Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines

BACKGROUND: Homocystinemia is a metabolic abnormality associated with endothelial dysfunction and increased cardiovascular disease risk. The underlying mechanisms of these effects, however, are obscure. OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.     

Effects of folate, vitamin B-12 and vitamin B-6 supplementation on methionine-induced hyperhomocysteinemia in rats

An excessive intake of dietary methionine increases plasma total homocysteine (tHcy, an independent risk factor for premature cardiovascular disease) by enhancing the synthesis of homocysteine. Information on the influence of excess dietary vitamins involved in homocysteine metabolism on the methionine-induced hyperhomocysteinemia is, however, limited. Thus, a six-week study was conducted to determine the influence of excess folic acid, vitamin B-12 and vitamin B-6 on the methionine-induced hyperhomocysteinemia in rats. Supplementation of the casein control diet with 10 and 20 g/kg L-Met increased plasma tHcy to 2.0 and 8.0 times control, respectively. The hyperhomocysteinemia caused by the addition of 10 g/kg L-Met to the control diet, was completely counteracted by extra folic acid or three vitamins combined (folic acid, 2 mg/kg; vitamin B-12, 25 μg/kg; plus vitamin B-6, 6 mg/kg) but the addition of extra vitamin B-12 or vitamin B-6 alone had no effect on plasma tHcy. Similarly, extra dietary folic acid or the three vitamins combined caused substantial reduction in plasma tHcy of rats fed the control diet supplemented with 20 g/kg L-Met but addition of vitamin B-12 or vitamin B-6 alone exacerbated plasma tHcy.     

The importance of endothelin-1 for microvascular dysfunction in diabetes

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET_A receptor antagonists are discussed.     

Effect of multivitamin supplementation on the homocysteine and methylmalonic acid blood concentrations in women over the age of 60 years

Summary Background Deficiency of folic acid, vitamin B₆ and/or vitamin B₁₂ can result in elevated total plasma homocysteine concentrations (tHcy), which are considered to be a risk factor for vascular disease. Studies have shown that supplementation of the three vitamins can lower tHcy even in subjects with tHcy in the normal range. Aim of the study The aim of this study was to evaluate the effect of a 6 month supplementation with vitamin B₆, B₁₂ and folate on the concentrations of total plasma homocysteine and serum methylmalonic acid (MMA) of elderly women. Methods The study was designed as a randomized placebo controlled doubleblind trial, and 220 healthy women (aged 60–91 years) were involved. The vitamin and mineral capsule contained pyridoxine (3.4 mg), folic acid (400 µg) and cobalamin (9 µg) in addition to other micronutrients. Blood concentrations of folate, cobalamin, tHcy, MMA and the activity coefficient of erythrocyte alpha-aspartic aminotransferase (alpha-EAST) were measured at baseline and after 6 months of supplementation. Dietary intake was evaluated at the beginning and the end of the intervention by two 3–day diet records. Results Median concentrations of serum cobalamin, serum folate and erythrocyte folate increased significantly and tHcy and alpha–EAST activity (indicative of improved status of vitamin B₆) coefficient decreased significantly in the supplemented group. Median MMA concentration of the supplemented group was significantly lower than that of the placebo group after the intervention. The vitamin supplementation had a greater decreasing effect on the tHcy concentration of volunteers with lower vitamin and higher tHcy initial concentrations. In a linear regression model, baseline tHcy, serum folate, age and alpha–EAST activity coefficient were significantly correlated with the change in tHcy. The change in MMA in the supplement group was significantly associated to the baseline MMA values. Conclusions Our results show that a 6 month supplementation including physiological dosages of B vitamins improves the status of these nutrients and reduces tHcy in presumed healthy elderly women.     

