Folic acid administration and antibodies against homocysteinylated proteins in subjects with hyperhomocysteinemia

SummaryGrowing evidence indicates that elevated total homocysteine (tHcy) levels can elicit autoimmune response in vivo. Antibodies against Nε-Hcy-proteins have been shown to be associated with stroke and premature myocardial infarction. The aim of the current study was to investigate the effect of treatment with folic acid on anti-Nε-Hcy-albumin and -hemoglobin antibodies. We recruited 20 apparently healthy men and 12 male patients with documented coronary artery disease (CAD). All participants had plasma fasting tHcy levels >15 µM. At baseline, and after three and six months of treatment with folic acid 1 mg daily, we determined tHcy, serum folate and vitamin B12 levels, along with serum anti-Nε-Hcy-albumin and -hemoglobin IgG antibodies using the home-made immunoenzymatic assays. Both groups did not differ with regard to age, tHcy, folate, lipid profile, and CRP. The only significant difference between healthy subjects and CAD patients was levels of antibodies against Nε-Hcy-albumin. As expected, folic acid administration led to significant decreases in tHcy and increases in folate levels in both groups. Levels of both anti-Nε-Hcy-albumin and -hemoglobin antibodies fell markedly following a three-month folic acid administration in healthy subjects, but not in CAD patients, without any changes at six months in either group. Folic acid administration resulted in a loss of significant correlations between tHcy and antibodies both following three and six months of the therapy in healthy subjects, in contrast to CAD patients. Carriers of the methylenetetrahydrofolate reductase (MTHFR) 677T allele with CAD had significantly higher levels of anti-Nε-Hcy-albumin before and during folic acid administration as compared to healthy subjects. In conclusion, our findings suggest that Hcy-related autoimmune response is resistant to folic acid administration in CAD patients, while in healthy subjects reduced tHcy levels are associated with suppressed production of antibodies against Nε-Hcyproteins. These observations might explain at least in part the failure of vitamin therapy to reduce the risk of cardiovascular events as recently reported.

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Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women

Nutrients ◽

10.3390/nu13041381 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1381

Author(s):

Keiji Kuroda ◽

Takashi Horikawa ◽

Yoko Gekka ◽

Azusa Moriyama ◽

Kazuki Nakao ◽

...

Keyword(s):

Folic Acid ◽

Methylenetetrahydrofolate Reductase ◽

Homocysteine Level ◽

Folic Acid Supplementation ◽

Serum Folate ◽

Folate Level ◽

Multivitamin Supplementation ◽

Mthfr Polymorphisms ◽

Mthfr Genotype ◽

Multivitamin Supplements

Methylenetetrahydrofolate reductase (MTHFR) has various polymorphisms, and the effects of periconceptional folic acid supplementation for decreasing neural tube defects (NTDs) risk differ depending on the genotypes. This study analyzed the effectiveness of multivitamin supplementation on folate insufficiency and hyperhomocysteinemia, depending on MTHFR polymorphisms. Of 205 women, 72 (35.1%), 100 (48.8%) and 33 (16.1%) had MTHFR CC, CT and TT, respectively. Serum folate and homocysteine levels in women with homozygous mutant TT were significantly lower and higher, respectively, than those in women with CC and CT. In 54 women (26.3% of all women) with a risk of NTDs, multivitamin supplementation containing folic acid and vitamin D for one month increased folate level (5.8 ± 0.9 to 19.2 ± 4.0 ng/mL, p < 0.0001) and decreased the homocysteine level (8.2 ± 3.1 to 5.8 ± 0.8 nmol/mL, p < 0.0001) to minimize the risk of NTDs in all women, regardless of MTHFR genotype. Regardless of MTHFR genotype, multivitamin supplements could control folate and homocysteine levels. Tests for folate and homocysteine levels and optimal multivitamin supplementation in women with risk of NTDs one month or more before pregnancy should be recommended to women who are planning a pregnancy.

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Correlation between Therapeutic Efficacy of CD34+ Cell Treatment and Directed In Vivo Angiogenesis in Patients with End-Stage Diffuse Coronary Artery Disease

Stem Cells International ◽

10.1155/2018/9591421 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Tien-Hung Huang ◽

Cheuk-Kwan Sun ◽

Yi-Ling Chen ◽

Pei-Hsun Sung ◽

Chi-Hsiang Chu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Therapeutic Efficacy ◽

