Chapter 7 Vitamin C in Pneumonia and Sepsis

In humans, ascorbic acid is an essential vitamin, anti-oxidant and co-factor of a variety of metal ion-dependent enzymatic reactions. In this review, the transport of L-ascorbic acid is described from food to target cells. Transport of ascorbic acid across the plasma membrane is facilitated by members of the SLC23 family, SLC23A1/SVCT1 and SLC23A2/SVCT2. We present in silico models of these transporters that provide new insights into the structure of the SLC23 family. While SVCT1 is mainly responsible for uptake of ascorbic acid from the intestine into the blood and for reabsorption in the kidney, the more broadly expressed transporter SVCT2 delivers ascorbic acid into tissues that are in high demand of the vitamin. The oxidized form of ascorbic acid, dehydroascorbic acid (DHA), is a substrate of the GLUT transporters belonging to the SLC2 family. They play important roles in ascorbic acid recycling, such as in the brain and in erythrocytes. Ascorbic acid serves as an essential co-factor of metal ion-dependent enzymes, keeping their metal ions in the reduced state. In addition, it serves as an effective antioxidant in cells with high metabolic activity such as neurons. Thus, it is not too surprising that changes in expression and function of the SVCTs have nutritional and pathological consequences such as during ageing, malnutrition and chronic alcohol abuse or in cancer, neurodegenerative diseases and chronic inflammation diseases. In the future, SVCT1 and SVCT2 may furthermore prove useful as drug delivery systems, to enhance transport of novel pharmaceutical agents more efficiently across the intestinal epithelium and the blood-cerebrospinal fluid barrier

Chapter 7 Vitamin C in Pneumonia and Sepsis

In humans, ascorbic acid is an essential vitamin, anti-oxidant and co-factor of a variety of metal ion-dependent enzymatic reactions. In this review, the transport of L-ascorbic acid is described from food to target cells. Transport of ascorbic acid across the plasma membrane is facilitated by members of the SLC23 family, SLC23A1/SVCT1 and SLC23A2/SVCT2. We present in silico models of these transporters that provide new insights into the structure of the SLC23 family. While SVCT1 is mainly responsible for uptake of ascorbic acid from the intestine into the blood and for reabsorption in the kidney, the more broadly expressed transporter SVCT2 delivers ascorbic acid into tissues that are in high demand of the vitamin. The oxidized form of ascorbic acid, dehydroascorbic acid (DHA), is a substrate of the GLUT transporters belonging to the SLC2 family. They play important roles in ascorbic acid recycling, such as in the brain and in erythrocytes. Ascorbic acid serves as an essential co-factor of metal ion-dependent enzymes, keeping their metal ions in the reduced state. In addition, it serves as an effective antioxidant in cells with high metabolic activity such as neurons. Thus, it is not too surprising that changes in expression and function of the SVCTs have nutritional and pathological consequences such as during ageing, malnutrition and chronic alcohol abuse or in cancer, neurodegenerative diseases and chronic inflammation diseases. In the future, SVCT1 and SVCT2 may furthermore prove useful as drug delivery systems, to enhance transport of novel pharmaceutical agents more efficiently across the intestinal epithelium and the blood-cerebrospinal fluid barrier

Global Vitamin C Status and Prevalence of Deficiency: A Cause for Concern?

Vitamin C is an essential nutrient that must be obtained through the diet in adequate amounts to prevent hypovitaminosis C, deficiency and its consequences—including the potentially fatal deficiency disease scurvy. Global vitamin C status and prevalence of deficiency has not previously been reported, despite vitamin C’s pleiotropic roles in both non-communicable and communicable disease. This review highlights the global literature on vitamin C status and the prevalence of hypovitaminosis C and deficiency. Related dietary intake is reported if assessed in the studies. Overall, the review illustrates the shortage of high quality epidemiological studies of vitamin C status in many countries, particularly low- and middle-income countries. The available evidence indicates that vitamin C hypovitaminosis and deficiency is common in low- and middle-income countries and not uncommon in high income settings. Further epidemiological studies are required to confirm these findings, to fully assess the extent of global vitamin C insufficiency, and to understand associations with a range of disease processes. Our findings suggest a need for interventions to prevent deficiency in a range of at risk groups and regions of the world

Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective

A recent review of global vitamin C status has indicated a high prevalence of deficiency, particularly in low- and middle-income countries, as well as in specific subgroups within high-income countries. Here, we provide a narrative review of potential factors influencing vitamin C status globally. The in vivo status of vitamin C is primarily affected by dietary intake and supplement use, with those who supplement having a higher mean status and a lower prevalence of deficiency. Dietary intake can be influenced by cultural aspects such as traditional cooking practices and staple foods, with many staple foods, such as grains, contributing negligible vitamin C to the diet. Environmental factors can also affect vitamin C intake and status; these include geographic region, season, and climate, as well as pollution, the latter partly due to enhanced oxidative stress. Demographic factors such as sex, age, and race are known to affect vitamin C status, as do socioeconomic factors such as deprivation, education and social class, and institutionalization. Various health aspects can affect vitamin C status; these include body weight, pregnancy and lactation, genetic variants, smoking, and disease states, including severe infections as well as various noncommunicable diseases such as cardiovascular disease and cancer. Some of these factors have changed over time; therefore, we also explore if vitamin C status has shown temporal changes. Overall, there are numerous factors that can affect vitamin C status to different extents in various regions of the world. Many of these factors are not taken into consideration during the setting of global dietary intake recommendations for vitamin

Vitamin C: Current Concepts in Human Physiology

ca. 200 words; this text will present the book in all promotional forms (e.g. flyers). Please describe the book in straightforward and consumer-friendly terms. [Vitamin C is synthesized by almost all animals. However, for humans, it is a vitamin that needs constant replenishment in the diet. While its role as an anti-oxidant and for preventing scurvy have been known for a long time, novel functions and unrecognized associations continue to be identified for this enigmatic molecule. In the past decade, new details have emerged regarding differences in its uptake by oral and intravenous modes. While vitamin C deficiency remains largely unknown and poorly addressed in many segments of the population, novel pharmacological roles for high-dose, intravenous vitamin C in many disease states have now been postulated and investigated. This has shifted its role in health and disease from the long-perceived notion as merely a vitamin and an anti-oxidant to a pleiotropic molecule with a broad anti-inflammatory, epigenetic, and anti-cancer profile. This Special Issue comprises original research papers and reviews on vitamin C metabolism and function that relate to the following topics: understanding its role in the modulation of inflammation and immunity, therapeutic applications and safety of pharmacological ascorbate in disease, and the emerging role of vitamin C as a pleiotropic modulator of critical care illness and cancer.

Vitamin C in Health and Disease

Vitamin C is a pivotal water soluble electron donor in nature and an essential nutrient in man. Despite its many years as a research focus, new and increasingly regulatory functions of vitamin C in human health are continually being unravelled. This improved mechanistic insight is starting to provide rationales explaining the extensive epidemiological literature that, for decades, has consistently shown strong associations between poor vitamin C status and increased morbidity and mortality. In this Special Issue, we include original research and literature reviews by experts in the field outlining the roles of vitamin C in early, daily and late life, as well as the roles of deficiency in cardiovascular disease, inflammation and cancer

The Emerging Role of Vitamin C in the Prevention and Treatment of COVID-19

Investigation into the role of vitamin C in the prevention and treatment of pneumonia and sepsis has been underway for many decades. This research has laid a strong foundation for translation of these findings into patients with severe coronavirus disease (COVID-19). Research has indicated that patients with pneumonia and sepsis have low vitamin C status and elevated oxidative stress. Administration of vitamin C to patients with pneumonia can decrease the severity and duration of the disease. Critically ill patients with sepsis require intravenous administration of gram amounts of the vitamin to normalize plasma levels, an intervention that some studies suggest reduces mortality. The vitamin has pleiotropic physiological functions, many of which are relevant to COVID-19. These include its antioxidant, anti-inflammatory, antithrombotic and immuno-modulatory functions. Preliminary observational studies indicate low vitamin C status in critically ill patients with COVID-19. There are currently a number of randomized controlled trials (RCTs) registered globally that are assessing intravenous vitamin C monotherapy in patients with COVID-19. Since hypovitaminosis C and deficiency are common in low–middle-income settings, and many of the risk factors for vitamin C deficiency overlap with COVID-19 risk factors, it is possible that trials carried out in populations with chronic hypovitaminosis C may show greater efficacy. This is particularly relevant for the global research effort since COVID-19 is disproportionately affecting low–middle-income countries and low-income groups globally. One small trial from China has finished early and the findings are currently under peer review. There was significantly decreased mortality in the more severely ill patients who received vitamin C intervention. The upcoming findings from the larger RCTs currently underway will provide more definitive evidence. Optimization of the intervention protocols in future trials, e.g., earlier and sustained administration, is warranted to potentially improve its efficacy. Due to the excellent safety profile, low cost, and potential for rapid upscaling of production, administration of vitamin C to patients with hypovitaminosis C and severe respiratory infections, e.g., COVID-19, appears warranted

Estimating vitamin C intake requirements in diabetes mellitus : Analysis of NHANES 2017-2018 and EPIC-Norfolk cohorts

Acknowledgments We would like to acknowledge the principal investigators and staff of the EPIC-Norfolk study. We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. Funding The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU-12015/1 and MC-UU-00006/1) and Cancer Research UK (C864/A14136).Peer reviewedPublisher PD

Vitamin C and COVID-19: should clinical trials be prioritised for low income settings and vitamin C-deficient populations?

Lette

Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine β-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock