PMID: 

Indian J Exp Biol. 2011 Dec ;49(12):904-8. PMID: 22403863

Abstract Title: 

Inhibition of platelet aggregation and immunomodulation of NK lymphocytes by administration of ascorbic acid.

Abstract: 

Platelets aggregation around migrating tumor cells offers protection against the cytotoxic activity of the natural killers cells (NKC). The ascorbic acid in 3 x 10(-3) M concentration completely inhibited platelet aggregation, decreased thromboxane B2 levels, and inhibited the expression of platelet membranic receptor GpIIb/IIIa in non stimulated platelets, and increased the NKC cytotoxicity in an average rate of 105, 61, and 285% in the NKC/targets cells ratios 12.5:1, 25:1 and 50:1 respectively. The results suggest the role of ascorbic acid in increasing the susceptibility of tumor cells to NKC; the ascorbic acid could be used as part of a multidrug therapy to treat diseases which up to now have been treated only through chemotherapy.

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PMID: 

Am J Physiol Lung Cell Mol Physiol. 2012 Jul 1 ;303(1):L20-32. Epub 2012 Apr 20. PMID: 22523283

Abstract Title: 

Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.

Abstract: 

Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.

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PMID: 

J Clin Periodontol. 2012 Oct ;39(10):905-12. Epub 2012 Jul 30. PMID: 22845498

Abstract Title: 

Vitamin C in plasma and leucocytes in relation to periodontitis.

Abstract: 

AIM: To test the hypothesis that vitamin C concentrations in plasma, polymorphonuclear neutrophilic leucocytes (PMNs) and peripheral blood mononuclear cells (PBMCs) are lower in periodontitis patients compared with healthy controls.METHODS: Twenty-one untreated periodontal patients and 21 healthy controls matched for age, gender, race and smoking habits were selected. Dietary vitamin C intake was assessed by a self-administered dietary record. Fasting blood samples were obtained and analysed for vitamin C concentrations in plasma, PMNs and PBMCs by means of high-pressure liquid chromatography (HPLC).RESULTS: Plasma vitamin C was lower in periodontitis patients compared with controls (8.3 and 11.3 mg/l, respectively, p = 0.03). Only in the control group a positive correlation was present between vitamin C intake and plasma values. No differences could be assessed between patients and controls regarding vitamin C dietary intake and levels in PMNs and PBMCs. In the patient group, pocket depth appeared to be negatively associated with the vitamin C concentration in PMNs.CONCLUSION: Although the relationship between low plasma vitamin C levels and periodontitis is clear, the disease cannot be explained by insufficient vitamin C storage capacity of leucocytes; the question remains through which mechanism low plasma vitamin C levels are related to periodontitis.

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PMID: 

Nutrients. 2013 Aug 9 ;5(8):3131-51. Epub 2013 Aug 9. PMID: 23939536

Abstract Title: 

Vitamin C: a novel regulator of neutrophil extracellular trap formation.

Abstract: 

INTRODUCTION: Neutrophil extracellular trap (NET) formation was recently identified as a novel mechanism to kill pathogens. However, excessive NET formation in sepsis can injure host tissues. We have recently shown that parenteral vitamin C (VitC) is protective in sepsis. Whether VitC alters NETosis is unknown.METHODS: We used Gulo-/- mice as they lack the ability to synthesize VitC. Sepsis was induced by intraperitoneal infusion of a fecal stem solution (abdominal peritonitis, FIP). Some VitC deficient Gulo-/- mice received an infusion of ascorbic acid (AscA, 200 mg/kg) 30 min after induction of FIP. NETosis was assessed histologically and by quantification for circulating free DNA (cf-DNA) in serum. Autophagy, histone citrullination, endoplasmic reticulum (ER) stress, NFκB activation and apoptosis were investigated in peritoneal PMNs.RESULTS: Sepsis produced significant NETs in the lungs of VitC deficient Gulo-/- mice and increased circulating cf-DNA. This was attenuated in the VitC sufficient Gulo-/- mice and in VitC deficient Gulo-/- mice infused with AscA. Polymorphonuclear neutrophils (PMNs) from VitC deficient Gulo-/- mice demonstrated increased activation of ER stress, autophagy, histone citrullination, and NFκB activation, while apoptosis was inhibited. VitC also significantly attenuated PMA induced NETosis in PMNs from healthy human volunteers.CONCLUSIONS: Our in vitro and in vivo findings identify VitC as a novel regulator of NET formation in sepsis. This study complements the notion that VitC is protective in sepsis settings.

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PMID: 

Cytotherapy. 2014 May ;16(5):674-82. Epub 2013 Oct 29. PMID: 24176546

Abstract Title: 

Ascorbic acid induces osteoblast differentiation of human suspension mononuclear cells.

Abstract: 

BACKGROUND AIMS: Suspension mononuclear cells (MNCs) can be differentiated into osteoblasts with the induction of ascorbic acid andβ-glycerophosphate. The aim of this study was to determine the ability of suspension MNCs to differentiate into osteoblasts using ascorbic acid only.METHODS: Suspension MNCs were obtained by a combination of gradient centrifugation and culture selection. Suspension MNCs were subjected to differentiation assay by culturing them inside proliferation medium supplemented with 10μg/mL, 30 μg/mL, 50 μg/mL, 60 μg/mL, 90 μg/mL and 500 μg/mL of ascorbic acid. Proliferation medium supplemented with 50 μg/mL ascorbic acid and 10 mmol/L β-glycerophosphate was used as a positive control for osteoblast induction, and proliferation medium without ascorbic acid was used as anegative control. Differentiation analysis was performed using alkaline phosphatase (ALP) assay, von Kossa staining and expression of osteoblast-related genes.RESULTS: With all concentrations of ascorbic acid used, there was a significant increase (P 

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PMID: 

Vnitr Lek. 2012 Oct ;58(10):743-9. PMID: 23121060

Abstract Title: 

[Vitamin C and its physiological role with respect to the components of the immune system].

Abstract: 

Vitamin C is a water soluble micronutrient commonly found in our diet which orchestrates the function of both innate and adaptive immune system, influencing both cellular and humoral immune responses. Vitamin C inhibits excessive activation of the immune system to prevent tissue damage, but also supports antibacterial activity, stimulates NK cells and differentiation of Th0 subset into Th1 characterized by interferonγ production. In addition, vitamin C interferes with the synthesis of proinflammatory cytokines, or with the expression of adhesive molecules. Moreover, vitamin C as an antioxidat protects the immune cells against intracellular ROS (reactive oxygen species) formed in the inflammatory response. Vitamin C as an enzymatic cofactor is extremely important in maintaining tissue integrity, and plays a crucial role in formation of skin, epithelial and endothelial barriers.

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PMID: 

Indian J Clin Biochem. 2013 Oct ;28(4):314-28. Epub 2013 Sep 1. PMID: 24426232

Abstract Title: 

Vitamin C in disease prevention and cure: an overview.

Abstract: 

The recognition of vitamin C is associated with a history of an unrelenting search for the cause of the ancient haemorrhagic disease scurvy. Isolated in 1928, vitamin C is essential for the development and maintenance of connective tissues. It plays an important role in bone formation, wound healing and the maintenance of healthy gums. Vitamin C plays an important role in a number of metabolic functions including the activation of the B vitamin, folic acid, the conversion of cholesterol to bile acids and the conversion of the amino acid, tryptophan, to the neurotransmitter, serotonin. It is an antioxidant that protects body from free radical damage. It is used as therapeutic agent in many diseases and disorders. Vitamin C protects the immune system, reduces the severity of allergic reactions and helps to fight off infections. However the significance and beneficial effect of vitamin C in respect to human disease such as cancer, atherosclerosis, diabetes, neurodegenerative disease and metal toxicity however remains equivocal. Thus further continuous uninterrupted efforts may open new vistas to understand its significance in disease management.

