Vitamin C (or ascorbic acid) is regarded as the most important water-soluble antioxidant in human plasma and mammalian cells which have mechanisms to recycle and accumulate it against a concentration gradient, suggesting that the vitamin might also have important intracellular functions. In this review we summarize evidence from human trials that have attempted an association between vitamin C supplementation and an effect on biomarkers of oxidative DNA damage. Most studies reviewed herein showed either a vitamin C-mediated reduction in oxidative DNA damage or a null effect, whereas only a few studies showed an increase in specific base lesions. We also address the possible beneficial effects of vitamin C supplementation for the prevention of cancer and cardiovascular disease. Finally, we discuss the contribution of cell culture studies to our understanding of the mode of action of vitamin C and we review recent evidence that vitamin C is able to modulate gene expression and cellular function, with a particular interest in cell differentiation.

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH), which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment.

Significance: Oxygen metabolism and iron homeostasis are closely linked. Iron facilitates the oxygen-carrying capacity of blood, and its deficiency causes anemia. Conversely, excess free iron is detrimental for stimulating the formation of reactive oxygen species, causing tissue damage. The amount and distribution of iron thus need to be tightly regulated by the liver-expressed hormone hepcidin. This review analyzes the roles of key oxygen-sensing pathways in cellular and systemic regulation of iron homeostasis; specifically, the prolyl hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) and the Kelch-like ECH-associated protein 1/NF-E2 p45-related factor 2 (KEAP1/NRF2) pathways, which mediate tissue adaptation to low and high oxygen, respectively. Recent Advances: In macrophages, NRF2 regulates genes involved in hemoglobin catabolism, iron storage, and iron export. NRF2 was recently identified as the molecular sensor of iron-induced oxidative stress and is responsible for BMP6 expression by liver sinusoidal endothelial cells, which in turn activates hepcidin synthesis by hepatocytes to restore systemic iron levels. Moreover, NRF2 orchestrates the activation of antioxidant defenses that are crucial to protect against iron toxicity. On the contrary, low iron/hypoxia stabilizes renal HIF2a via inactivation of iron-dependent PHD dioxygenases, causing an erythropoietic stimulus that represses hepcidin via an inhibitory effect of erythroferrone on bone morphogenetic proteins. Intestinal HIF2a is also stabilized, increasing the expression of genes involved in dietary iron absorption. Critical Issues: An intimate crosstalk between oxygen-sensing pathways and iron regulatory mechanisms ensures that fluctuations in systemic iron levels are promptly detected and restored. Future Directions: The realization that redox-sensitive transcription factors regulate systemic iron levels suggests novel therapeutic approaches. Antioxid. Redox Signal . 35, 433–452.