Decreased Plasma Homocysteine Levels Research Articles

Homocysteine Levels and Cardiovascular Risk: Potential Predictor of Morbidity and Mortality

Based on the results of this type of studies, studies aimed at counteracting hyperhomocysteinemia with vitamin B6, vitamin B12 and folate have been postulated, to assess the impact of this intervention on the process of atherosclerosis and decreased plasma homocysteine levels, finding favorable results in murine knockout models.

Stable clinical course in three siblings with late-onset isolated sulfite oxidase deficiency: a case series and literature review

BackgroundIsolated sulfite oxidase deficiency (ISOD) is an autosomal recessive disorder caused by a deficiency of sulfite oxidase, which is encoded by the sulfite oxidase gene (SUOX). Clinically, the disorder is classified as one of two forms: the late-onset mild form or the classic early-onset form. The latter is life-threatening and always leads to death during early childhood. Mild ISOD cases are rare and may benefit from dietary therapy. To date, no cases of ISOD have been reported to recover spontaneously. Here, we present three mild ISOD cases in one family, each with a stable clinical course and spontaneous recovery.Case presentationAll three siblings had two novel compound heterozygous mutations in the SUOX gene (NM_000456; c.1096C > T [p.R366C] and c.1376G > A [p.R459Q]). The siblings included two males and one female with late ages of onset (12–16 months) and presented with specific neuroimaging abnormalities limited to the bilateral globus pallidus and substantia nigra. The three patients had decreased plasma homocysteine levels. They exhibited a monophasic clinical course continuing up to 8.5 years even without dietary therapy.ConclusionThis is the first report of mild ISOD cases with a stable clinical course and spontaneous recovery without dietary therapy. Our study provides an expansion for the clinical spectrum of ISOD. Furthermore, we highlight the importance of including ISOD in the differential diagnosis for patients presenting with late-onset symptoms, bilaterally symmetric regions of abnormal intensities in the basal ganglia, and decreased plasma homocysteine levels.

Влияние витаминов группы В на раннее развитие крысят с пренатальной гипергомоцистеинемией

High plasma homocysteine levels - hyperhomocysteinemia (hHCy), are considered as an independent risk factor for early abortion of pregnancy, placental abruption, preeclampsia, and other complications. One of the factors of hHCy development is a deficiency of vitamins B. At the same time, both deficiency and excess of B vitamins can induce neurotoxic effects and oxidative stress. The aim of our work was to analyze the treatment of rats with hHCy with vitamins B during pregnancy on the early development and glutathione level in plasma of the offspring. In the offspring of rats with hHCy we observed high mortality, reduced body weight, increased concentrations of homocysteine and reduced glutathione level in plasma, and a delay in the development of sensory-motor reflexes and different types of behavior analyzed in the Open Field and Rotarod tests. Administration of vitamins B (B6,9,12) to pregnant rats with hHCy led to lower mortality and higher body weight of the offspring, increased level of glutathione, and partial prevention of sensory-motor deficit of the offspring. At the same time, we observed decreased plasma homocysteine levels, which, however, did not reach the control values. Positive effects of vitamins B on the level of anxiety and muscle strength of animals with prenatal hHCy were observed. However, the horizontal motor activity, rearing, motor balance were not restored. Thus, despite positive effects of vitamins B therapy on the physical development and the formation of sensory-motor reflexes, the impairments of motor coordination in complex behavior acts were not prevented, which may be explained by the fact that plasma homocysteine levels were not restored to the control values and/or the inability of the B vitamins completely neutralize the consequences of chronic hHCy.

Evidence for interactions between homocysteine and genistein: insights into stroke risk and potential treatment.

Elevated plasma homocysteine (2-amino-4-sulfanylbutanoic acid) level is a risk factor for stroke. Moreover, it has been suggested that high levels of homocysteine in the acute phase of an ischemic stroke can predict mortality, especially in stroke patients with the large-vessel atherosclerosis subtype. In clinical studies, supplementation with genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) decreased plasma homocysteine levels considerably. Therefore, genistein could be considered as a potential drug for prevention and/or treatment of stroke. However, the mechanism of the effect of genistein on homocysteine level remains to be elucidated. In this report, direct functional interactions between homocysteine and genistein are demonstrated in in vitro experimental systems for determination of methylenetetrahydrofolate reductase (MetF) and glutathione peroxidase (GPx) activities, reconstructed with purified compounds, and in a simple in vivo system, based on measurement of growth rate of Vibrio harveyi and Bacillus subtilis cultures. Results of molecular modelling indicated that homocysteine can directly interact with genistein. Therefore, genistein-mediated decrease in plasma levels of homocysteine, and alleviation of biochemical and physiological effects of one of these compounds by another, might be ascribed to formation of homocysteine-genistein complexes in which biological activities of these molecules are abolished or alleviated.

Folic acid attenuates homocysteine and enhances antioxidative capacity in atherosclerotic rats.

Atherosclerosis is a chronic disease that can seriously endanger human life. Folic acid supplementation modulates several disorders, including atherosclerosis, via its antiapoptotic and antioxidative properties. This study investigated whether folic acid alleviates atherogenesis by restoring homocysteine levels and antioxidative capacity in atherosclerosis Wistar rats. To this end, 28 Wistar rats were randomly divided into 4 groups (7 rats/group) as follows: (i) wild-type group, fed only the AIN-93 semi-purified rodent diet (folic acid: 2.1 mg/kg); (ii) high-fat + folic acid-deficient group (HF+DEF) (folic acid: 0.2 mg/kg); (iii) high-fat + normal folic acid group (folic acid: 2.1 mg/kg); and (iv) high-fat + folic acid-supplemented group (folic acid: 4.2 mg/kg). After 12 weeks, histopathological changes in the atherosclerotic lesions of the aortic arch were determined. In addition, serum folate levels, plasma homocysteine levels, plasma S-adenosyl-homocysteine levels, antioxidant status, oxidant status, and lipid profiles were evaluated. The results show aggravated atherosclerotic lesions in the HF+DEF group. Folic acid supplementation increased concentrations of serum folate. Further, folic acid supplementation increased high-density lipoprotein-cholesterol, decreased plasma homocysteine levels, and improved antioxidant capacity in atherogenic rats. These findings are consistent with the hypothesis that folic acid alleviates atherogenesis by reducing plasma homocysteine levels and improving antioxidant capacity in rats fed a high-fat diet.

Effect of arginine:lysine and glycine:methionine intake ratios on dyslipidemia and selected biomarkers implicated in cardiovascular disease: A study with hypercholesterolemic rats.

The effect of intake ratios of arginine (Arg): lysine (Lys) and glycine (Gly): methionine (Met) on lipid profile and selected cardiovascular disease markers, was studied, in rats maintained on a hypercholesterolemic diet. The rise in blood cholesterol was countered by 32%, 24%, and 49%, respectively, through increased oral supplementation of Arg, Gly, and Arg+Gly; a corresponding increase in plasma phospholipids at the end of the 8-week study was observed. The elevated plasma cholesterol to phospholipids ratio was countered by 27, 40, and 57%, respectively, through oral supplementation of Arg, Gly, and Arg+Gly. The elevation in hepatic cholesterol was lowered by 18, 29, and 51%, respectively, while phospholipids concentration was concomitantly increased by these amino acids. The elevated cholesterol to phospholipids ratio was, thus, significantly countered in the hypercholesterolemic situation by orally supplemented Arg, Gly, and Arg+Gly. Increased plasma asymmetric dimethylarginine (ADMA) levels, under hypercholesterolemic conditions, were lowered by 12, 15 and 34%, respectively, while plasma symmetric dimethylarginine (SDMA) levels were lowered by 14, 10 and 17%, respectively, with orally supplemented Arg, Gly and Arg+Gly. Only Gly and Arg+Gly decreased plasma homocysteine levels. Total nitric oxide (NO) concentration was considerably increased by Gly supplementation in hypercholesterolemic rats. Thus, altered ratios of Arg:Lys or Gly:Met offered beneficial influence on the lipid profile and plasma levels of ADMA, SDMA and homocysteine in hypercholesterolemic rats. Optimal beneficial effects, among ratios tested, was observed when Arg:Lys and Gly:Met ratios were maintained in ratios of 1:1 and 2:1, respectively.

Sulfur amino acid metabolism in Zucker diabetic fatty rats

The present study was aimed to investigate the metabolomics of sulfur amino acids in Zucker diabetic fatty (ZDF) rats, an obese type 2 diabetic animal model. Plasma levels of total cysteine, homocysteine and methionine, but not glutathione (GSH) were markedly decreased in ZDF rats. Hepatic methionine, homocysteine, cysteine, betaine, taurine, spermidine and spermine were also decreased. There are no significant difference in hepatic S-adenosylmethionine, S-adenosylhomocysteine, GSH, GSH disulfide, hypotaurine and putrescine between control and ZDF rats. Hepatic SAH hydrolase, betaine-homocysteine methyltransferase and methylene tetrahydrofolate reductase were up-regulated while activities of gamma-glutamylcysteine ligase and methionine synthase were decreased. The area under the curve (AUC) of methionine and methionine-d4 was not significantly different in control and ZDF rats treated with a mixture of methionine (60mg/kg) and methionine-d4 (20mg/kg). Moreover, the AUC of the increase in plasma total homocysteine was comparable between two groups, although the homocysteine concentration curve was shifted leftward in ZDF rats, suggesting that the plasma total homocysteine after the methionine loading was rapidly increased and normalized in ZDF rats. These results show that the AUC of plasma homocysteine is not responsive to the up-regulation of hepatic BHMT in ZDF rats. The present study suggests that the decrease in hepatic methionine may be responsible for the decreases in its metabolites, such as homocysteine, cysteine, and taurine in liver and consequently decreased plasma homocysteine levels.

Hepatocyte-specific Dyrk1a gene transfer rescues plasma apolipoprotein A-I levels and aortic Akt/GSK3 pathways in hyperhomocysteinemic mice

Hyperhomocysteinemia, characterized by high plasma homocysteine levels, is recognized as an independent risk factor for cardiovascular diseases. The increased synthesis of homocysteine, a product of methionine metabolism involving B vitamins, and its slower intracellular utilization cause increased flux into the blood. Plasma homocysteine level is an important reflection of hepatic methionine metabolism and the rate of processes modified by B vitamins as well as different enzyme activity. Lowering homocysteine might offer therapeutic benefits. However, approximately 50% of hyperhomocysteinemic patients due to cystathionine-beta-synthase deficiency are biochemically responsive to pharmacological doses of B vitamins. Therefore, effective treatments to reduce homocysteine levels are needed, and gene therapy could provide a novel approach. We recently showed that hepatic expression of DYRK1A, a serine/threonine kinase, is negatively correlated with plasma homocysteine levels in cystathionine-beta-synthase deficient mice, a mouse model of hyperhomocysteinemia. Therefore, Dyrk1a is a good candidate for gene therapy to normalize homocysteine levels. We then used an adenoviral construct designed to restrict expression of DYRK1A to hepatocytes, and found decreased plasma homocysteine levels after hepatocyte-specific Dyrk1a gene transfer in hyperhomocysteinemic mice. The elevation of pyridoxal phosphate was consistent with the increase in cystathionine-beta-synthase activity. Commensurate with the decreased plasma homocysteine levels, targeted hepatic expression of DYRK1A resulted in elevated plasma paraoxonase-1 activity and apolipoprotein A-I levels, and rescued the Akt/GSK3 signaling pathways in aorta of mice, which can prevent homocysteine-induced endothelial dysfunction. These results demonstrate that hepatocyte-restricted Dyrk1a gene transfer can offer a useful therapeutic targets for the development of new selective homocysteine lowering therapy.

Effect of folic acid supplementation on hepatic antioxidant function and mitochondrial-related gene expression in weanling intrauterine growth retarded piglets

The aim of the present study was to investigate the effect of dietary folic acid supplementation on antioxidant function and mRNA expression levels of genes involved in mitochondrial biogenesis and function in the liver of piglets affected by intrauterine growth retardation (IUGR). Sixteen piglets at normal birth weight and 16 IUGR piglets were fed either a control diet (C) or a folic acid-supplemented diet (FS, C+5mg/kg folic acid) from 14d of age to 35d of age postnatal. Blood and liver samples were collected at the end of the study. The results showed that body weight was lower for IUGR piglets than that of NBW piglets at 14d of age and 35d of age postnatal (P<0.05). Dietary folic acid supplementation increased plasma folic acid concentrations and hepatic GPx activity, but decreased plasma homocysteine levels (P<0.05). Reduced activities of Mn-SOD and T-AOC, mitochondrial DNA (mtDNA) content, and ATP concentration (P<0.05) were observed in the liver of IUGR pigs fed a control diet. However, the changes in mtDNA content and activities of Mn-SOD and T-AOC were negated in IUGR pigs fed a FS diet (P<0.05). Also, dietary folic acid supplementation decreased protein carbonyls and MDA concentration in the liver of IUGR piglets (P<0.05). Expression levels of genes encoding for PPARγ coactivator-1α (PGC-1α), mammalian silencing information regulator-2α (SIRT-1), nuclear respiratory factor-1 (NRF-1), mt transcription factor A (TFAM), mt single-strand DNA-binding protein (mt SSB), mt polymerase r (mt polr), glucokinase, citrate synthase (CS), ATP synthase (ATPS), and cytochrome c oxidase (CcOX) subunit I and V were decreased in IUGR piglets compared with NBW piglets. However, mRNA levels of PGC-1α, SIRT-1, NRF-1, TFAM, and mt polr in the liver of IUGR pigs fed FS diet were not different from that of NBW pigs. Gene mRNA expression abundance of CcOX IV was enhanced by folic acid supplementation (P<0.05) regardless of birth weight. The present study indicates that IUGR impaired hepatic antioxidant function and mRNA expression levels of genes are involved in mitochondrial biogenesis and function. Dietary folic acid supplementation prevented the harmful effect of IUGR on hepatic antioxidant function and mtDNA biogenesis, but had no effect on mRNA expression levels of genes involved in mitochondrial function.

Preliminary Evidence for Cell Membrane Amelioration in Children with Cystic Fibrosis by 5-MTHF and Vitamin B12 Supplementation: A Single Arm Trial

BackgroundCystic fibrosis (CF) is one of the most common fatal autosomal recessive disorders in the Caucasian population caused by mutations of gene for the cystic fibrosis transmembrane conductance regulator (CFTR). New experimental therapeutic strategies for CF propose a diet supplementation to affect the plasma membrane fluidity and to modulate amplified inflammatory response. The objective of this study was to evaluate the efficacy of 5-methyltetrahydrofolate (5-MTHF) and vitamin B12 supplementation for ameliorating cell plasma membrane features in pediatric patients with cystic fibrosis.Methodology and Principal FindingsA single arm trial was conducted from April 2004 to March 2006 in an Italian CF care centre. 31 children with CF aged from 3 to 8 years old were enrolled. Exclusion criteria were diabetes, chronic infections of the airways and regular antibiotics intake. Children with CF were supplemented for 24 weeks with 5-methyltetrahydrofolate (5-MTHF, 7.5 mg /day) and vitamin B12 (0.5 mg/day). Red blood cells (RBCs) were used to investigate plasma membrane, since RBCs share lipid, protein composition and organization with other cell types. We evaluated RBCs membrane lipid composition, membrane protein oxidative damage, cation content, cation transport pathways, plasma and RBCs folate levels and plasma homocysteine levels at baseline and after 24 weeks of 5-MTHF and vitamin B12 supplementation. In CF children, 5-MTHF and vitamin B12 supplementation (i) increased plasma and RBC folate levels; (ii) decreased plasma homocysteine levels; (iii) modified RBC membrane phospholipid fatty acid composition; (iv) increased RBC K+ content; (v) reduced RBC membrane oxidative damage and HSP70 membrane association.Conclusion and Significance5-MTHF and vitamin B12 supplementation might ameliorate RBC membrane features of children with CF.Trial RegistrationClinicalTrials.gov NCT00730509

Effects of Hormone Replacement Therapy on Plasma Homocysteine and C-Reactive Protein Levels

In order to investigate the effect of hormone replacement therapy (HRT) on plasma homocysteine and C-reactive protein (CRP) levels 46 healthy postmenopausal women were prospectively enrolled. HRT, which was either 0.625 mg/day conjugated equine estrogen (CEE) plus 2.5 mg/day medroxyprogesterone acetate (MPA) or 0.625 mg/day CEE alone were administered. After 6 months, estrogen alone significantly increased serum CRP concentrations (p = 0.039), however, estrogen plus progesterone therapy did not significantly alter serum CRP levels. Both regimens significantly decreased plasma homocysteine levels (CEE group p = 0.034, CEE+MPA group p = 0.007). It was concluded that the reduction in plasma homocysteine levels with both regimens might contribute to the cardiovascular benefit of HRT and the CRP raising effect of estrogen might be partially prevented by the addition of progesterone.