ascorbic-acid and Hyperhomocysteinemia

Vitamin C and a vitamin B are essential nutrients to maintain bone density and bone quality. Recent literature clearly shows that vitamin C and B affect bone quality determinant "collagen cross-link formation" . Mildly elevated plasma homocysteine levels induced by vitamin B insufficiency and methylenetetrahydrofolate reductase (MTHFR) deteriorate normal collagen cross-link formation (Saito M, Osteoporos Int 2009 May 30. [Epub ahead of print] , Shiraki M and Saito M, J Bone Miner Metab [6] 2008) . In this review, we describe the effects of vitamin C and vitamin B insufficiency and hyperhomocysteinemia on bone quality in terms of collagen cross-link formation in bone that have been reported in the literature.

Topics: Ascorbic Acid; Ascorbic Acid Deficiency; Bone Density; Collagen; Homocysteine; Humans; Hyperhomocysteinemia; Vitamin B Complex; Vitamin B Deficiency

Hyperhomocysteinemia causes connective tissue pathology. Several theories on the mechanism of homocysteine toxicity in connective tissue are reviewed briefly. A possible new mechanism was revealed recently in the discovery of a reaction in which homocysteine thiolactone is converted to mercaptopropionaldehyde. The reaction is the Strecker degradation of amino acids in which ninhydrin is replaced by the structurally similar dehydroascorbic acid. The reaction may occur in vivo and may be pathogenic to connective tissue in four ways: (1) the reaction may deplete ascorbic acid that is required for collagen synthesis, (2) the mercaptoaldehyde product may interfere with collagen synthesis, (3) the mercaptoaldehyde may cause abnormal cross-linking of collagen molecules, and (4) the mercaptoaldehyde may attach to collagen molecules rendering them antigenic and triggering an autoimmune response.

Topics: Animals; Aryldialkylphosphatase; Ascorbic Acid; Autoimmune Diseases; Collagen; Connective Tissue Diseases; Homocysteine; Humans; Hyperhomocysteinemia; Sulfhydryl Compounds

This review gives a brief overview of the main types of dementia and summarizes current thinking on the relationship between nutritional-related factors and disorders, and dementia. Dementia is a multi-factor pathological condition, and nutrition is one factor that may play a role on its onset and progression. An optimal intake of nutrients doesn't protect people from dementia. However, studies in this area show that inadequate dietary habits, which are of particular concern in elderly populations, may increase the risk of developing a number of age-related diseases, including disorders of impaired cognitive function. They show that a deficiency in essential nutrients, such as certain B complex vitamins, can result in hyperhomocysteinemia, a well-known risk factor for atherosclerosis and recently associated with cognitive impairment in old age. A deficiency of antioxidants such as vitamins C and E, and beta-carotene, as well as nutrition-related disorders like hypercholesterolemia, hypertension, and diabetes, may also have some role in cognitive impairment. These factors can be present for a long time before cognitive impairment becomes evident, therefore they could be potentially detected and corrected in a timely manner.

Topics: Alzheimer Disease; Antioxidants; Ascorbic Acid; Dementia; Diabetes Mellitus; Diet; Humans; Hyperhomocysteinemia; Hyperlipidemias; Hypertension; Nutrition Disorders; Nutritional Physiological Phenomena; Oxidative Stress; Risk Factors; Vitamin A; Vitamin B Complex; Vitamin E

A plethora of agents have been proposed to combat atherosclerosis, and many of these come from outside mainstream medicine. The majority have anti-oxidant properties, which is the scientific basis for their supposed action. Some of these agents have been evaluated carefully in randomized, double-blinded studies, whereas others have gained popularity despite a paucity of valid data. Although many are prescribed or physician recommended, most are used without the knowledge of the patient's physician. In some cases these "medications" may have harmful side effects or impact negatively on other aspects of the patients medical or surgical care. Others, however, may be extremely beneficial although not utilized because the doctor is unaware of their potential. Accordingly, it is important that the vascular surgeon become acquainted with these compounds. This report attempts to summarize the most commonly used herbs, vitamins, foods and other sundry "treatments" and makes recommendations for their use based on our current understanding of their scientific and clinical merit.

Topics: Alcohol Drinking; Antioxidants; Arginine; Arteriosclerosis; Ascorbic Acid; Cholesterol, LDL; Complementary Therapies; Diet; Estrogen Replacement Therapy; Ginkgo biloba; Humans; Hyperhomocysteinemia; Particle Size; Vitamin E

Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1.. In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique.. Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups).. Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress.

