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Life Extension Magazine

May 9, 2000

National Academy of Sciences References


41. Carcinogenesis 1996 Mar;17(3):559-62Ascorbic acid may protect against human gastric cancer by scavenging mucosaloxygen radicals.Drake IM, Davies MJ, Mapstone NP, Dixon MF, Schorah CJ, White KL, Chalmers DM,Axon ATThe Centre for Digestive Diseases, The General Infirmary at Leeds, UK.

High dietary ascorbic acid intake appears to protect against gastric cancer.This may be due to its action as a scavenger of reactive radical species formedin the gastric mucosa, resulting in a reduced level of radical-mediated DNAdamage. We have studied 82 patients, of whom 37 had Helicobacterpylori-associated gastritis, a condition which predisposes to gastric cancer.Using electron paramagnetic resonance (EPR) spectroscopy we have demonstrated,for the first time, that ascorbyl radicals are generated in human gastricmucosa, presumably as a result of scavenging of free radicals by ascorbic acid.Quantification of ascorbyl radicals demonstrates that there is a higherconcentration in those patients with H.pylori gastritis compared with subjectswith normal histology (P < 0.01). We also found gastric mucosal luminol-enhancedchemiluminescence and malondialdehyde concentrations (which are believed to bemarkers of radical generation and tissue damage) to be higher in patients withH.pylori gastritis compared with those with normal histology (P < 0.001 and P <0.01 respectively). The observed concentrations of the ascorbyl radicalcorrelate with the level of luminol-enhanced chemiluminescence (r = 0.41, P <0.001), but not with malondialdehyde concentrations (r = 0.08, P = 0.47).Mucosal ascorbic acid and total vitamin C concentrations did not vary betweenhistological groups, nor did they correlate with mucosal levels of the ascorbylradical, chemiluminescence or malondialdehyde. These data suggest that ascorbicacid is acting as a scavenger of free radicals generated in human gastricmucosa. The experiments therefore provide direct supportive evidence for thehypothesis that ascorbic acid protects against gastric cancer by scavengingreactive radical species which would otherwise react with DNA, with resultantgenetic damage.

42. Biochim Biophys Acta 1995 Aug 3;1257(3):279-87Vitamin C prevents metal ion-dependent initiation and propagation of lipidperoxidation in human low-density lipoprotein.Retsky KL, Frei BWhitaker Cardiovascular Institute, Boston University School of Medicine, MA,USA.

Lipid peroxidation and oxidative modification of low-density lipoprotein (LDL)have been implicated as causal factors in the pathogenesis of atherosclerosis,and prevention of LDL oxidation by antioxidants may be an effective strategy toinhibit the progression of the disease. We investigated the effects of thereduced form of vitamin C (L-ascorbic acid, AA) and its two-electron oxidationproduct (dehydro-L-ascorbic acid, DHA) upon metal ion-dependent oxidativemodification of human LDL. We found that low micromolar concentrations of bothAA and DHA protect LDL against oxidation induced by Cu2+ or by hemin andhydrogen peroxide. In a dose-dependent manner, AA and DHA prevented theinitiation of lipid peroxidation in LDL, as determined by a sensitive andselective assay for lipid hydroperoxides utilizing HPLC with chemiluminescencedetection. AA and DHA also preserved the LDL-associated antioxidantsalpha-tocopherol, beta-carotene, and lycopene, but not ubiquinol-10.Furthermore, AA was able to stop propagation of lipid peroxidation in LDL,whereas DHA lacked this ability. The addition of 60 microM AA to LDL containingup to 38 nmol/mg protein of pre-formed lipid hydroperoxides led to their rapiddisappearance; this activity of AA was dependent on the presence of redox-activecopper, but did not lead to the formation of lipid hydroxides, the reduced formof lipid hydroperoxides. Our data show that in Cu(2+)-exposed LDL (i) vitamin Cprimarily spares, rather than regenerates, alpha-tocopherol and other endogenousantioxidants, except for AA and DHA prevent initiation of lipid peroxidation inLDL; and (iii) AA can terminate lipid peroxidation, thereby protecting partiallyoxidized LDL against further oxidative modification.