Plasma endothelin-1 levels in patients with peripheral arterial occlusive disease at different Fontaine's stages

Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogenic peptide produced and secreted by endothelial cells, which can play a potential role in the development of atherosclerosis and in the pathophysiology of extreme vasoconstriction of various diseases. METHODS: To assess plasma endothelin-1 (ET-1) concentrations in patients with peripheral arterial occlusive disease (PAOD) at different Fontaine's stages, we measured plasma ET-1 by radioimmunoassay in 14 stage II PAOD patients (12 men, 2 women; mean age 59.5 +/- 3.4 years) and in 10 stage III-IV PAOD patients (8 men, 2 women, mean age 61.2 +/- 3.3 years). Ten normal subjects (8 men, 2 women, mean age 58.1 +/- 7.2 years) were considered as controls. RESULTS: Mean (+/- SD) plasma ET-1 levels, as measured by radioimmunoassay, were significantly greater in stage II and stage III-IV PAOD patients than in control subjects (4 +/- 0.4 and 5 +/- 0.4 pmol/L vs 2.5 +/- 0.6 pmol/L, respectively, p < 0.001). Furthermore, plasma levels of ET-1 in stage III-IV patients were significantly higher than in stage II patients (p < 0.01). A significant correlation was found between plasma ET-1 levels and number of the arterial obstructive lesions in PAOD patients (r = 0.698; p < 0.0001). No significant correlation was found between plasma ET-1 concentrations and pain-free walking distance (r = -0.279, p = 0.333, in stage II patients; r = 0.137, p = 0.705, in stage III-IV patients), and between plasma ET-1 levels and ankle/arm pressor index (r = 0.032, p = 0.913, in stage II patients; r = 0.149, p = 0.681, in stage III-IV patients) in the PAOD patients. CONCLUSIONS: Raised plasma ET-1 could be a sensible marker both of endothelial damage and disease extension. It could also promote the progression of atherosclerotic plaques and enhance the microvascular resistance in these patients.     

抗氧化维生素对氧化低密度脂蛋白作用的主动脉内皮细胞脂质过氧化损伤的影响

为深入探讨抗氧化维生素（维生素Ｅ、维生素Ｃ及β－胡萝卜素）对氧化低密度脂蛋白（ｏｘＬＤＬ）损伤内皮细胞的防治作用及可能机理,我们以体外培养的小牛主动脉内皮细胞为模型、在培养的主动脉内皮细胞中加入不同剂量的抗氧化维生素,共同培养１２ｈ,再与终浓度为０．１ｇ／Ｌ的ｏｘＬＤＬ继续培养２４ｈ,取贴壁细胞及培养液,通过硫代巴比妥酸荧光比色法（ＴＢＡ）和单核细胞（ＨＬ６０）粘附计数法观察不同浓度的抗氧化维生素对ｏｘＬＤＬ损伤的内皮细胞脂质过氧化及单核细胞粘附性的影响。结果表明,抗氧化维生素各组细胞培养液中丙二醛（ＭＤＡ）含量以及内皮细胞粘附的ＨＬ６０细胞数均明显低于ｏｘＬＤＬ组,提示维生素Ｅ、维生素Ｃ及β－胡萝卜素三种抗氧化维生素均可减轻ｏｘＬＤＬ对内皮细胞的脂质过氧化损伤,阻止单核细胞的粘附。这些可能是抗氧化维生素防治动脉粥样硬化的重要机理之一。     

抗氧化维生素对氧化密度脂蛋白作用的主动脉内皮细胞脂质过氧化损伤？…

为深入探讨抗氧化维生素（维生素Ｅ、维生素Ｃ及β－胡萝卜素）对氧化低密度脂蛋白（ｏｘＬＤＬ）损伤内皮细胞的防治作用及可能机理,我们以体外培养的小年主支脉内皮细胞为模型,在培养的主动脉内皮细胞中加入不同剂量的抗氧化维生素,共同培养１２ｈ,再与终浓度为０．１ｇ／Ｌ的ｏｘＬＤＬ继续培养２４ｈ,取贴壁细胞及培养液,通过硫代巴比妥酸荧光比色法（ＴＢＡ）和单核细胞（ＨＬ６０）粘附计数法观察不同浓度的抗氧化维生素     

Folate Status Worsens in Recently Institutionalized Elderly People without Evidence of Functional Deterioration

Objective: To follow folate status, hematological and cognitive changes during the first year of institutionalization among elderly subjects.

Design: Prospective study.

Setting: Long-stay unit of the Dijon University Geriatric Hospital.

Subjects: Twenty women and four men older than 65 years admitted consecutively.