Topics: Adult; Ascorbic Acid; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Female; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Male; Methionine; Oxidative Stress; Signal Transduction; Vasodilation; Vitamin E

Homocysteinemia is associated with elevated oxidative stress and impaired endothelial function. In the present study we examined the impact of oxidative stress in the development of endothelial dysfunction in both chronic and acute (methionine-induced) homocysteinemia in humans. We also examined the role of endothelin-1 (ET-1) in the development of endothelial dysfunction in these two conditions.. In this double-blind placebo controlled study, 28 subjects of both genders (14 with homocysteinemia and 14 healthy controls) underwent methionine-loading (100mg/Kg body weight) in a standard juice, containing vitamins C (2g) plus E (800IU) (n = 14) or no vitamins (placebo group, n = 14). Forearm vasodilatory response to reactive hyperemia, plasma total homocysteine (tHcy), oxidized LDL (ox-LDL), ET-1 and soluble vascular cell adhesion molecule (sVCAM-1), were evaluated at baseline and 4 hours post methionine loading (4hPML).. Chronic homocysteinemia was associated with increased oxLDL (p < 0.01), higher ET-1 (p < 0.05) and impaired endothelial function (p < 0.01). However, oxLDL (but not ET-1) was increased 4hPML in the placebo group, an effect prevented by antioxidant vitamins. The development of severe endothelial dysfunction 4hPML was not however prevented by antioxidants. In linear regression analysis, fasting tHcy was an independent predictor of baseline oxLDL (p = 0.0001), but not of ET-1 levels. On the contrary, oxLDL was the main predictor of ET-1 (p = 0.008), suggesting that tHcy may increase ET-1 by enhancing the production of oxLDL.. Both chronic and acute methionine-induced homocysteinemia are associated with elevated oxidative stress status. Although ET-1 is increased in chronic homocysteinemia, it does not participate in the rapid development of endothelial dysfunction after methionine loading. These findings suggest that despite its potential role in chronic homocysteinemia, ET-1 has a limited contribution to the development of endothelial dysfunction in acute, methionine-induced homocysteinemia in humans.

Topics: Analysis of Variance; Antioxidants; Ascorbic Acid; Double-Blind Method; Endothelin-1; Endothelium, Vascular; Fasting; Female; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Lipoproteins, LDL; Male; Methionine; Oxidative Stress; Regional Blood Flow; Vitamin E

Elevated plasma homocysteine levels are associated with the risk of atherosclerosis and arterial and venous thrombosis. We have previously demonstrated that rabbits rendered hyperhomocysteinemic by parenteral administration of homocysteine develop a dysfibrinogenemia that is associated with the formation of fibrin clots that are abnormally resistant to fibrinolysis. We suggested that this acquired dysfibrinogenemia contributes to the thrombotic tendency in hyperhomocysteinemia. However, it was possible that the homocysteine-associated dysfibrinogenemia was an artifact of the parenteral administration model. Therefore, the goals of the current study were to develop a diet-induced model of homocysteinemia in rabbits and determine whether a dysfibrinogenemia and evidence of oxidative stress develop in this model as they do when homocysteine is injected. We found that rabbits fed a diet severely deficient in folate and mildly deficient in choline develop mild hyperhomocysteinemia: 14.8+/-4.0 microM in deficient rabbits compared to 9.0+/-1.7 microM in controls. The deficient rabbits also develop evidence of oxidant stress: increased lipid peroxidation in liver, impaired mitochondrial enzyme activities in liver and elevated caspase-3 levels in plasma. Most importantly, the deficient rabbits also develop a dysfibrinogenemia characterized by increased resistance to fibrinolysis. We believe that this dietary model of homocysteinemia is clinically relevant and reproduces many features associated with hyperhomocysteinemia in previous work using in vitro and in vivo models. Our findings suggest that an acquired dysfibrinogenemia could play a role in the increased risk of atherothrombotic disease in mildly hyperhomocysteinemic human subjects.

Topics: Animals; Antioxidants; Ascorbic Acid; Caspase 3; Choline Deficiency; Diet; Disease Models, Animal; Female; Fibrinolysis; Folic Acid Deficiency; Homocysteine; Hyperhomocysteinemia; Mitochondria; Oxidative Stress; Rabbits; Risk Factors; Thrombosis; Vitamin E

Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure.. We examined the effect of asymmetrical dimethylarginine (ADMA) on endothelial dysfunction in methionine-induced and chronic homocystinemia and evaluated the regulatory role of oxidative stress and proinflammatory cytokines on the release of ADMA.. In this double-blind, placebo-controlled parallel group study, 30 subjects of both sexes (15 with homocystinemia and 15 healthy controls) underwent methionine loading, with simultaneous administration of a combination of vitamin C (2 g) plus alpha-tocopherol (800 IU) or placebo. Endothelial function in forearm resistance vessels and concentrations of ADMA, oxidized LDL, and proinflammatory cytokines were determined at baseline and 4 h after methionine loading.. Both chronic and methionine-induced homocystinemia were associated with increased oxidized LDL (P < 0.01), higher expression of the proinflammatory cytokine interleukin 6 (P < 0.05), and endothelial dysfunction (P < 0.01). Although ADMA rapidly increased in acute homocystinemia (P < 0.01) and was correlated with forearm hyperemic response at 4 h after methionine loading (r = -0.722, P = 0.0001), it was not higher in subjects with high versus low fasting homocysteine. High-dose antioxidant treatment prevented methionine-induced elevation of oxidized LDL and interleukin 6 but failed to prevent the increase in ADMA or endothelial dysfunction.. Both chronic and methionine-induced homocystinemia are characterized by increased oxidative stress and proinflammatory cytokines, which may contribute to the development of endothelial dysfunction. However, the ADMA pathway is activated only in acute homocystinemia by mechanisms not mediated by oxidized LDL or proinflammatory stimuli.

Topics: Adult; alpha-Tocopherol; Arginine; Ascorbic Acid; Cholesterol, LDL; Chronic Disease; Cytokines; Double-Blind Method; Endothelium, Vascular; Female; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Inflammation; Interleukin-6; Male; Methionine; Oxidative Stress; Time Factors; Vascular Resistance; von Willebrand Factor

Hyperhomocysteinemia has been identified as an independent risk factor for coronary artery disease. One mechanism is considered to be deteriorated endothelial function that is recovered by vitamin C. However, its direct action on coronary circulation has yet to be examined. This study was designed to test the hypothesis that experimental acute hyperhomocysteinemia would impair coronary flow velocity reserve (CFR) by increasing oxidative stress.. Eleven healthy male volunteers (aged 23.3+/-0.9 years) were enrolled. CFR induced by intravenous 5'-adenosine triphosphate infusion was measured by transthoracic-Doppler echocardiography. Measurements were taken before and 4 h after administration of a placebo, oral methionine (L-methionine 0.1 g/kg) or oral methionine plus vitamin C (2 g) on 3 separate days.. The baseline average diastolic peak velocity (APV) was similar in all 3 groups. In the methionine group, plasma homocysteine increased (12.9+/-7.0 to 32.1+/-9.4 nmol/ml, p<0.0001), while APV under hyperemic conditions (APV-hyp) and CFR significantly decreased (87.2+/-11.4 cm/sec and 4.02+/-0.70 to 73.2+/-10.2 cm/sec and 3.35+/-0.52, p=0.0022 and 0.0030, respectively). Moreover, there was a significant inverse correlation between the plasma homocysteine and CFR (r=-0.620, p=0.0021). However, upon simultaneous administration of vitamin C, APV-hyp and CVR did not decrease despite an elevation in plasma homocysteine.. Experimentally induced acute hyperhomocysteinemia significantly decreased CFR, and this decrease was significantly reversed by vitamin C administration. Oxidative stress is suggested to play a major role in the deleterious effects of homocysteine on the coronary microcirculation.

Topics: Adenosine Triphosphate; Administration, Oral; Adult; Antioxidants; Ascorbic Acid; Biomarkers; Blood Flow Velocity; Coronary Circulation; Endothelium, Vascular; Homocysteine; Humans; Hyperhomocysteinemia; Male; Methionine; Oxidative Stress; Reference Values; Research Design; Superoxide Dismutase; Time Factors

The aim of the study was to evaluate the effects of acute hyperhomocysteinemia on distensibility and compliance of large peripheral arteries. Isoprostanes generation and antioxidant vitamins were used to assess the role of oxidative stress.. A cross-over, double-blind study on distensibility (DC: distensibility coefficient) and compliance (CC: cross-sectional compliance) of common femoral and brachial arteries was performed in 12 healthy young male volunteers by means of a wall track system before and 4 h after a single oral methionine (100 mg/kg) or placebo administration. The effects of methionine load were investigated also after oral administration of vitamin C (1g/day) and vitamin E (800 mg/day) for 8 consecutive days.. Oral methionine induced a significant increase in plasmatic levels of homocysteine. Distensibility and compliance of brachial and femoral arteries were significantly reduced after methionine load in comparison to placebo. This acute impairment of arterial wall mechanical properties was associated to endothelial dysfunction, since altered flow-dependent vasodilatation (P < 0.05 versus placebo) was observed in the same arterial districts. A significant increase in urinary 8-iso-prostaglandin F2alpha was observed after methionine. Pretreatment with vitamins C and E prevented the effects of methionine on femoral and brachial arteries as well as on urinary 8-iso-prostaglandin F2alpha excretion.. Hyperhomocysteinemia seems responsible for altered arterial wall elasticity and for endothelial dysfunction. A pivotal role can be attributed to oxidative stress.