43. J Lipid Res 1994 Jun;35(6):1085-92A critical assessment of the effects of aminoguanidine and ascorbate on theoxidative modification of LDL: evidence for interference with some assays oflipoprotein oxidation by aminoguanidine.Scaccini C, Chiesa G, Jialal ICenter for Human Nutrition, University of Texas, Southwestern Medical Center atDallas 75235.

Several lines of evidence support a role for oxidized low density lipoprotein(LDL) in the genesis of the atherosclerotic lesion. Hence, the effect ofcompounds with antioxidant properties on LDL oxidation assumes greatsignificance. Ascorbate, a potent water-soluble chain-breaking antioxidant, hasbeen shown to inhibit LDL oxidation. Aminoguanidine (AMG) is a pharmacologicalinhibitor of advanced non-enzymatic glycosylation. Recently it has beensuggested that aminoguanidine might have an inhibitory effect on LDL oxidation,but total lipid peroxidation assayed by conjugated diene formation was notinhibited. Thus, in this study, we compared the effect of aminoguanidine withascorbate to obtain a better appreciation of the effect of AMG onCu(2+)-catalyzed LDL oxidation. Oxidative modification of LDL was monitored byassaying intermediates and end products of lipid peroxidation, conjugated dienes(CD), lipid peroxides (LPO), and relative electrophoretic mobility (REM).Apolipoprotein B-100 modification (increased fluorescence, fragmentation onSDS-PAGE, and 125I-labeled LDL degradation by human macrophages) was alsomeasured. Ascorbate (100 microM) inhibited LDL oxidation by > 95%, as evidencedby all of the selected indices. Aminoguanidine (20 mM) substantially decreasedthiobarbituric acid-reactive substances (TBARS) activity and lipid peroxideformation, but only partially prevented the increase of REM (-55%), apoBfluorescence (-39%), and degradation by macrophages (-54%). Unlike ascorbate,AMG failed to preserve alpha-tocopherol in LDL, prevent apoB-100 fragmentation,or inhibit conjugated diene formation during LDL oxidation. Furthermore,incubation of AMG with already oxidized LDL resulted in a significant decreasein TBARS activity and LPO, and 26.9% decrease in the REM of LDL.

44. J Lipid Res 1994 Jun;35(6):1085-92A critical assessment of the effects of aminoguanidine and ascorbate on theoxidative modification of LDL: evidence for interference with some assays oflipoprotein oxidation by aminoguanidine.Scaccini C, Chiesa G, Jialal ICenter for Human Nutrition, University of Texas, Southwestern Medical Center atDallas 75235.

Several lines of evidence support a role for oxidized low density lipoprotein(LDL) in the genesis of the atherosclerotic lesion. Hence, the effect ofcompounds with antioxidant properties on LDL oxidation assumes greatsignificance. Ascorbate, a potent water-soluble chain-breaking antioxidant, hasbeen shown to inhibit LDL oxidation. Aminoguanidine (AMG) is a pharmacologicalinhibitor of advanced non-enzymatic glycosylation. Recently it has beensuggested that aminoguanidine might have an inhibitory effect on LDL oxidation,but total lipid peroxidation assayed by conjugated diene formation was notinhibited. Thus, in this study, we compared the effect of aminoguanidine withascorbate to obtain a better appreciation of the effect of AMG onCu(2+)-catalyzed LDL oxidation. Oxidative modification of LDL was monitored byassaying intermediates and end products of lipid peroxidation, conjugated dienes(CD), lipid peroxides (LPO), and relative electrophoretic mobility (REM).Apolipoprotein B-100 modification (increased fluorescence, fragmentation onSDS-PAGE, and 125I-labeled LDL degradation by human macrophages) was alsomeasured. Ascorbate (100 microM) inhibited LDL oxidation by > 95%, as evidencedby all of the selected indices. Aminoguanidine (20 mM) substantially decreasedthiobarbituric acid-reactive substances (TBARS) activity and lipid peroxideformation, but only partially prevented the increase of REM (-55%), apoBfluorescence (-39%), and degradation by macrophages (-54%). Unlike ascorbate,AMG failed to preserve alpha-tocopherol in LDL, prevent apoB-100 fragmentation,or inhibit conjugated diene formation during LDL oxidation. Furthermore,incubation of AMG with already oxidized LDL resulted in a significant decreasein TBARS activity and LPO, and 26.9% decrease in the REM of LDL.