Main outcome measures: Folate and vitamin B-6 dietary intake was evaluated by a five-day record on admission (day 1 or d 1), at day 45 (d 45), day 90 (d 90), day 135 (d 135), day 180 (d 180), day 360 (d 360). Circulating levels of folate, vitamin B-6, total homocysteine (tHcy), blood counts and cognitive performance were determined in parallel.

Results: From d 1 to d 360, mean folate and vitamin B-6 intakes remained below the French RDA and mean folate intakes decreased significantly (Δ = ?10.2%, p <0.05). Mean plasma or erythrocyte folate decreased significantly (Δ = ?33.7%, p <0.05 and Δ = ?30.2%, p <0.001, respectively) from d 1 to d 360; no significant change was observed for the other blood parameters. The incidence of folate deficiency increased (8% vs. 37% for plasma folate <6.8 nmol/L and 8% vs. 17% for erythrocyte folate <340 nmol/L) from d 1 to d 360. Mean plasma pyridoxal 5′-phosphate (PLP) remained <20 nmol/L during the one-year follow-up. There was no difference between genders for plasma tHcy. Although mean plasma tHcy was <14 μmol/L, plasma tHcy was >14 μmol/L in about one-third of the subjects. At each period, 50% or more subjects were anemic (Hct <35% in women and Hct <40% in men), but the anemia was normocytic (MCV <100 fL). Subjects had a moderate dementia at admission, and no change was observed during the study.

Conclusions: Subjects were already vitamin B-6 deficient at admission. Folate status was impaired during the study. Low vitamin intakes were the main cause of vitamin B-6 deficiency and folate status deterioration. Hematology and mental status capacity were not aggravated by folate status deterioration. Plasma tHcy didn’t appear to be an earlier predictor of folate deficiency.     

Effects of weight loss from a high-calcium energy-reduced diet on biomarkers of inflammatory stress,fibrinolysis, and endothelial function in obese subjects

ObjectiveObesity is characterized by chronic subclinical inflammation, which is critical to endothelial dysfunction. Weight loss, induced by lifestyle interventions, is associated with a decline in biomarkers of inflammation and endothelial dysfunction. There is little evidence that high dietary calcium intake may reduce inflammation and improve endothelial function. The purpose of this study was to evaluate the effects of weight loss from a high-calcium energy-reduced diet on biomarkers of inflammation, fibrinolysis, and endothelial function in obese individuals.MethodsIn this randomized clinical trial, we analyzed the data from 35 obese adults who lost at least 3% of initial body weight, during a period of 16 wk of energy restriction (?800 Kcal/d). Individuals were randomized into the following dietary regimens: (1) a high calcium diet (HCD; 1200–1300 mg/d) or (2) a low-calcium diet (LCD; <500 mg/d).ResultsAfter 16 wk of intervention subjects on HCD compared with those on LCD exhibited greater reduction in waist circumference and waist-to-hip ratio. Participants on HCD presented a significant reduction in all biomarkers of endothelial dysfunction evaluated in the study (intracellular adhesion molecule-1, vascular cell adhesion molecule 1, and E-Selectin), whereas subjects on LCD showed a significant decrease in intracellular adhesion molecule-1 and E-Selectin. Biomarkers of inflammation and fibrinolysis were reduced in both diets, although without reaching statistical significance. The reduction in all markers of inflammation, fibrinolysis, and endothelial dysfunction was similar in both diets.ConclusionThe findings of this study suggest that increased calcium intake during weight loss has no benefits with respect to biomarkers of inflammation, fibrinolysis, and endothelial function.     

Successful weight loss reduces endothelial activation in individuals with severe obesity participating in a multimodal weight loss program