Topics: Acute Disease; Adult; Ascorbic Acid; Blood Flow Velocity; Brachial Artery; Compliance; Cross-Over Studies; Double-Blind Method; Femoral Artery; Homocysteine; Humans; Hyperhomocysteinemia; Male; Methionine; Oxidative Stress; Regional Blood Flow; Time Factors; Vasodilation

Topics: Aged; Aged, 80 and over; Aging; Ascorbic Acid; Chromatography, High Pressure Liquid; Female; Folic Acid; Humans; Hyperhomocysteinemia; Lipid Peroxides; Male; Nitric Oxide; Oxidative Stress; Predictive Value of Tests; Stroke; Vitamin B 12

We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P

Topics: Acute Disease; Adult; Ascorbic Acid; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Fibrinolysis; Forearm; Humans; Hyperhomocysteinemia; Male; Methionine; Nitroprusside; Platelet Aggregation; Regional Blood Flow; Substance P; Tissue Plasminogen Activator; Vasodilation; Vasodilator Agents

Manipulation of total homocysteine concentration with oral methionine is associated with impairment of endothelial-dependent vasodilation. This may be caused by increased oxidative stress. Vitamin C is an aqueous phase antioxidant vitamin and free radical scavenger. We hypothesised that if the impairment of endothelial function related to experimental hyperhomocysteinaemia was free radically mediated then co-administration of vitamin C should prevent this.. Ten healthy adults took part in this crossover study. Endothelial function was determined by measuring forearm blood flow (FBF) in response to intra-arterial infusion of acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). Subjects received methionine (100 mg/Kg) plus placebo tablets, methionine plus vitamin C (2 g orally) or placebo drink plus placebo tablets. Study drugs were administered at 9 am on each study date, a minimum of two weeks passed between each study. Homocysteine (tHcy) concentration was determined at baseline and after 4 hours. Endothelial function was determined at 4 hours. Responses to the vasoactive substances are expressed as the area under the curve of change in FBF from baseline. Data are mean plus 95% Confidence Intervals.. Following oral methionine tHcy concentration increased significantly versus placebo. At this time endothelial-dependent responses were significantly reduced compared to placebo (31.2 units [22.1-40.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). Endothelial-independent responses were unchanged. Co-administration of vitamin C did not alter the increase in homocysteine or prevent the impairment of endothelial-dependent responses (31.4 [19.5-43.3] vs. 46.4 units [42.0-50.8], p < 0.05 vs. Placebo). This study demonstrates that methionine increased tHcy with impairment of the endothelial-dependent vasomotor responses. Administration of vitamin C did not prevent this impairment and our results do not support the hypothesis that the endothelial impairment is mediated by adverse oxidative stress.

Topics: Acetylcholine; Administration, Oral; Adult; Area Under Curve; Ascorbic Acid; Cross-Over Studies; Endothelium, Vascular; Forearm; Homocysteine; Humans; Hyperhomocysteinemia; Injections, Intra-Arterial; Male; Methionine; Oxidative Stress; Plethysmography; Regional Blood Flow; Single-Blind Method; Vasodilation

Hyperhomocysteinemia is a major and independent risk factor for vascular disease. The mechanisms by which homocysteine promotes atherosclerosis are not well understood. We hypothesized that elevated homocysteine concentrations are associated with rapid onset endothelial dysfunction, which is mediated through oxidant stress mechanisms and can be inhibited by the antioxidant vitamin C.. We studied 17 healthy volunteers (10 male and 7 female) aged 33 (range 21 to 59) years. Brachial artery diameter responses to hyperemic flow (endothelium dependent), and glyceryltrinitrate (GTN, endothelium independent) were measured with high resolution ultrasound at 0 hours (fasting), 2 hours, and 4 hours after (1) oral methionine (L-methionine 100 mg/kg), (2) oral methionine preceded by vitamin C (1g/day, for 1 week), and (3) placebo, on separate days and in random order. Plasma homocysteine increased (0 hours, 12.8+/-1.4; 2 hours, 25.4+/-2.5; and 4 hours, 31. 2+/-3.1 micromol/l, P<0.001), and flow-mediated dilatation fell (0 hours, 4.3+/-0.7; 2 hours, 1.1+/-0.9; and 4 hours, -0.7+/-0.8%) after oral L-methionine. There was an inverse linear relationship between homocysteine concentration and flow-mediated dilatation (P<0. 001). Pretreatment with vitamin C did not affect the rise in homocysteine concentrations after methionine (0 hours, 13.6+/-1.6; 2 hours, 28.3+/-2.9; and 4 hours, 33.8+/-3.7 micromol/l, P=0.27), but did ameliorate the reduction in flow-mediated dilatation (0 hours, 4. 0+/-1.0; 2 hours, 3.5+/-1.2 and 4 hours, 2.8+/-0.7%, P=0.02). GTN-induced endothelium independent brachial artery dilatation was not affected after methionine or methionine preceded by vitamin C.. We conclude that an elevation in homocysteine concentration is associated with an acute impairment of vascular endothelial function that can be prevented by pretreatment with vitamin C in healthy subjects. Our results support the hypothesis that the adverse effects of homocysteine on vascular endothelial cells are mediated through oxidative stress mechanisms.

