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Sample records for homocysteine induces hypophosphorylation

  1. High homocysteine induces betaine depletion.

    PubMed

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J

    2015-04-28

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

  2. Diphenyl ditelluride induces hypophosphorylation of intermediate filaments through modulation of DARPP-32-dependent pathways in cerebral cortex of young rats.

    PubMed

    Heimfarth, Luana; Loureiro, Samanta Oliveira; Reis, Karina Pires; de Lima, Bárbara Ortiz; Zamboni, Fernanda; Lacerda, Sabrina; Soska, Angela Kronbauer; Wild, Luisa; da Rocha, João Batista Teixeira; Pessoa-Pureur, Regina

    2012-02-01

    We studied the effect of different concentrations of diphenyl ditelluride (PhTe)(2) on the in vitro phosphorylation of glial fibrillary acidic protein (GFAP) and neurofilament (NF) subunits from cerebral cortex and hippocampus of rats during development. (PhTe)(2)-induced hypophosphorylation of GFAP and NF subunits only in cerebral cortex of 9- and 15-day-old animals but not in hippocampus. Hypophosphorylation was dependent on ionotropic glutamate receptors, as demonstrated by the specific inhibitors 10 μM DL-AP5 and 50 μM MK801, 100 μM CNQX and 100 μM DNQX. Also, 10 μM verapamil and 10 μM nifedipine, two L-voltage-dependent Ca(2+) channels (L-VDCC) blockers; 50 μM dantrolene, a ryanodine channel blocker, and the intracellular Ca(2+) chelator Bapta-AM (50 μM) totally prevented this effect. Results obtained with 0.2 μM calyculin A (PP1 and PP2A inhibitor), 1 μM Fostriecin a potent protein phosphatase 2A (PP2A) inhibitor, 100 μM FK-506 or 100 μM cyclosporine A, specific protein phosphatase 2B inhibitors, pointed to PP1 as the protein phosphatase directly involved in the hypophosphorylating effect of (PhTe)(2). Finally, we examined the activity of DARPP-32, an important endogenous Ca(2+)-mediated inhibitor of PP1 activity. Western blot assay using anti-DARPP-32, anti-pThr34DARPP-32, and anti-pThr75DARPP-32 antibodies showed a decreased phosphorylation level of the inhibitor at Thr34, compatible with inactivation of protein kinase A (PKA) by pThr75 DARPP-32. Decreased cAMP and catalytic subunit of PKA support that (PhTe)(2) acted on neuron and astrocyte cytoskeletal proteins through PKA-mediated inactivation of DARPP-32, promoting PP1 release and hypophosphorylation of IF proteins of those neural cells. Moreover, in the presence of Bapta, the level of the PKA catalytic subunit was not decreased by (PhTe)(2), suggesting that intracellular Ca(2+) levels could be upstream the signaling pathway elicited by this neurotoxicant and targeting the

  3. Inhibition of homocysteine-induced endoplasmic reticulum stress and endothelial cell damage by l-serine and glycine.

    PubMed

    Sim, Woo-Cheol; Han, Inhoi; Lee, Wonseok; Choi, You-Jin; Lee, Kang-Yo; Kim, Dong Gwang; Jung, Seung-Hwan; Oh, Seon-Hee; Lee, Byung-Hoon

    2016-08-01

    Hyperhomocysteinemia is an independent risk factor for several cardiovascular diseases. The use of vitamins to modulate homocysteine metabolism substantially lowers the risk by reducing plasma homocysteine levels. In this study, we evaluated the effects of l-serine and related amino acids on homocysteine-induced endoplasmic reticulum (ER) stress and endothelial cell damage using EA.hy926 human endothelial cells. Homocysteine treatment decreased cell viability and increased apoptosis, which were reversed by cotreatment with l-serine. l-Serine inhibited homocysteine-induced ER stress as verified by decreased glucose-regulated protein 78kDa (GRP78) and C/EBP homologous protein (CHOP) expression as well as X-box binding protein 1 (xbp1) mRNA splicing. The effects of l-serine on homocysteine-induced ER stress are not attributed to intracellular homocysteine metabolism, but instead to decreased homocysteine uptake. Glycine exerted effects on homocysteine-induced ER stress, apoptosis, and cell viability that were comparable to those of l-serine. Although glycine did not affect homocysteine uptake or export, coincubation of homocysteine with glycine for 24h reduced the intracellular concentration of homocysteine. Taken together, l-serine and glycine cause homocysteine-induced endothelial cell damage by reducing the level of intracellular homocysteine. l-Serine acts by competitively inhibiting homocysteine uptake in the cells. However, the mechanism(s) by which glycine lowers homocysteine levels are unclear. PMID:27064126