Peripheral Blood Mononuclear ◽

Angiogenesis Assay ◽

Diffuse Coronary Artery Disease ◽

Significant Difference ◽

Artery Disease ◽

End Stage

Background. This study was aimed at testing the association between the therapeutic efficacy of CD34+ cell treatment in patients with end-stage diffuse coronary artery disease as reflected in angiographic grading and results of directed in vivo angiogenesis assay (DIVAA) on their isolated peripheral blood mononuclear cell- (PBMC-) derived endothelial progenitor cells (EPCs). Methods. Angiographic grades (0: <5%; 1: 5–35%; 2: 35–75%; 3: >75%) which presented the improvement of vessel density pre- and post-CD34+ treatment were given to 30 patients with end-stage diffuse coronary artery disease having received CD34+ cell treatment. The patients were categorized into low-score group (angiographic grade 0 or 1, n=12) and high-score group (angiographic grade 2 or 3, n=18). The percentages of circulating EPCs with KDR+/CD34+/CD45−, CD133+/CD34+/CD45−, and CD34+ were determined in each patient using flow cytometry. PBMC-derived EPCs from all patients were subjected to DIVAA through a 14-day implantation in nude mice. The DIVAA ratio (i.e., mean fluorescent units in angioreactors with EPCs/mean fluorescent units in angioreactors without EPCs) was obtained for each animal with implanted EPCs from each patient. Results and Conclusions. The number of EPCs showed no significant difference among the two groups. The DIVAA ratio in the high-score group was significantly higher than that in the low-score group (p=0.0178). Logistic regression revealed a significant association between the DIVAA ratio and angiographic grading (OR 3.12, 95% CI: 1.14–8.55, p=0.027). The area under the ROC curve (AUC) was 0.8519 (p=0.0013). We proposed that DIVAA may be a reliable tool for assessing coronary vascularization after CD34+ cell treatment.

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VITAMIN B12 AND FOLIC ACID VALUES IN PREMATURE INFANTS

PEDIATRICS ◽

10.1542/peds.50.4.584 ◽

1972 ◽

Vol 50 (4) ◽

pp. 584-589

Author(s):

Ambadas Pathak ◽

Herman A. Godwin ◽

Luis M. Prudent

Keyword(s):

Folic Acid ◽

Vitamin B12 ◽

Premature Infants ◽

Serum Vitamin ◽

Serum Folate ◽

Born Infant ◽

Low Concentrations ◽

Folate And Vitamin B12 ◽

Relationship Of ◽

The Relationship

The relationship of serum vitamin B12 and folic acid was studied in 24 premature infants. In 14 of the 24, low serum vitamin B12 values were found around 40 days of age. Serum folic acid concentrations were less frequently depressed and were usually associated with normal red cell folate values. No correlation between hematocrits and vitamin B12 or folate levels was found. It is suggested that low concentrations of serum folate and vitamin B12 result from low dietary intake coupled with increased demand by the prematurely born infant.

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Plasma homocysteine and aminothiol levels in idiopathic epilepsy patients receiving antiepileptic drugs

Turkish Journal of Biochemistry ◽

10.1515/tjb-2018-0218 ◽

2019 ◽

Vol 44 (5) ◽

pp. 661-666

Author(s):

Dilber Çoban Ramazan ◽

Ülker Anadol ◽

A. Destina Yalçın ◽

A. Süha Yalçın

Keyword(s):

Valproic Acid ◽

Folic Acid ◽

Vitamin B12 ◽

Antiepileptic Drug ◽

Antiepileptic Drugs ◽

Serum Vitamin ◽

Idiopathic Epilepsy ◽

Serum Folate ◽

Significant Difference ◽

Epileptic Patients

Abstract Objective Homocysteine is a sulfur containing amino acid that is formed during methionine metabolism. Patients under long-term antiepileptic drug treatment often have hyperhomocysteinemia. These patients have low levels of serum folate, vitamin B12 and vitamin B6, all of which are associated with homocysteine metabolism. We have investigated the effects of valproic acid and new generation antiepileptic drugs (lamotrigine and levetiracetam) on plasma levels of homocysteine and aminothiols as well as serum vitamin B12 and folic acid. Materials and methods Forty-seven idiopathic epileptic patients on antiepileptic drugs were compared with 38 age-matched healthy controls. Commercial immunoassay methods were used for vitamin B12 and folic acid analyses. Homocysteine, cysteine, cysteinylglycine and glutathione levels were determined by high performance liquid chromatography. Results There was no significant difference in patient and control values in terms of vitamin B12, folic acid and homocysteine. Valproic acid and lamotrigine seemed to effect aminothiol redox status. Glutathione levels of epileptic patients receiving valproic acid and lamotrigine were higher than controls. Conclusion Our results suggest that redox homeostasis may be impaired and glutathione synthesis increased in response to the oxidative stress caused by antiepileptic drug use.

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Folate: In Vitro and in Vivo Effects on VLDL and LDL Oxidation

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.77.1.66 ◽

2007 ◽

Vol 77 (1) ◽

pp. 66-72 ◽

Cited By ~ 7

Author(s):

McEneny ◽

Couston ◽

McKibben ◽

Young ◽

Woodside

Keyword(s):

Folic Acid ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Folic Acid Supplementation ◽

Serum Folate ◽

Ldl Oxidation ◽

Low Density ◽

Acid Supplementation

Raised total homocysteine (tHcy) levels may be involved in the etiology of cardiovascular disease and can lead to damage of vascular endothelial cells and arterial wall matrix. Folic acid supplementation can help negate these detrimental effects by reducing tHcy. Recent evidence has suggested an additional anti-atherogenic property of folate in protecting lipoproteins against oxidation. This study utilized both an in vitro and in vivo approach. In vitro: Very-low-density lipoprotein (VLDL) and low density lipoprotein (LDL) were isolated by rapid ultracentrifugation and then oxidized in the presence of increasing concentrations (0→ μmol/L) of either folic acid or 5-methyltetrahydrofolate (5-MTHF). In vivo: Twelve female subjects were supplemented with folic acid (1 mg/day), and the pre- and post-VLDL and LDL isolates subjected to oxidation. In vitro: 5-MTHF, but not folic acid, significantly increased the resistance of VLDL and LDL to oxidation. In vivo: Following folic acid supplementation, tHcy decreased, serum folate increased, and both VLDL and LDL displayed a significant increase in their resistance to oxidation. These results indicated that in vitro, only the active form of folate, 5-MTHF, had antioxidant properties. In vivo results demonstrated that folic acid supplementation reduced tHcy and protected both VLDL and LDL against oxidation. These findings provide further support for the use of folic acid supplements to aid in the prevention of atherosclerosis.

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Oxidative stress and platelet activation in subjects with moderate hyperhomocysteinaemia due to MTHFR 677 C→T polymorphism

Thrombosis and Haemostasis ◽

10.1160/th11-12-0899 ◽

2012 ◽

Vol 108 (09) ◽

pp. 533-542 ◽

Cited By ~ 14

Author(s):

Alfredo Dragani ◽

Angela Falco ◽

Francesca Santilli ◽

Stefania Basili ◽

Giancarlo Rolandi ◽

...

Keyword(s):

Lipid Peroxidation ◽

Folic Acid ◽

Platelet Activation ◽

Methylenetetrahydrofolate Reductase ◽

Folic Acid Supplementation ◽

Control Group ◽

Loading Test ◽

Study Objective ◽

Acid Supplementation

SummaryThe methylenetetrahydrofolate reductase (MTHFR) 677 C→T polymorphism may be associated with elevated total homocysteine (tHcy) levels, an independent risk factor for cardiovascular disease. It was the study objective to evaluate in vivo lipid peroxidation and platelet activation in carriers of the MTHFR 677 C→T polymorphism and in non-carriers, in relation to tHcy and folate levels. A cross-sectional comparison of urinary 8-iso-prostaglandin (PG)F2α and 11-dehydro-thromboxane (TX)B2 (markers of in vivo lipid peroxidation and platelet activation, respectively) was performed in 100 carriers and 100 non-carriers of the polymorphism. A methionine-loading test and folic acid supplementation were performed to investigate the causal relationship of the observed associations. Urinary 8-iso-PGF2α and 11-dehydro-TXB2 were higher in carriers with hyperhomocysteinaemia than in those without hyperhomocysteinaemia (p<0.0001). Hyperhomocysteinaemic carriers had lower folate levels (p=0.0006), higher urinary 8-iso-PGF2α (p<0.0001) and 11-dehydro-TXB2 (p<0.0001) than hyperhomocysteinaemic non-carriers. On multiple regression analysis, high tHcy (p<0.0001), low folate (p<0.04) and MTHFR 677 C→T polymorphism (p<0.001) independently predicted high rates of 8-iso-PGF2α excretion. Methionine loading increased plasma tHcy (p=0.002), and both urinary prostanoid metabolites (p=0.002). Folic acid supplementation was associated with decreased urinary 8-iso-PGF2α and 11-dehydro-TXB2 excretion (p<0.0003) in the hyperhomocysteinaemic group, but not in the control group, with substantial inter-individual variability related to baseline tHcy level and the extent of its reduction. In conclusion, hyperhomocysteinaemia due to the MTHFR 677 C→T polymorphism is associated with enhanced in vivo lipid peroxidation and platelet activation that are reversible, at least in part, following folic acid supplementation. An integrated biomarker approach may help identifying appropriate candidates for effective folate supplementation.