Topics: Adult; Ascorbic Acid; Blood Flow Velocity; Brachial Artery; Endothelium, Vascular; Female; Homocysteine; Humans; Hyperhomocysteinemia; Male; Methionine; Middle Aged; Oxidative Stress; Time Factors

An elevated plasma total homocysteine level (tHcy) is considered an independent risk factor for atherosclerosis. The mechanisms by which hyperhomocysteinemia induces atherosclerosis are only partially understood, but promotion of LDL oxidation and endothelial injury have been suggested. The purpose of this study was to test the hypothesis that a high plasma tHcy is associated in men with increased in vivo lipid peroxidation, as measured by plasma F2-isoprostane concentrations. We investigated this association in a subset of the participants in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Of 256 male participants, a subsample of 100 consecutive men was selected for F2-isoprostane assays. The mean tHcy was 11.0 micromol/L, and the mean F2-isoprostanes was 29.6 ng/L. The simple correlation coefficient for association between tHcy and F2-isoprostane was 0.40 (P<0.001). In a linear regression model, the variables with the strongest associations with F2-isoprostane were tHcy (standardized coefficient 0.33, P<0.001), serum triglycerides (0.21, P=0.042), carbohydrate-deficient transferrin (0.15, P=0.132), and plasma lipid-standardized alpha-tocopherol (-0.11, P=0.252) (R2=0.24, P<0. 001 for model). Plasma F2-isoprostane levels increased linearly across quintiles of tHcy (P<0.001). The unadjusted mean (95% confidence interval) F2-isoprostanes was 47.5% greater in the highest tHcy quintile (37.4, 31.1 to 43.6 ng/L) than in the lowest quintile (25.3, 21.3 to 29.3 ng/L). Adjustment for the strongest other determinants of F2-isoprostane reduced this difference to 28. 2% (P=0.010). Our present data suggest that elevated fasting plasma tHcy is associated with enhanced in vivo lipid peroxidation in men.

Topics: Arteriosclerosis; Ascorbic Acid; beta Carotene; Dinoprost; Double-Blind Method; Fasting; Humans; Hyperhomocysteinemia; Linear Models; Lipid Peroxidation; Male; Middle Aged; Risk Factors; Transferrin; Triglycerides; Vitamin E

The aim of this study was to investigate the protective effect of vitamin C towards hyperhomocysteinemia (hHcy) induced oxidative DNA damage using the comet assay. The increase in plasma homocysteine levels is an important risk factor for vascular and cardiovascular diseases through free radical production. This study was also conducted to investigate the histopathological changes in the thoracic aorta and the oxidant/antioxidant status in heart, liver and kidney tissues. Twenty-four adult male Wistar rats were divided as control, hHcy and hHcy+vitamin C group. Chronic hHcy was induced by oral administration of l-methionine (1g/kg/day) for 28 days. Vitamin C was given 150mg/kg/day within the specified days. DNA damage was measured by use of the comet assay in lymphocytes. Levels of malondialdehyde (MDA) and glutathione (GSH) as well as catalase (CAT) and superoxide dismutase (SOD) activities were determined in heart, liver and renal tissues. Results show that l-methionine administration significantly increased % Tail DNA and Mean Tail Moment in hHcy group as compared with other groups. Vitamin C treatment significantly decreased the high MDA levels and increased activity of antioxidant enzymes in tissues. Aortic diameter and thickness of aortic elastic laminae were significantly lower in hHcy+vitamin C group. Comet assay can be used for the assessment of primary DNA damage caused by hHcy. Histopathological findings showed that vitamin C may have a preventive effect in alleviating the negative effects of hHcy. Vitamin C might be useful in the prevention of endothelial dysfunction caused by hHcy.