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PMID: 

Immunobiology. 2014 Jul ;219(7):554-64. Epub 2014 Mar 20. PMID: 24698552

Abstract Title: 

Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8(+) memory T cell production capacity of these cells in vivo.

Abstract: 

Vitamin C has been found to stimulate dendritic cells (DCs) to secrete more IL-12 and thereby drive naïve CD4(+) T cells to differentiate into Th1 cells. In the present study, we evaluated the effect of these vitamin C-treated DCs on CD8(+) T cell differentiation both in vitro and in vivo. Mouse bone marrow-derived DCs were prepared in the presence of GM-CSF and IL-15. With vitamin C treatment, these DCs, when LPS-stimulated, secreted more IL-12p70 and IL-15 than did untreated DCs. And when co-cultured with T cells, they yielded a higher frequency of IFN-γ(+) CD8(+) T cells. Moreover, we found that administering vitamin C-treated and tumor lysate-loaded DCs into mice yielded a higher frequency of CD44(high) CD62L(low) CD8(+) effector and effector memory T cells, which showed an increased ex vivo killing effect of the tumor cells. These DCs also elicited enhanced protective effects against inoculated tumor cells, most probably by way of the increased cytotoxic T cells, as was revealed by the decreased growth of the inoculated tumor cells in these mice. This ex vivo vitamin C treatment effect on DCs can be considered as a strategy for boosting DC vaccination potency against tumors.

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PMID: 

Nutrition. 2015 Feb ;31(2):406-8. Epub 2014 Aug 23. PMID: 25592020

Abstract Title: 

Lymphocyte vitamin C levels as potential biomarker for progression of Parkinson's disease.

Abstract: 

OBJECTIVES: Vitamin C is a major antioxidant and also is known as a neuromodulator in dopaminergic neurons. The aim of this study was to investigate the association between lymphocyte and plasma vitamin C levels in various stages of Parkinson's disease (PD).METHODS: Sixty-two individuals with PD (age 71 ± 8.8 y [mean ± SD]) being treated at Shizuoka General Hospital from December 2007 to August 2013 were consecutively recruited. PD severity was classified using the Hoehn-Yahr scale for staging PD. Fasting blood samples were collected, and plasma and lymphocyte vitamin C levels were measured. The association between PD severity and vitamin C levels was estimated by ordinal logistic regression with confounding variables.RESULTS: The distribution of Hoehn-Yahr stages in patients was as follows: stage I, 7; II, 28; III, 16; and IV, 11. Lymphocyte vitamin C levels in patients with severe PD were significantly lower (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.80-0.97; P 

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PMID: 

Cytotherapy. 2015 May ;17(5):613-20. Epub 2015 Mar 5. PMID: 25747742

Abstract Title: 

Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy.

Abstract: 

BACKGROUND AIMS: Natural killer (NK) cell-based immunotherapy is a promising treatment for a variety of malignancies. However, generating sufficient cell numbers for therapy remains a challenge. To achieve this, optimization of protocols is required.METHODS: Mature NK cells were expanded from peripheral blood mononuclear cells PBMCs in the presence of anti-CD3 monoclonal antibody and interleukin-2. Additionally, NK-cell progenitors were generated from CD34(+) hematopoietic stem cells or different T/NK-cell progenitor populations. Generated NK cells were extensively phenotyped, and functionality was determined by means of cytotoxicity assay.RESULTS: Addition of ascorbic acid (AA) resulted in more proliferation of NK cells without influencing NK-cell functionality. In more detail, PBMC-derived NK cells expanded 2362-fold (median, range: 90-31,351) in the presence of AA and were capable of killing tumor cells under normoxia and hypoxia. Moreover, hematopoietic stem cell-derived progenitors appeared to mature faster in the presence of AA, which was also observed in the NK-cell differentiation from early T/NK-cell progenitors.CONCLUSIONS: Mature NK cells proliferate faster in the presence of phospho-L-AA, resulting in higher cell numbers with accurate functional capacity, which is required for adoptive immunotherapy.

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