombotic, and antiviral effects along with its protective effects against respiratory infections have generated a great interest in vitamin C (vitC) as an attractive functional/nutraceutical ingredient for the management of COVID-19. However, the oral bioavailability and pharmacokinetics of vitC have been shown to be complex and exhibit dose-dependent non-linear kinetics. Though sustained-release forms and liquid liposomal formulations have been developed, only marginal enhancement was observed in bioavailability. Here we report a novel surface-engineered liposomal formulation of calcium ascorbate (CAAS), using fenugreek galactomannan hydrogel in powder form, and its pharmacokinetics following a randomized, double-blinded, single-dose, 3-way crossover study on healthy human volunteers (n = 14). The physicochemical characterization and in vitro release studies revealed the uniform impregnation of CAAS liposomes within the pockets created by the sterically hindered galactomannan network as multilaminar liposomal vesicles with good encapsulation efficiency (>90%) and their stability and sustained-release under gastrointestinal pH conditions. Further human studies demonstrated >7-fold enhancement in the oral bioavailability of ascorbate with a significant improvement in pharmacokinetic properties (Cmax, Tmax, T1/2, and AUC), compared to the unformulated counterpart (UF-CAAS) when supplemented at an equivalent dose of 400 mg of CAAS as tablets and capsules.

Activation of adenosine A3 receptors regulates vitamin C transport and redox balance in neurons

Adenosine is an important neuromodulator in the CNS, regulating neuronal survival and synaptic transmission. The antioxidant ascorbate (the reduced form of vitamin C) is concentrated in CNS neurons through a sodium-dependent transporter named SVCT2 and participates in several CNS processes, for instance, the regulation of glutamate receptors functioning and the synthesis of neuromodulators. Here we studied the interplay between the adenosinergic system and ascorbate transport in neurons. We found that selective activation of A3, but not of A1 or A2a, adenosine receptors modulated ascorbate transport, decreasing intracellular ascorbate content. Förster resonance energy transfer (FRET) analyses showed that A3 receptors associate with the ascorbate transporter SVCT2, suggesting tight signaling compartmentalization between A3 receptors and SVCT2. The activation of A3 receptors increased ascorbate release in an SVCT2-dependent manner, which largely altered the neuronal redox status without interfering with cell death, glycolytic metabolism, and bioenergetics. Overall, by regulating vitamin C transport, the adenosinergic system (via activation of A3 receptors) can regulate ascorbate bioavailability and control the redox balance in neurons.

Dopamine-Induced Ascorbate Release From Retinal Neurons Involves Glutamate Release, Activation of AMPA/Kainate Receptors and Downstream Signaling Pathways

Ascorbate, the reduced form of Vitamin C, is one of the most abundant and important low-molecular weight antioxidants in living tissues. Most animals synthesize vitamin C, but some primates, including humans, have lost this capacity due to disruption in L-gulono-gamma-lactone oxidase gene. Because of this incapacity, those animals must obtain Vitamin C from the diet. Ascorbate is highly concentrated in the central nervous system (CNS), including the retina, and plays essential roles in neuronal physiology. Ascorbate transport into cells is controlled by Sodium Vitamin C Co-Transporters (SVCTs). There are four SVCT isoforms and SVCT2 is the major isoform controlling ascorbate transport in the CNS. Regarding ascorbate release from retinal neurons, Glutamate, by activating its ionotropic receptors leads to ascorbate release via the reversion of SVCT2. Moreover, dopamine, via activation of D1 receptor/cyclic AMP/EPAC2 pathway, also induces ascorbate release via SVCT2 reversion. Because the dopaminergic and glutamatergic systems are interconnected in the CNS, we hypothesized that dopamine could regulate ascorbate release indirectly, via the glutamatergic system. Here we reveal that dopamine increases the release of D-Aspartate from retinal neurons in a way independent on calcium ions and dependent on excitatory amino acid transporters. In addition, dopamine-dependent SVCT2 reversion leading to ascorbate release occurs by activation of AMPA/Kainate receptors and downstream ERK/AKT pathways. Overall, our data reveal a dopamine-to-glutamate signaling that regulates the bioavailability of ascorbate in neuronal cells.