  4. Inhibition of homocysteine-induced endoplasmic reticulum stress and endothelial cell damage by l-serine and glycine.

    PubMed

    Sim, Woo-Cheol; Han, Inhoi; Lee, Wonseok; Choi, You-Jin; Lee, Kang-Yo; Kim, Dong Gwang; Jung, Seung-Hwan; Oh, Seon-Hee; Lee, Byung-Hoon

    2016-08-01

    Hyperhomocysteinemia is an independent risk factor for several cardiovascular diseases. The use of vitamins to modulate homocysteine metabolism substantially lowers the risk by reducing plasma homocysteine levels. In this study, we evaluated the effects of l-serine and related amino acids on homocysteine-induced endoplasmic reticulum (ER) stress and endothelial cell damage using EA.hy926 human endothelial cells. Homocysteine treatment decreased cell viability and increased apoptosis, which were reversed by cotreatment with l-serine. l-Serine inhibited homocysteine-induced ER stress as verified by decreased glucose-regulated protein 78kDa (GRP78) and C/EBP homologous protein (CHOP) expression as well as X-box binding protein 1 (xbp1) mRNA splicing. The effects of l-serine on homocysteine-induced ER stress are not attributed to intracellular homocysteine metabolism, but instead to decreased homocysteine uptake. Glycine exerted effects on homocysteine-induced ER stress, apoptosis, and cell viability that were comparable to those of l-serine. Although glycine did not affect homocysteine uptake or export, coincubation of homocysteine with glycine for 24h reduced the intracellular concentration of homocysteine. Taken together, l-serine and glycine cause homocysteine-induced endothelial cell damage by reducing the level of intracellular homocysteine. l-Serine acts by competitively inhibiting homocysteine uptake in the cells. However, the mechanism(s) by which glycine lowers homocysteine levels are unclear.

  5. Turkish propolis supresses MCF-7 cell death induced by homocysteine.

    PubMed

    Tartik, Musa; Darendelioglu, Ekrem; Aykutoglu, Gurkan; Baydas, Giyasettin

    2016-08-01

    Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway. PMID:27470414

  6. Sensitivity of staurosporine-induced differentiated RGC-5 cells to homocysteine

    PubMed Central

    Ganapathy, Preethi S.; Dun, Ying; Ha, Yonju; Duplantier, Jennifer; Allen, John Bradley; Farooq, Amina; Bozard, B. Renee; Smith, Sylvia B.

    2011-01-01

    PURPOSE Homocysteine is implicated in ganglion cell death associated with glaucoma. To understand mechanisms of homocysteine-induced cell death, we analyzed the sensitivity of the RGC-5 cell line, differentiated using staurosporine, to physiologically-relevant levels of the excitotoxic amino acid homocysteine. METHODS RGC-5 cells were differentiated 24 h using 316 nM staurosporine and tested for expression of Thy 1.2 via immunodetection, RT-PCR and immunoblotting. The sensitivity of staurosporine-differentiated RGC-5 cells to physiological levels of homocysteine (50, 100, 250 µM) and to high levels of homocysteine (1 mM), glutamate (1 mM) and oxidative stress (25 µM:10 mU/ml xanthine:xanthine oxidase) was assessed by TUNEL assay and by immunodetection of cleaved caspase-3. The sensitivity of undifferentiated RGC-5 cells to high (1, 5, and 10 mM) homocysteine was also examined. RESULTS Undifferentiated RGC-5 cells express Thy 1.2 mRNA and protein. Staurosporine-differentiated RGC-5 cells extend neurite processes and express Thy 1.2 after 24 h differentiation; they express NF-L after 1 and 3 days differentiation. Treatment of staurosporine-differentiated RGC-5 cells with 50, 100 or 250µM homocysteine did not alter neurite processes nor induce cell death (detected by TUNEL and active caspase-3) to a level greater than that observed in non-homocysteine-treated, staurosporine-differentiated cells. The 1 mM dosage of homocysteine in staurosporine-differentiated RGC-5 cells also did not induce cell death above control levels, although 18 h treatment of non-differentiated RGC-5 cells with 5 mM homocysteine decreased survival by 50%. CONCLUSIONS RGC-5 cells differentiated for 24 h with 316 nM staurosporine project robust neurite processes and are positive for ganglion cell markers consistent with a more neuronal phenotype than non- staurosporine-differentiated RGC-5 cells. However, concentrations of homocysteine known to induce ganglion cell death in vivo and in primary

  7. NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice

    PubMed Central

    Murray, Thomas V.A.; Dong, Xuebin; Sawyer, Greta J.; Caldwell, Anna; Halket, John; Sherwood, Roy; Quaglia, Alberto; Dew, Tracy; Anilkumar, Narayana; Burr, Simon; Mistry, Rajesh K.; Martin, Daniel; Schröder, Katrin; Brandes, Ralf P.; Hughes, Robin D.; Shah, Ajay M.; Brewer, Alison C.