Topics: Animals; Antioxidants; Aorta; Ascorbic Acid; Comet Assay; Disease Models, Animal; DNA Damage; Hyperhomocysteinemia; Male; Oxidative Stress; Rats; Rats, Wistar

In the present study we investigate the effect of homocysteine on glutamate uptake, Na+,K+-ATPase, enzymatic antioxidant defenses, as well as reactive species levels in hippocampus of rats. The influence of vitamin C, a classic antioxidant, on the effects elicited by homocysteine was also tested. Results showed that chronic hyperhomocysteinemia decreased glutamate uptake and the activities of Na+,K+-ATPase, catalase and superoxide dismutase in hippocampus of rats. Reactive species levels were increased by chronic homocysteine administration. Concomitant administration of vitamin C significantly prevented these alterations caused by homocysteine. According to our results, it seems possible to suggest that the reduction in glutamate uptake and Na+,K+-ATPase activity may be mediated by oxidative stress, since vitamin C prevented these effects. We suggest that the administration of antioxidants should be considered as an adjuvant therapy to specific diet in homocystinuria.

Topics: Animals; Antioxidants; Ascorbic Acid; Catalase; Glutamic Acid; Hippocampus; Homocysteine; Homocystinuria; Hyperhomocysteinemia; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Superoxide Dismutase

Nitric oxide synthase (NOS) inhibitor asymmetrical dimethylarginine (ADMA) is synthesized by the methylation of arginine as part of the methionine/homocysteine cycle. However, the mechanisms regulating ADMA synthesis in hypertension are unclear.. We investigated the role of ADMA and antioxidants in endothelial dysfunction during methionine-induced homocysteinemia in hypertensives. Thirty-nine hypertensives and forty-nine normotensive controls underwent methionine loading (100 mg methionine/kg BW), after being randomized to receive vitamin C (2 g) and E (800 IU) or placebo. Endothelium-dependent dilation (EDD) was evaluated by plethysmography (baseline and 4-h post-methionine loading (4-h PML)).. Hypertensives had higher homocysteine at baseline (P < 0.001) and 4-h PML (P < 0.05), whereas methionine increased homocysteine in all groups. EDD was decreased in both vitamins and placebo groups in controls (P < 0.01 for both) and vitamins- and placebo-treated hypertensives (P < 0.05 and P < 0.01, respectively). In controls, ADMA was increased in both vitamin- and placebo groups (P < 0.01 for both) at 4-h PML. Hypertensives had higher ADMA at baseline (P < 0.01 vs. normotensive) and remained unchanged at 4-h PML (P = NS in placebo and vitamins treated).. ADMA is elevated in hypertensives but remains unchanged after methionine loading, suggesting that ADMA plays an important role in endothelial dysfunction in hypertensives, but it is not responsible for homocysteine-induced endothelial dysfunction in these patients.

Topics: Adult; Antioxidants; Arginine; Ascorbic Acid; Endothelium, Vascular; Female; Homocysteine; Humans; Hyperhomocysteinemia; Hypertension; Male; Methionine; Middle Aged; Vasodilation; Vitamin E

Recent studies demonstrate that hyperhomocysteinemia is a risk factor for heart failure. Oxidant stress is a major mediator of the pathogenic effects of hyperhomocysteinemia.. We utilized a rat model of diet-induced hyperhomocysteinemia to examine whether treatment with an anti-oxidant vitamin (C&E) combination will prevent hyperhomocysteinemia-induced myocardial fibrosis.. Dietary anti-oxidant therapy attenuated hyperhomocysteinemia-induced increases in myocardial oxidant stress and myocardial fibrosis, and diastolic dysfunction.. Hyperhomocysteinemia acts via oxidant stress to promote myocardial fibrosis and dysfunction. Dietary anti-oxidant therapy could be an important preventive and therapeutic strategy in diastolic heart failure.