45. Int J Infect Dis 2000;4(1):46-50Generation of reactive oxygen species and formation and membrane lipid peroxidesin cells infected with Chlamydia trachomatis.Azenabor AA, Mahony JBDepartment of Pathology and Regional Virology, and Chlamydiology Laboratory,McMaster University, Hamilton, Ontario, Canada.

OBJECTIVES: Chlamydiae are obligate intracellular pathogens that cause manydiseases for which the pathogenic mechanisms are largely unknown. Becausereactive oxygen species (ROS) have been implicated in pathogenesis of many viraland bacterial infections, the authors assessed the release of ROS in selectedhost cells (monocytes, Sup-T1 cells, and Hep-2 cells) infected with Chlamydiatrachomatis. METHODS: Infected cell cultures demonstrated a dramatic depletionof uric acid from culture media that was not seen in uninfected cultures.Reactive oxygen species generated in infected cultures were associated with theformation of lipid peroxides in host cell membrane. RESULTS: There was asignificant increase in lipid peroxide levels in infected cells compared touninfected controls. Ascorbic acid treatment of infected cell cultures reducedthe formation of membrane lipid peroxides. CONCLUSIONS: These results suggestthat ROS produced during chlamydial replication cause membrane lipidperoxidation. The role of ROS-induced membrane damage in chlamydial pathogenesisis discussed.

46. Am J Clin Nutr 1977 Jul;30(7):1077-81Effect of mega doses of vitamin C on bactericidal ativity of leukocytes.Shilotri PG, Bhat KS

Effect of ingesting mega doses of ascorbic acid was studied on the leukocytefunction in five normal human subjects. During the first 15 days the subjectsreceived daily supplements of 200 mg of ascorbic acid, and during the next 2weeks they were given 2 g of vitamin C per day. Supplementation of 200 mg aswell as 2 g of ascorbic acid stimulated hexose monophosphate shunt activity ofresting leukocytes indicating an increase in resting metabolism. Intakes of 200mg of ascorbic acid per day did not affect bacterial killing by leukocytes. Onthe other hand, daily intakes of 2 g of ascorbic acid for 2 weeks significantlyimpaired bactericidal activity. Four weeks after withdrawal of the viatminsupplementation, bactericidal activity returned to normal.

47. Int J Vitam Nutr Res Suppl 1982;23:23-34Effects of ascorbate on normal and abnormal leucocyte functions.Anderson R

The stimulatory effects of ascorbate on neutrophil motility in vitro and in vivoand lymphocyte transformation to mitogens following ingestion or intravenousinjection of ascorbate have been found to be related entirely to inhibition ofthe autooxidative effect of the myeloperoxidase/hydrogen peroxide/halide system(MPO/H2O2/halide system). Stimulation of neutrophil migration and lymphocytetransformation following a single intravenous injection of 1 g of ascorbate wasassociated with inhibition of the MPO/H2O2/halide system. The immunostimulatoryactivity and peroxidase inhibitory activity was related entirely to the serumascorbate level. The relationship between inhibition of theperoxidase/h2O2/halide system and stimulation of neutrophil motility andlymphocyte mitogen-induced transformation was further established by using thehorseradish peroxidase (HRP)/H2O2/halide system in vitro. Neutrophils andlymphocytes, exposed to this system, manifested markedly impaired chemotacticresponsiveness and mitogen-induced transformation, respectively. Howeverinclusion of ascorbate with the peroxidative system protected the neutrophilsand lymphocytes from these inhibitory effects. Further studies in 3 patientswith chronic granulomatous disease (CGD) and 10 patients with bronchial asthmasuggested that ascorbate may be of value to improve the primary immunologicalabnormalities (neutrophil motility and antimicrobial activity) in CGD and thesecondary abnormalities (neutrophil motility and lymphocyte transformation)found in some individuals with bronchial asthma.

48. Arch Otolaryngol 1982 Feb;108(2):122-4Malignant external otitis and polymorphonuclear leukocyte migration impairment.Improvement with ascorbic acid.Corberand J, Nguyen F, Fraysse B, Enjalbert L

Malignant external otitis (MEO) is a rare disease due to a Pseudomonas infectionof the external ear occurring in an elderly patient with uncontrolled diabetesmellitus. Its high mortality raises the question of an alteration of the defensemechanisms of the body. A 58-year-old man was affected with MEO, and afterseveral months of unsuccessful treatment, a study of the function of hispolymorphonuclear neutrophil leukocytes (PMNs) revealed a defect of themigration capability. Ascorbic acid (vitamin C) was proved in vitro to be ableto improve the results of the migration test. The patient was treated for onemonth with ascorbic acid and, parallel to the normalization of the chemotaxistest results, the ear lesions healed. The mechanism of such an alteration of thePMN function, implying several factors (the active infection, old age, anddiabetes mellitus), is still unclear. Nevertheless, it is certainly important totest the PMN function in patients with MEO and treat them with immunomodulators.

49. S Afr Med J 1979 Sep 8;56(11):429-33Effects of ascorbate on leucocytes: Part III. In vitro and in vivo stimulationof abnormal neutrophil motility by ascorbate.Anderson R, Theron A

Abnormal in vitro neutrophil motility was found in 10 patients with recurrentbacterial infection. The defect appeared to be primary in 3 patients, secondaryto hyperimmunoglobulinaemia E in 2 patients and secondary to bacterial infectionin 5 patients. In 7 patients impaired polymorphonuclear leucocyte (PMN) motilitywas the only detectable abnormality; defective lymphocyte function was found in2 patients and 1 had a total IgA deficiency. Increased random motility andmigration to endotoxin-activated serum (EAS) and partially purified C5a wasobserved when patients' neutrophils were incubated with 5 x 10(-2)M calciumascorbate or 10(-1)M sodium ascorbate in the presence of 5% autologous serum invitro. Six of the patients, 4 children and 2 adults, were given oral ascorbate,1 g daily for children and 3 g daily for adults, and tests of neutrophilmigration were performed at monthly intervals thereafter. Improved neutrophilmotility was observed in all patients and this correlated with clinicalimprovement in 5 of the 6.

50. Immunopharmacol Immunotoxicol 1989;11(1):119-29Monocyte locomotion in anergic chronic brucellosis patients: the in vivo effectof ascorbic acid.Boura P, Tsapas G, Papadopoulou A, Magoula I, Kountouras G2nd Medical Department, Aristotelian University, Thessaloniki, Greece.

In 14 patients suffering from relapsing chronic brucellosis who were anergic tobrucella antigens, we have studied peripheral blood monocyte random migrationand chemotaxis against non-specific and specific leukoattractants, as well asplasma and monocyte ascorbic acid levels. We found that all parameters studied,were significantly beneath normal, when compared to normal subjects. After theoral administration of ascorbic acid at a daily dose of 1gr for 15 consequetivedays, random and directed migration against a non-specific stimulus (casein)returned to normal. Directed migration against disease associatedleukoattractants (brucella melitensis and brucella abortus) antigens improvedsignificantly, without reaching normal values. We concluded that ascorbic acidsupplementation might partially restore peripheral, monocyte function and helpthe monocyte-macrophage system to mount an effective immune response againstchronicity of brucella infection.