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Chronic hyper nutrition is associated with marked oxidative stress and inflammation. Recent studies show that intravenously administered ascorbic acid (IVC), which has been used to treat conditions including fatigue, infection, and cancer, can have an effect on gene expression and epigenetic phenomena. Hence, we analyzed the effect of IVC on mRNA levels of several genes involved in inflammation and stress response. The gene expression modulation in peripheral blood mononuclear cells (PBMCs) from 20 overweight or obese subjects was determined. Participants were infused twice with 15 grams ascorbic acid (AA), with a one-day interval between treatments. The expression profile of several genes related to the inflammation and anti-oxidative enzymes was quantified by real time reverse transcription polymerase chain reaction (qRT-PCR). Total AA and dehydroascorbic acid (DHA) were measured in plasma before and after each treatment. Lipid profile and C-reactive protein (CRP) were measured by Bio-Center Laboratory of the Riordan Clinic by standard procedures. We confirmed that, in our subjects expression of mRNA levels of Interleukin 4 (IL-4) and Interleukin 6 (IL-6) correlated with inflammation, as indicated by CRP levels. Moreover, mRNA expression of these genes tended to correlate with body mass index (BMI) and high blood lipid levels. Treatments by IVC resulted in significant increase of blood AA and DHA concentrations. Analysis of mRNA levels on PBMC before and after IVC showed down-regulation of genes coding for Interleukin 8 (IL-8) and up-regulation of Nuclear factor erythroid-derived 2 (NRf2), IL-4, Interleukin 10 (IL-10), Tumor necrosis factor alpha (TNF-α), and Interferon gamma (IFN-γ). IVC treatment yielded regulation of immunological genes in PBMCs, suggesting potential benefits in regulating inflammation and redox potential. Introduction Obesity can be accompanied by chronic low grade inflammation, oxidative stress, and a cluster of symptoms including hypertension, dyslipidemia, impaired glucose tolerance, and insulin resistance [1–6]. These symptoms, in turn, are associated with respiratory and cardiovascular disease, type two diabetes, fatty liver, visceral adiposis, early aging, cancer, and increased mortality [1,2,7–9]. In an effort to understand the development of adiposity, the interplay between inflammation, oxidative stress, and obesity has been studied extensively [1,2]. The chronic low-grade inflammation that accompanies abdominal obesity is of particular interest, since expression of inflammation markers, such as CRP and pro-inflammatory cytokines, correlate with symptoms such as hypertension and insulin resistance [2,5,8,9-17]. Pro-inflammatory cytokines such TNF-α and IL-6 are overexpressed in obese subjects, as is nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the transcription factor that controls many genes associated with inflammation. Moreover, subjects with adiposity show reduced serum levels of the anti-inflammatory cytokine IL-10 [11–13]. The production of adipokines also changes in patients with adiposity. Adipose tissue cells produce both pro-inflammatory (leptin, plasminogen activation inhibitor 1, TNF-α, angiotensinogen, IL-6 and anti-inflammatory (adiponectin) cytokines, but the balance tilts toward production of the pro-inflammatory cytokines in overweight and obese subjects [2]. Changes in cellular gene expression have also been detected in overweight and obese patients. In obese individuals, adipose tissue cells and PBMCs exhibit an increase in gene expression of proinflammatory cytokines [2,10–12,14–16,18]. In addition, mononuclear cells in these subjects are characterized by increased expression and activities of transcription factors NF-κB, as well as decreased levels of the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase beta (IKKB-B) [11,14]. Diet induced weight loss in patients with adiposity has been shown to correct gene expression abnormalities related to pro-inflammatory cytokine production and to reduce NF-κB activation in PBMCs. The inflammation observed in obese subjects may be triggered by oxidative stress [19,20]. Excess consumption of glucose and fatty acids leads to tricarboxylic acid (TCA) cycle overload and increased Acetyl-CoA production [2]. Excess Acetyl-CoA stimulates production of reactive oxygen species (ROS) from the electron transport chain reactions in mitochondria, leading to hydrogen peroxide buildup [2]. This oxidative stress induces changes in the expression of genes associated with cancer progression [21,22]. Oxidation may also influence the length of telomeres, nucleotide sequences at the end of chromosomes that play a role in cancer and are inversely related Correspondence to: Nina Mikirova, Riordan Clinic, 3100 North Hillside, Wichita, KS, USA, E-mail: nmikirova@riordanclinic.org #These authors contributed equally to this work

Intravenous high-dose ascorbic acid reduces the expression of inflammatory markers in peripheral mononuclear cells of subjects with metabolic syndrome