IntroductionEndothelial dysfunction is a very common finding in obesity and metabolic syndrome. The aim of our study was to investigate if longterm weight reduction (WR) success may reverse endothelial activation in individuals with severe obesity participating in a multimodal WR program.MethodsParticipants with obesity (øBMI 40.3 ±7.5 kg/m²) underwent a standardized non-surgical 1-year WR program. Carotid artery studies and determination of endothelial function biomarkers were performed at baseline and after 1 year. Individuals were dichotomized in “successful WR” (% WR≥10% of initial body weight) and “failed WR” (% WR<10% of initial body weight).ResultsFrom 191 people with obesity, 115 achieved successful WR. Compared to controls without obesity (n=44) participants with obesity had higher carotid intima media thickness as well as higher sICAM-1, sE-selectin, MMP-9, hsCRP and IL-6 levels. After 12 months follow up delta values of inflammation and endothelial adhesion markers were significantly different between participants with obesity and successful WR and participants with obesity and failed WR, in favour of the successful WR group (mean ± standard deviation): ΔhsCRP (?5.2 mg/L ±7.8 vs. 1.1 mg/L ±5.1, P<0.001; P_adj=0.009), ΔIL-6 (?1.0 pg/mL ±3.4 vs. 0.5 pg/mL ±2.6, P<0.001; P_adj=0.057), ΔsE-selectin (?19.0 ng/mL ±24.4 vs. 39.2 ng/mL ±20.3, P<0.001; P_adj<0.001), ΔsICAM-1 (-26.4 ng/mL ±68.8 vs. 10.6 ng/mL ±73.9, P=0.004; P_adj=0.805) and ΔoxLDL (?4 mg/dL ±30 vs. 5 mg/dL ±25, P=0.004; P_adj=0.473). In linear regression analysis reduction of BMI was significantly associated with improvement of several endothelial dysfunction biomarkers with the strongest effects for ΔsE-selectin and ΔhsCRP.ConclusionOur data corroborate the finding that obesity leads to endothelial dysfunction. Furthermore, successful non-surgical WR may at least partially reverse endothelial activation implicating cardiovascular health benefits of WR in people with severe obesity.     

<Emphasis Type="SmallCaps">l</Emphasis>-Arginine and B vitamins improve endothelial function in subjects with mild to moderate blood pressure elevation

Purpose

The aim of this trial was to investigate the influence of a dietetic product consisting of a unique combination of l-arginine with the vitamins B₆, folic acid and B₁₂ (Telcor^® Arginin plus) on endothelial dysfunction.

Methods

Subjects aged 40–65 years with mild to moderate blood pressure (BP) elevation not treated with anti-hypertensive drugs were randomly assigned to either the dietetic product (n = 40) or a matching placebo (n = 41) for 3 months with open follow-up for a further 3 months. Postprandial change in endothelial function was assessed using the validated reactive hyperaemia index (RHI) at 3 months compared to the study onset (RHI post–pre, visit 3–visit 1; ΔΔRHI). Secondary parameters included BP and plasma homocysteine concentration.

Results

The primary efficacy analysis revealed superiority of the nutritional intervention over placebo (p = 0.0349) in reducing the deterioration of endothelial function. While in the active group ΔΔRHI increased (0.371 ± 0.122), almost no change could be detected in the placebo group (0.031 ± 0.100), thus demonstrating a significant improvement in vascular function in the intervention group. Moreover, the intervention reduced BP and homocysteine levels. Non-serious adverse events were equally distributed in both groups, and none of the events were assessed as possibly intervention-related by the investigators.

Conclusions

This trial confirmed the effective and safe use of dietary management with l-arginine in combination with B vitamins. The primary efficacy analysis demonstrated a statistically significant superiority of the combination of l-arginine with B vitamins over placebo in improving and restoring impaired endothelial function and lowering BP in patients with mild to moderate blood pressure elevation.

     

Coffee bean polyphenols ameliorate postprandial endothelial dysfunction in healthy male adults

Abstract

To reveal the effect of coffee bean polyphenols (CBPs) on blood vessels, this study aimed to investigate the effect of CBPs on acute postprandial endothelial dysfunction. Thirteen healthy non-diabetic men (mean age, 44.9?±?1.4 years) consumed a test beverage (active: containing CBPs, placebo: no CBPs) before a 554-kcal test meal containing 14?g of protein, 30?g of fat and 58?g of carbohydrates. Then, a crossover analysis was performed to investigate the time-dependent changes in flow-mediated dilation (FMD) in the brachial artery. In the active group, the postprandial impairment of FMD was significantly improved, the two-hour postprandial nitric oxide metabolite levels were significantly increased and the six-hour postprandial urinary 8-epi-prostaglandin F2α levels were significantly reduced compared to the placebo group. The test meal increased the levels of blood glucose, insulin and triglycerides in both groups with no significant intergroup differences. These findings indicate that CBPs intake ameliorates postprandial endothelial dysfunction in healthy men.     

Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study

BACKGROUND: Deficiencies of vitamin B-12, folic acid, and vitamin B-6-as defined by laboratory measures-occur in 10-20% of elderly subjects. The clinical significance remains unresolved. OBJECTIVE: The objective was to explore any association between vitamin status and vitamin treatment and movement and cognitive performance in elderly subjects. DESIGN: Community-dwelling subjects (n = 209) with a median age of 76 y were randomly assigned to daily oral treatment with 0.5 mg cyanocobalamin, 0.8 mg folic acid, and 3 mg vitamin B-6 or placebo (double blind) for 4 mo. Movement and cognitive performance tests were performed before and after treatment. RESULTS: A high plasma total homocysteine (tHcy) concentration (> or =16 micromol/L) was found in 64% of men and in 45% of women, and a high serum methylmalonic acid (MMA) concentration (> or =0.34 micromol/L) was found in 11% of both sexes. Movement time, digit symbol, and block design (adjusted for age, sex, smoking, and creatinine) correlated independently with plasma tHcy (P < 0.01, < 0.05, and < 0.01, respectively); the simultaneity index and block design correlated with serum MMA (P < 0.05 for both). Vitamin therapy significantly decreased plasma tHcy (32%) and serum MMA (14%). No improvements were found in the movement or cognitive tests compared with placebo. Neither vitamin therapy nor changes in plasma tHcy, serum MMA, serum vitamin B-12, plasma folate, or whole-blood folate correlated with changes in movement or cognitive performance. CONCLUSIONS: High plasma tHcy and serum MMA were prevalent and correlated inversely with movement and cognitive performance. Oral B vitamin treatment normalized plasma tHcy and serum MMA concentrations but did not affect movement or cognitive performance. This might have been due to irreversible or vitamin-independent neurocognitive decline or to an insufficient dose or duration of vitamins.     

Neuroprotective effects of curcumin on endothelin-1 mediated cell death in hippocampal neurons

Objectives: Alzheimer's disease is a progressive neurodegenerative disease characterized by loss of hippocampal neurons leading to memory deficits and cognitive decline. Studies suggest that levels of the vasoactive peptide endothelin-1 (ET-1) are increased in the brain tissue of Alzheimer's patients. Curcumin, the main ingredient of the spice turmeric, has been shown to have anti-inflammatory, anti-cancer, and neuroprotective effects. However, the mechanisms underlying some of these beneficial effects are not completely understood. The objective of this study was to determine if curcumin could protect hippocampal neurons from ET-1 mediated cell death and examine the involvement of c-Jun in this pathway.

Methods: Primary hippocampal neurons from rat pups were isolated using a previously published protocol. Viability of the cells was measured by the live/dead assay. Immunoblot and immunohistochemical analyses were performed to analyze c-Jun levels in hippocampal neurons treated with either ET-1 or a combination of ET-1 and curcumin. Apoptotic changes were evaluated by immunoblot detection of cleaved caspase-3, cleaved fodrin, and a caspase 3/7 activation assay.

Results: ET-1 treatment produced a 2-fold increase in the levels of c-Jun as determined by an immunoblot analysis in hippocampal neurons. Co-treatment with curcumin significantly attenuated the ET-1 mediated increase in c-Jun levels. ET-1 caused increased neuronal cell death of hippocampal neurons indicated by elevation of cleaved caspase-3, cleaved fodrin and an increased activity of caspases 3 and 7 which was attenuated by co-treatment with curcumin. Blockade of JNK, an upstream effector of c-Jun by specific inhibitor SP600125 did not fully protect from ET-1 mediated activation of pro-apoptotic enzymes in primary hippocampal cells.

Discussion: Our data suggests that one mechanism by which curcumin protects against ET-1-mediated cell death is through blocking an increase in c-Jun levels. Other possible mechanisms include decreasing pro-apoptotic signaling activated by ET-1 in primary hippocampal neurons.     