The epigenetic role of vitamin C in health and disease.

Recent advances have uncovered a previously unknown function of vitamin C in epigenetic regulation. Vitamin C exists predominantly as an ascorbate anion under physiological pH conditions. Ascorbate was discovered as a cofactor for methylcytosine dioxygenases that are responsible for DNA demethylation, and also as a likely cofactor for some JmjC domain-containing histone demethylases that catalyze histone demethylation. Variation in ascorbate bioavailability thus can influence the demethylation of both DNA and histone, further leading to different phenotypic presentations. Ascorbate deficiency can be presented systematically, spatially and temporally in different tissues at the different stages of development and aging. Here, we review how ascorbate deficiency could potentially be involved in embryonic and postnatal development, and plays a role in various diseases such as neurodegeneration and cancer through epigenetic dysregulation.

Regulation of the Epigenome by Vitamin C

Emerging evidence suggests that ascorbate, the dominant form of vitamin C under physiological pH conditions, influences activity of the genome via regulating epigenomic processes. Ascorbate serves as a cofactor for Ten-eleven translocation (TET) dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), and further to 5-formylcytosine (5fC) and to 5-carboxylcytosine (5caC), which are ultimately replaced by unmodified cytosine. The Jumonji C (JmjC)-domain-containing histone demethylases also require ascorbate as a cofactor for histone demethylation. Thus, by primarily participating in the demethylation of both DNA and histones, ascorbate appears to be a mediator of the interface between the genome and environment. Furthermore, redox status has a profound impact on the bioavailability of ascorbate in the nucleus. In order to bridge the gap between redox biology and genomics, we suggest an interdisciplinary research field that can be termed redox genomics to study dynamic redox processes in health and diseases. This review examines the evidence and potential molecular mechanism of ascorbate in the demethylation of the genome, and it highlights potential epigenetic roles of ascorbate in various diseases.

Determination of plasma and leukocyte ascorbate concentrations in a randomized, double‐blind trial (830.3)

Plasma ascorbate reflects recent intake, whereas leukocyte ascorbate more closely reflects cellular stores and total body pool.Objective was to evaluate the bioavailability of ascorbate in plasma and leukocytes from a novel vitamin C formulation.In this double‐blind, cross‐over, males and females between 18‐60 years were randomized to receive one of the following: Placebo (P, 0mg vitamin C), Ascorbic Acid (AA, 1000mg vitamin C) or Ester‐C® (EC, 1000mg vitamin C + threonate and furanone) as a single dosage. Plasma and leukocyte ascorbate were measured at 2, 4, 8, and 24 hours following treatment.An intention‐to‐treat analysis was conducted on thirty six subjects (18 males, 18 females). Plasma ascorbate percent change from Baseline was significantly higher for EC and AA at 2 hours compared to P (EC=135.55±176, AA=126.60±135, P=2.35±33; p<0.001). At 4, 8, and 24 hours the percent change from Baseline was only significantly higher for EC compared to P (all p蠄0.035). The percent change in leukocyte ascorbate was significantly higher from Baseline for EC at 2, 4, 8, and 24 hours (all p蠄0.041) and P at 4 and 24 hours (p蠄0.035) but there was no change from Baseline for the AA group.Vitamin C from Ester‐C and Ascorbic Acid has greater plasma bioavailability than Placebo. Compared to Baseline, Ester‐C® provides a higher percent change in leukocyte ascorbate, which may be due to the presence of threonate and furanone in the formula.

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H2O2). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H2O2-mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls.