Topics: Animals; Antioxidants; Ascorbic Acid; Body Weight; Collagen; Coronary Vessels; Diastole; Endomyocardial Fibrosis; Heart; Homocysteine; Hyperhomocysteinemia; Male; Organ Size; Rats; Rats, Sprague-Dawley; Vitamin E

Topics: Administration, Oral; Antioxidants; Ascorbic Acid; Blood Flow Velocity; Coronary Circulation; Coronary Disease; Endothelium, Vascular; Homocysteine; Humans; Hyperhomocysteinemia; Methionine

The endothelial dysfunction induced by hyperhomocysteinemia can be reversed by 5-methyltetrahydrofolate (5-MTHF) via homocysteine (Hcy) lowering. An additive antioxidant action of 5-MTHF has been suggested to ameliorate endothelial dysfunction through increased nitric oxide production and superoxide radical scavenging, independent of Hcy lowering. The aim of the study was to assess whether 5-MTHF affects the redox state in hyperhomocysteinemia. We examined the effect of 3 months of oral 5-MTHF treatment (15 mg/day) on the redox pattern in 48 hyperhomocysteinemic subjects compared to 24 untreated hyperhomocysteinemic subjects. By analysis of variance with repeated measures in the 72 subjects, 5-MTHF markedly decreased plasma total Hcy (p-tHcy; P = 0.0001) and blood-total glutathione (GSH; b-tGSH; P = 0.002). By multivariate linear regression in the treated subjects, p-tHcy changes from baseline to 3 months (adjusted by baseline p-tHcy levels) correlated only with changes in reduced cysteinylglycine (P = 0.001). The effects of treatment on Hcy lowering and GSH metabolism were greater in medium than in moderate hyperhomocysteinemia. In conclusion, high-dose 5-MTHF treatment for 3 months ensures marked Hcy lowering to normal values even in subjects with high Hcy levels, and should be the treatment of choice in medium hyperhomocysteinemia. Furthermore, 5-MTHF shows a favorable interaction with GSH metabolism.

Topics: Adult; Antioxidants; Ascorbic Acid; Chromatography, High Pressure Liquid; DNA; Female; Folic Acid; Homocysteine; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidation-Reduction; Sulfhydryl Compounds; Tetrahydrofolates; Vitamin B 12; Vitamin E

In the present study we investigate the effect of homocysteine (Hcy) administration, the main metabolite accumulating in homocystinuria, on butyrylcholinesterase (BuChE) activity in serum of rats. For the acute treatment, 29-day-old Wistar rats received one subcutaneous injection of Hcy (0.6 micromol/g) or saline (control) and were killed 1 h later. For the chronic treatment, Hcy was administered subcutaneously to rats from the 6th to the 28th day of life. Control rats received saline. The rats were killed 12 h after the last injection. In another set of experiments, rats were pretreated for one week with vitamins E and C or saline and 12 h after the last injection received one single injection of Hcy or saline, being killed 1 h later. Serum was used to determine BuChE activity. Our results showed that acute and chronic administration of Hcy significantly decreased BuChE activity. Furthermore, vitamins E and C per se did not alter BuChE activity, but prevented the reduction of this enzyme activity caused by acute administration of Hcy. The data suggest that the inhibitory effect of Hcy on BuChE activity is probably mediated by free radicals, since vitamins E and C administration prevented such effect.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Butyrylcholinesterase; Disease Models, Animal; Down-Regulation; Enzyme Activation; Free Radicals; Homocysteine; Homocystinuria; Hyperhomocysteinemia; Lipid Metabolism; Oxidative Stress; Rats; Rats, Wistar; Vitamin E

Metal-catalyzed LDL oxidation is enhanced by the presence of homocysteine. In this study, the effectiveness of ascorbic acid against low-density lipoprotein (LDL) oxidation by iron(III) and copper(II) in the presence of homocysteine and the main plasma disulfide cystine was investigated. Relative to the degree of LDL oxidation reached in the absence of antioxidants, ascorbic acid was particularly effective against iron-catalyzed LDL oxidation at pH 6.0. This can be explained from its stability under acidic conditions and is likely to be important in ischemia, in inflammation and exhausting exercise. At pH 7.4, an ascorbic acid concentration at least as high as the concentration of homocysteine might be necessary to efficiently inhibit LDL oxidation by iron(III) and copper(II) in the presence of homocysteine and cystine. Histidine increased the efficiency of ascorbic acid as an antioxidant against copper-mediated oxidation in this system. The capacity of homocysteine to regenerate ascorbic acid from dehydroascorbic acid appeared to play a minor role in inhibition of ascorbic acid oxidation by copper as compared to copper chelation by homocysteine.