Homocysteine lowering effect of different multivitamin preparations in patients with end-stage renal disease.

OBJECTIVE: Hyperhomocysteinemia occurs in nearly 100% of patients with end-stage renal disease (ESRD) and is associated with increased morbidity and mortality. Means to reduce elevated homocysteine concentrations is supplementation with folic acid, vitamin B6, and vitamin B12. However, doses of vitamins required for optimized treatment are subject of debate. Therefore, the effect of 2 different multivitamin preparations on the homocysteine concentrations in patients with ESRD were compared. DESIGN: Patients received 3 times per week either 2 tablets of preparation A (800 microg folic acid, 6 microg vitamin B12, 10 mg vitamin B6), 2 tablets of preparation B (160 microg folic acid, no vitamin B12, 10 mg vitamin B6), or placebo for a period of 12 weeks with control of total homocysteine (tHcy) levels at baseline, and at 4, 8, and 12 weeks. SETTING: The study was performed at the University Hospital of Magdeburg, Germany in patients with ESRD treated with chronic intermittent maintenance hemodialysis. RESULTS: Preparation A reduced the tHcy concentration significantly by nearly 50%, whereas preparation B did not change the tHcy concentration in comparison with placebo. However, tHcy was not normalized in the majority of patients receiving preparation A. CONCLUSION: The reduction of tHcy achieved by a multivitamin containing 800 microg folic acid was substantial and even higher than the reduction reported in supplementation studies using higher doses of folic acid alone. Nevertheless, hyperhomocysteinemia in ESRD patients appears relatively refractory to vitamin supplementation, in contrast with results obtained in healthy volunteers.     

A phase 1 study of the safety,reactogenicity, and immunogenicity of a Schistosoma mansoni vaccine with or without glucopyranosyl lipid A aqueous formulation (GLA-AF) in healthy adults from a non-endemic area

BackgroundSchistosomiasis caused by Schistosoma mansoni (Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent schistosomiasis would represent a major breakthrough in public health.MethodsThe safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18–50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant (Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3.ResultsVaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both).Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose–response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001).ConclusionsSm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.     

The Effects of Choline and Magnesium Co-Supplementation on Metabolic Parameters,Inflammation, and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus: A Randomized,Double-Blind,Placebo-Controlled Trial

Abstract

Objective: To our knowledge, no study has investigated the effects of choline and magnesium co-supplementation on metabolic parameters, inflammation, and endothelial dysfunction in patients with type 2 diabetes mellitus (T2DM). The aim of this study was investigation of the effects of the choline and magnesium co-supplementation on metabolic parameters, inflammation, and endothelial dysfunction in patients with T2DM.

Methods: A randomized double-blind placebo-controlled parallel clinical trial was carried out among 96 diabetic patients. Ninety-six patients were randomly assigned to either choline, magnesium, choline-magnesium, or placebo for 2 months. Anthropometric measurement; metabolic, inflammatory, and endothelial markers; dietary intake; and physical activity were assessed at baseline and after treatment.

Results: There was a significant change in serum magnesium in both magnesium and choline-magnesium groups (p?<?0.05). Also, significant changes were observed in interleukin (IL)-6 levels in magnesium and choline-magnesium groups (p?<?0.05). Moreover, vascular cell adhesion molecule-1 (VCAM-1) levels decreased in choline and choline-magnesium groups (p?<?0.05). When adjusted for potential confounders, inflammation and endothelial factors (IL-6 and VCAM-1) decreased significantly in the choline-magnesium group as compared to other groups (p?<?0.05). Compared to baseline values there were no significant differences in all anthropometric measurements and metabolic factors among four groups (p?>?0.05).

Conclusions: Choline and magnesium co-supplementation was more effective in improving inflammation and endothelial dysfunction than supplementation with choline or magnesium alone.     