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Quantitative assessment of choriocapillaris flow deficits in diabetic retinopathy: A swept-source optical coherence tomography angiography study

PLoS ONE ◽

10.1371/journal.pone.0243830 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0243830

Author(s):

Yining Dai ◽

Hao Zhou ◽

Qinqin Zhang ◽

Zhongdi Chu ◽

Lisa C. Olmos de Koo ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Diabetic Retinopathy ◽

Healthy Subjects ◽

Optical Coherence Tomography Angiography ◽

Optical Coherence ◽

Swept Source ◽

Significant Difference ◽

En Face ◽

The Mean

Purpose To quantitatively assess choriocapillaris (CC) flow deficits in eyes with diabetic retinopathy (DR) using swept-source optical coherence tomography angiography (SS-OCTA). Methods Diabetic subjects with different stages of DR and age-matched healthy subjects were recruited and imaged with SS-OCTA. The en face CC blood flow images were generated using previously published and validated algorithms. The percentage of CC flow deficits (FD%) and the mean CC flow deficit size were calculated in a 5-mm-diameter circle centered on the fovea from the 6×6-mm scans. Results Forty-five diabetic subjects and 27 control subjects were included in the study. The CC FD% in diabetic eyes was on average 1.4-fold greater than in control eyes (12.34±4.14% vs 8.82±2.61%, P < 0.001). The mean CC FD size in diabetic eyes was on average 1.4-fold larger than in control eyes (2151.3± 650.8μm2 vs 1574.4±255.0 μm2, P < 0.001). No significant difference in CC FD% or mean CC FD size was observed between eyes with nonproliferative DR and eyes with proliferative DR (P = 1.000 and P = 1.000, respectively). Conclusions CC perfusion in DR can be objectively and quantitatively assessed with FD% and FD size. In the macular region, both CC FD% and CC FD size are increased in eyes with DR. SS-OCTA provides new insights for the investigations of CC perfusion status in diabetes in vivo.

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Low Levels of MicroRNA-10a in Cardiovascular Endothelium and Blood Serum Are Related to Human Atherosclerotic Disease

Cardiology Research and Practice ◽

10.1155/2021/1452917 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Jong-Tar Kuo ◽

Hsiao-En Tsai ◽

Ching-Ting Lin ◽

Chih-I Lee ◽

Pei-Ling Lee ◽

...

Keyword(s):

Coronary Arteries ◽

Healthy Subjects ◽

Expression Patterns ◽

Human Coronary Artery ◽

Downstream Target ◽

Atherosclerotic Lesions ◽

Human Atherosclerosis ◽

Artery Disease ◽

Human Coronary Artery Disease

Background. MicroRNA-10a (miR-10a) inhibits transcriptional factor GATA6 to repress inflammatory GATA6/VCAM-1 signaling, which is regulated by blood flow to affect endothelial function/dysfunction. This study aimed to identify the expression patterns of miR-10a/GATA6/VCAM-1 in vivo and study their implications in the pathophysiology of human coronary artery disease (CAD), i.e., atherosclerosis. Methods. Human atherosclerotic coronary arteries and nondiseased arteries were used to detect the expressions of miR-10a/GATA6/VCAM-1 in pathogenic vs. normal conditions. In addition, sera from CAD patients and healthy subjects were collected to detect the level of circulating miR-10a. Results. The comparison of human atherosclerotic coronary arteries with nondiseased arteries demonstrated that lower levels of endothelial miR-10a are related to human atherogenesis. Moreover, GATA6/VCAM-1 (a downstream target of miR-10a) was highly expressed in the endothelium, accompanied by the reduced levels of miR-10a during the development of human atherosclerosis. In addition, CAD patients had a significantly lower concentration of miR-10a in their serum compared to healthy subjects. Conclusions. Our findings suggest that low miR-10a and high GATA6/VCAM-1 in the cardiovascular endothelium correlates to the development of human atherosclerotic lesions, suggesting that miR-10a signaling has the potential to be developed as a biomarker for human atherosclerosis.

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Observations on the Presence of Pteroyl Polyglutamates in Human Serum

Blood ◽

10.1182/blood.v28.6.913.913 ◽

1966 ◽

Vol 28 (6) ◽

pp. 913-917 ◽

Cited By ~ 4

Author(s):

D. K. BANERJEE ◽

J. B. CHATTERJEA

Keyword(s):

Folic Acid ◽

Normal Level ◽

The Other ◽

Serum Folate ◽

Individual Values ◽

Significant Difference ◽

Pteroic Acid ◽

The Individual ◽

Derivatives Of ◽

Chicken Pancreas

Abstract Treatment of serum with folic acid conjugase obtained from fresh chicken pancreas indicated the presence therein of polyglutamyl derivatives of pteroic acid. The polyglutamyl derivatives appeared to belong to a group higher than the triglutamate. Two groups of subjects, one with normal level and the other with low level of unconjugated folate, were studied. In the normal group, the level of unconjugated serum folate varied between 3.2 and 18.0 ng./ml., while that of total folate (unconjugated plus conjugated) varied between 14.0 and 47.0 ng./ml. In the other group, the level of unconjugated folate varied from 2.0 to 2.6 ng./ ml., while that of total folate varied from 14.5 to 31.0 ng./ml. No significant difference, either in the individual values or in their means, was noticed in the two groups of subjects.

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