Preface

Ascorbic acid is a small, simple, water soluble molecule, synthesised by most plants and animals, with the exception of humans and some animal species due to mutations in the gene encoding the terminal enzyme in the biosynthetic pathway. For humans, it is thus a vitamin (vitamin C) that must be obtained from the diet, with complete deficiency resulting in the fatal disease scurvy. Many functions have been attributed to this fascinating molecule and, despite nearly 90 years of research since its discovery, new roles are still being uncovered, including recent discoveries that it acts as a regulator of epigenetic marks and transcription factors (1). In this volume we begin with a review by Michels and Frei on specific factors that need to be taken into consideration when carrying out vitamin C research. Translational research normally comprises a progression from *in vitro*/cell culture studies to animal models and finally to clinical trials. At each of these stages, there are requirements specific to vitamin C research that need to be integrated into study designs and this review describes these in detail.

Although normal vitamin C intake in humans is via ingestion, in the past decades there has been a surge of interest in the effects of intravenous administration of supra-physiological doses of vitamin C. This is particularly common in the treatment of cancer, and is an area of great controversy (2), most of which can be attributed to the lack of an agreed mechanism of action and numerous issues around study design, including a lack of understanding of vitamin C pharmacokinetics (3). Vitamin C administered intravenously bypasses the regulated intestinal uptake mechanism and results in significantly higher plasma concentrations than are obtained through oral intake. It is proposed that, at these high doses, vitamin C acts as a prodrug via metal ion-dependent generation of cytotoxic hydrogen peroxide, although other potential anticancer mechanisms are also possible (1). In the contribution by Park, pharmacologic studies of the effects of high dose vitamin C on cancer cells are reviewed. In addition, Azqueta *et al.* have investigated the pro- and anti-oxidant effects of vitamin C on DNA damage and repair in cultured cervical cancer cells. High dose vitamin C has also been shown to improve the outcomes of patients with sepsis (4). In their contribution, Mohammed *et al.* used a knockout murine model to investigate the effect of parenteral vitamin C on neutrophil extracellular trap formation, autophagy and apoptosis, in experimentally induced sepsis.

The highest levels of vitamin C in the body are found in the brain and neuroendocrine tissue. The brain is also relatively resistant to vitamin C depletion, indicating a vital role for the vitamin. Vitamin C likely has many functions in the brain (5), including acting as a cofactor for monooxygenase-dependent synthesis of neurotransmitters and neuropeptide hormones, as well as recycling of the enzyme cofactor tetrahydrobiopterin. In their contribution, Harrison *et al.* review the role for vitamin C in the aging brain, covering vitamin C transport, animal studies, and human studies that suggest potential usefulness of vitamin C against cognitive decline. Iwata *et al.* have investigated the anti-inflammatory and antiapoptotic effects of vitamin C in the brains of diabetic rats with cerebral ischemia-reperfusion. They also reported vitamin C-dependent regulation of the vitamin C transporter SVCT2, the transporter isoform responsible for vitamin C uptake in neuronal tissue (5).

Early vitamin C research, particularly in animal models, indicated that food-derived vitamin C may have enhanced bioavailability compared with synthetic vitamin C. This was attributed to the presence of plant-derived bio-flavonoids. We recently carried out a comparative bioavailability study in the gulonolactone oxidase knockout mouse and found significantly enhanced uptake of fruit-derived vitamin C (6). In this volume, we present two translational comparative bioavailability studies carried out in non-smoking males, one a steady state study and the other a pharmacokinetic study. Vitamin C was assessed in plasma, urine, leukocytes, and skeletal muscle, and showed no differences in bioavailability between synthetic and fruit-derived vitamin C. A review of the literature indicated that comparative differences were more likely to be observed in animal models than human studies. This is possibly due to differential expression of the vitamin C transporter SVCT1 in the intestines of humans compared with rodents, as the latter normally synthesise vitamin C endogenously and thus do not need to obtain it through their diet.

Human requirements for vitamin C can vary greatly depending on a number of physiological and lifestyle factors (7). Genetic variants which affect vitamin C uptake and metabolism are associated with decreased plasma vitamin C status (8). In their contribution, Delanghe *et al.* correlate haptoglobin variant Hp2-2 and hereditary hemochromatosis, both associated with enhanced free iron and decreased vitamin C stability, with the incidence of scurvy observed in the European famine of the 1840s. Lindblad *et al.* provide a review of the transport and distribution of vitamin C in the body, and discuss its regulation during deficiency in cell culture studies and animal models. Plant foods are the major source of vitamin C in the diet, and, in his contribution to this volume, Gallie reviews strategies to increase the vitamin C content of food plants through increased synthesis and recycling of the vitamin.

We would like to acknowledge the authors who contributed to this volume, the reviewers of the original manuscripts published in the journal *Nutrients*, and the editorial staff at MDPI who contributed to the production of this volume on *Vitamin C and Human Health*.

Anitra C. Carr and Margreet M.C. Vissers *Guest Editors* 