Blood lipids,homocysteine, stress factors,and vitamins in clinically stable multiple sclerosis patients

Multiple Sclerosis (MS) patients present a decrease of antioxidants and neuroprotective and immunoregulatory vitamins and an increase of total homocysteine (tHcy), cholesterol (CHL), HDL-cholesterol, and of cellular stress markers, variably associated with the different phases of the disease. We compared the blood levels of uric acid, folic acid, vitamins B12, A, and E, tHcy, CHL, HDL-cholesterol, and triglycerides in forty MS patients during a phase of clinical inactivity with those of eighty healthy controls, matched for age and sex. We found higher levels of tHcy (p = 0.032) and of HDL-cholesterol (p = 0.001) and lower levels of vitamin E (p = 0.001) and the ratio vitamin E/CHL (p = 0.001) in MS patients. In conclusion, modifications of some biochemical markers of cell damage were detected in MS patients during a phase of clinical inactivity.     

Acute EGCG Supplementation Reverses Endothelial Dysfunction in Patients with Coronary Artery Disease

Background: Epidemiological studies demonstrate an inverse relation between dietary flavonoid intake and cardiovascular risk. Recent studies with flavonoid-containing beverages suggest that the benefits of these nutrients may relate, in part, to improved endothelial function.

Objective: We hypothesized that dietary supplementation with epigallocatechin gallate (EGCG), a major catechin in tea, would improve endothelial function in humans.

Design: We examined the effects of EGCG on endothelial function in a double blind, placebo-controlled, crossover design study. We measured brachial artery flow-mediated dilation by vascular ultrasound at six time points: prior to treatment with EGCG or placebo, two hours after an initial dose of EGCG (300 mg) or placebo, and after two weeks of treatment with EGCG (150 mg twice daily) or placebo. The order of treatments (EGCG or placebo) was randomized and there was a one-week washout period between treatments.

Results: A total of 42 subjects completed the study, and brachial artery flow-mediated dilation improved from 7.1 ± 4.1 to 8.6 ± 4.7% two hours after the first dose of 300 mg of EGCG (P = 0.01), but was similar to baseline (7.8 ± 4.2%, P = 0.12) after two weeks of treatment with the final measurements made approximately 14 hours after the last dose. Placebo treatment had no significant effect, and there were no changes in reactive hyperemia or the response to sublingual nitroglycerin. The changes in vascular function paralleled plasma EGCG concentrations, which increased from 2.6 ± 10.9 to 92.8 ± 78.7 ng/ml after acute EGCG (P < 0.001), but were unchanged from baseline after two weeks of treatment (3.4 ± 13.1 ng/ml).

Conclusion: EGCG acutely improves endothelial function in humans with coronary artery disease, and may account for a portion of the beneficial effects of flavonoid-rich food on endothelial function.     

The Effects of a Multivitamin/Mineral Supplement on Micronutrient Status,Antioxidant Capacity and Cytokine Production in Healthy Older Adults Consuming a Fortified Diet

Background: Inadequate micronutrient intake among older adults is common despite the increased prevalence of fortified/enriched foods in the American diet. Although many older adults take multivitamin supplements in an effort to compensate, studies examining the benefits of this behavior are absent.

Objective: To determine whether a daily multivitamin/mineral supplement can improve micronutrient status, plasma antioxidant capacity and cytokine production in healthy, free-living older adults already consuming a fortified diet.

Methods: An eight-week double-blind, placebo-controlled clinical trial among 80 adults aged 50 to 87 years (mean=66.5±8.6 years).

Results: Multivitamin treatment significantly increased (p<0.01, compared to placebo) plasma concentrations of vitamins D (77 to 100 nmol/L), E (27 to 32 μmol/L), pyridoxal phosphate (55.1 to 75.2 nmol/L), folate (23 to 33 nmol/L), B12 (286 to 326 pmol/L)), C (55 to 71 μmol/L), and improved the riboflavin activity coefficient (1.23 to 1.15), but not vitamins A and thiamin. The multivitamin reduced the prevalence of suboptimal plasma levels of vitamins E (p=0.003), B12 (p=0.004), and C (p=0.08). Neither glutathione peroxidase activity nor antioxidant capacity (ORAC) were affected. No changes were observed in interleukin?2, ?6 or ?10 and prostaglandin E₂, proxy measures of immune responses.

Conclusions: Supplementation with a multivitamin formulated at about 100% Daily Value can decrease the prevalence of suboptimal vitamin status in older adults and improve their micronutrient status to levels associated with reduced risk for several chronic diseases.