Dietary ascorbate intake affects steady state tissue concentrations in vitamin C–deficient mice: tissue deficiency after suboptimal intake and superior bioavailability from a food source (kiwifruit)

Humans acquire vitamin C (ascorbate) from their diet, and optimal tissue concentrations are required to maintain its enzyme cofactor and antioxidant activities. How dietary intake affects tissue concentrations is difficult to monitor and has generally been based on the measurement of plasma concentrations. We aimed to determine the effect of various ascorbate intakes on tissue concentrations in the Gulo mouse model of vitamin C deficiency and to compare the effectiveness of delivery when ascorbate was added to the drinking water or obtained through a fruit source (kiwifruit). Gulo(-/-) mice were fed various amounts of ascorbate for 1 mo, either in their drinking water or as a kiwifruit gel. Tissue vitamin C content was measured and compared with concentrations in wild-type mice. Ascorbate concentrations in serum, liver, kidney, heart, and white blood cells were extremely labile and were well below concentrations observed in the wild-type mice when serum concentrations were below saturation. All tissues except for brain were rapidly depleted when intake was stopped. Consumption of a preparation of fresh kiwifruit (either green or gold varieties) resulted in up to 5 times more effective delivery to tissues than when ascorbate was administered via the drinking water. Subsaturation concentrations of plasma ascorbate resulted in severe deficiency in many tissues, and saturating amounts were required to achieve tissue concentrations similar to those found in wild-type animals. It is possible that the bioavailability of ascorbate is superior from some foods, such as kiwifruit. These results have important implications for human nutrition.

Micronutrient antioxidant status in black South Africans with chronic pancreatitis: opportunity for prophylaxis

Biochemical assessments of micronutrient antioxidant status were done in 14 consecutive black patients with calcific chronic pancreatitis and 15 controls at Soweto, near Johannesburg in southern Africa. The patients showed subnormal levels of vitamin C in plasma; selenium, β-carotene and α-tocopherol in serum; and inorganic sulphate (as an index of long-term sulphur amino acid intake) in urine ( P < 0.001 for each): furthermore, among the patients ascorbate constituted a lower fraction of vitamin C ( P < 0.002), indicating heightened oxidation of the bioactive form. By comparing the results in Sowetan controls with reference ranges from Manchester, UK, the markedly lower vitamin C and, hence, ascorbate levels in the Sowetans was underlined ( P < 0.001) and their selenium levels were also lower ( P < 0.001), but β-carotene, α-tocopherol and inorganic sulphate levels were comparable. The very low bioavailability of ascorbate among Sowetan controls is reminiscent of our previous finding in outwardly healthy people at Madras in southern India: in both these areas chronic pancreatitis is currently endemic, has a propensity to pancreatic calculi and runs a virulent course towards premature death from diabetes, malnutrition or pancreatic cancer. Considering that low ascorbate levels are a feature in patients with chronic pancreatitis who develop pancreatic calculi at Manchester and that antioxidant supplements ameliorate painful symptoms, we suggest that poor antioxidant intake may predispose underprivileged tropical communities to the disease. If so, there could be an opportunity for prophylaxis through a daily tablet containing vitamin C, perhaps along with selenium at Soweto and β-carotene at Madras.

Relationships between acetone, cataracts, and ascorbate in hairless guinea pigs.

Acetone is one of the most commonly used industrial solvents. Recent literature indicated that in guinea pigs, but not rabbits, acetone is cataractogenic and that elevated acetone exposure is also associated with depressed aqueous ascorbate levels. Other work indicated that aqueous and lens levels of ascorbate are closely linked and that depressed ascorbate status is related to cataract. Taken together, these papers suggested that acetone exposure, depressed ascorbate levels, and cataract are related, possibly causally. While the possibility that acetone is cataractogenic presented a major health concern, it also presented an opportunity to develop a new model of cataract in which hypotheses regarding anticataractogenic effects of ascorbate could be tested. Albino hairless guinea pigs are immunocompetent animals derived from albino Hartley guinea pigs. Animals were fed diets containing low (4.9 mg/day) and high (55 mg/day) levels of ascorbate. This resulted in distinct groups of animals, one with high tissue ascorbate levels and the other with low, but nonscorbutic ascorbate levels. The tissue levels of ascorbate and the relationship between tissue ascorbate levels and dietary intake indicate that with respect to ascorbate uptake, transport, and concentration, these animals are identical to the standard albino Hartley animals. Daily exposure to acetone was extended for 6 months, with a total applied dose of 65 ml. Absorption of the solvent was maximized by the use of hairless animals. Despite exposure of the animals to higher levels of acetone, in no case (n = 20) were cataracts observed over a 2-year period. This is consistent with results using rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)