Topics: Ascorbic Acid; Catalysis; Cystine; Dehydroascorbic Acid; Ferric Compounds; Histidine; Homocysteine; Humans; Hydrogen-Ion Concentration; Hyperhomocysteinemia; Lipoproteins, LDL; Oxidation-Reduction; Sulfhydryl Compounds

We aimed to test the hypothesis that an enhanced level of reactive oxygen species (ROS) is primarily responsible for the impairment of nitric oxide (NO)-mediated regulation of arteriolar wall shear stress (WSS) in hyperhomocysteinemia (HHcy). Thus flow/WSS-induced dilations of pressurized gracilis muscle arterioles (basal diameter: approximately 170 microm) isolated from control (serum Hcy: 6 +/- 1 microM), methionine diet-induced HHcy rats (4 wk, serum Hcy: 30 +/- 6 microM), and HHcy rats treated with vitamin C, a known antioxidant (4 wk, 150 mg. kg body wt-1.day-1; serum Hcy: 32 +/- 10 microM), were investigated. In vessels of HHcy rats, increases in intraluminal flow/WSS-induced dilations were converted to constrictions. Constrictions were unaffected by inhibition of NO synthesis by N omega-nitro-L-arginine methyl ester (L-NAME). Vitamin C treatment of HHcy rats reversed the WSS-induced arteriolar constrictions to L-NAME-sensitive dilations but did not affect control responses. Similar changes in responses were obtained for the calcium ionophore A-23187. In addition, diastolic and mean arterial blood pressure and serum 8-isoprostane levels (a marker of in vivo oxidative stress) were significantly elevated in rats with HHcy, changes that were normalized by vitamin C treatment. Taken together, our data show that in chronic HHcy long-term vitamin C treatment, by decreasing oxidative stress in vivo, enhanced NO bioavailability, restored the regulation of shear stress in arterioles, and normalized systemic blood pressure. Thus our study provides evidence that oxidative stress is an important in vivo mechanism that is primarily responsible for the development of endothelial dysregulation of WSS in HHcy.

Topics: Animals; Antioxidants; Arterioles; Ascorbic Acid; Blood Pressure; Calcimycin; Dinoprost; F2-Isoprostanes; Hyperhomocysteinemia; Ionophores; Male; Muscle, Skeletal; Nitric Oxide Donors; Oxidative Stress; Penicillamine; Rats; Rats, Wistar; Signal Transduction; Stress, Mechanical; Vascular Resistance

This study was undertaken to evaluate two different doses of folic acid and their effects on the control of hyperhomocysteinemia, and on pro-oxidant and antioxidant changes in a group of 32 hemodialysis (HD) patients. Blood samples were collected in a group of patients at three different times: before (basal; B), after the first (S1), and after the second (S2) three-month supplementation periods, and compared to samples from a group of healthy individuals. Analysis of vitamins (C, E, folate, and B12), oxidant parameters (lipid and protein oxidation), and homocysteine were performed. Hyperhomocysteinemia of different degrees was observed in all patients on HD (45.30 +/- 24.89 microM). Oxidative stress was also detected, with lipoperoxidation and protein oxidation being associated with lower concentrations of antioxidant substances (vitamins E and C). The first folate dose (2.5 mg after each dialysis session) reduced by half the initial concentrations of homocysteine (44.92 +/- 22.05 to 20.56 +/- 6.79 microM; p < 0.05) but did not normalize its values. The second dose (15 mg) did not show an additional effect, but it was at this time that lipoperoxidation was significantly reduced, although the protein oxidation showed no change. It was concluded that the first dose of folic acid was efficient in reducing homocysteine concentrations, without normalization of values. The participation of hyperhomocysteinemia in oxidative stress appeared to be partial, but in combination with dialysis treatment, may contribute to the induction of an oxidative environment in this group. The possible antioxidant action of folate must also be considered in this case, acting directly against lipoperoxidation or through hyperhomocysteinemia control. Routine supplementations of folic acid and other antioxidant vitamins should be considered in hemodialysis in order to reduce homocysteine levels to lower values, that although not normal, may be more beneficial in minimizing the cardiovascular risk in this group.

Topics: Ascorbic Acid; Dietary Supplements; Female; Folic Acid; Hematinics; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Proteins; Renal Dialysis; Vitamin B 12; Vitamin E

Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress.. Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia ( approximately 25 micromol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477+/-82%; placebo, 673+/-110%; P=0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3+/-2.7%) compared with placebo (8. 2+/-1.6%, P=0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (P=0.03).. Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension. Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

Topics: Acetylcholine; Adult; Antioxidants; Ascorbic Acid; Endothelium, Vascular; Female; Homocysteine; Humans; Hyperhomocysteinemia; Male; Methionine; Nitroprusside; Oxidative Stress; Vasodilation; Vasodilator Agents; Verapamil

Topics: Anticholesteremic Agents; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cholesterol, LDL; Diet; Europe; Folic Acid; Greece; Humans; Hyperhomocysteinemia; Lipoproteins; Pravastatin; Pyridoxine; Risk Factors; Societies, Medical; Triglycerides