    2015-01-01

    Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins. PMID:26472193

  8. Existence of molten globule state in homocysteine-induced protein covalent modifications.

    PubMed

    Kumar, Tarun; Sharma, Gurumayum Suraj; Singh, Laishram Rajendrakumar

    2014-01-01

    Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state--an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity. PMID:25405350

  9. Salidroside Improves Homocysteine-Induced Endothelial Dysfunction by Reducing Oxidative Stress

    PubMed Central

    Leung, Sin Bond; Zhang, Huina; Lau, Chi Wai; Huang, Yu; Lin, Zhixiu

    2013-01-01

    Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS) level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO) bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction. PMID:23589720

  10. Salidroside improves homocysteine-induced endothelial dysfunction by reducing oxidative stress.

    PubMed

    Leung, Sin Bond; Zhang, Huina; Lau, Chi Wai; Huang, Yu; Lin, Zhixiu

    2013-01-01

    Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS) level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO) bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction. PMID:23589720

  11. Homocysteine Induces Heme Oxygenase-1 Expression via Transcription Factor Nrf2 Activation in HepG2 Cells

    PubMed Central

    Mani, Monireh; Golmohammadi, Taghi; Khaghani, Shahnaz; Zamani, Zahra; Azadmanesh, Kayhan; Meshkani, Reza; Pasalar, Parvin

    2013-01-01

    Background: Elevated level of plasma homocysteine has been related to various diseases. Patients with hyperhomocysteinemia can develop hepatic steatosis and fibrosis. We hypothesized that oxidative stress induced by homocysteine might play an important role in pathogenesis of liver injury. Also, the cellular response designed to combat oxidative stress is primarily controlled by the transcription factor Nrf2, a principal inducer of anti-oxidant and phase II-related genes. Methods: HepG2 cells were treated with homocysteine in different time periods. Glutathione content was measured by flowcytometry. Using electrophoretic mobility shift assay (EMSA) and Western-blotting, anti-oxidant response element (ARE)-binding activity of Nrf2 for heme ocygenase-1 (HO-1) was demonstrated. Real time RT-PCR and Western-blotting were performed to evaluate whether homocysteine was able to induce mRNA and protein expression of HO-1. Results: The role of Nrf2 in cellular response to homocysteine is substantiated by the following observations in HepG2 cells exposed to homocysteine (i) Western-blotting revealed that Nrf2 is strongly stabilized and became detectable in nuclear extracts. (ii) EMSA demonstrated increased binding of Nrf2 to oligomers containing HO-1 promoter-specific ARE-binding site. (iii) Real time RT-PCR and Western-blotting revealed increased mRNA and protein expression of inducible gene HO-1 after treatment with homocysteine. Conclusion: Data presented in the current study provide direct evidence that the immediate cellular response to oxidative stress provoked by homocysteine is orchestrated mainly by the Nrf2-ARE pathway. Therefore, induction of Nrf2-ARE-dependent expression of HO-1 could be a therapeutic option for hepatic cells damage induced by homocysteine. PMID:23567851

  12. Dysregulated Hepatic Methionine Metabolism Drives Homocysteine Elevation in Diet-Induced Nonalcoholic Fatty Liver Disease.

    PubMed

    Pacana, Tommy; Cazanave, Sophie; Verdianelli, Aurora; Patel, Vaishali; Min, Hae-Ki; Mirshahi, Faridoddin; Quinlivan, Eoin; Sanyal, Arun J

    2015-01-01

    Methionine metabolism plays a central role in methylation reactions, production of glutathione and methylarginines, and modulating homocysteine levels. The mechanisms by which these are affected in NAFLD are not fully understood. The aim is to perform a metabolomic, molecular and epigenetic analyses of hepatic methionine metabolism in diet-induced NAFLD. Female 129S1/SvlmJ;C57Bl/6J mice were fed a chow (n = 6) or high-fat high-cholesterol (HFHC) diet (n = 8) for 52 weeks. Metabolomic study, enzymatic expression and DNA methylation analyses were performed. HFHC diet led to weight gain, marked steatosis and extensive fibrosis. In the methionine cycle, hepatic methionine was depleted (30%, p< 0.01) while s-adenosylmethionine (SAM)/methionine ratio (p< 0.05), s-adenosylhomocysteine (SAH) (35%, p< 0.01) and homocysteine (25%, p< 0.01) were increased significantly. SAH hydrolase protein levels decreased significantly (p <0.01). Serine, a substrate for both homocysteine remethylation and transsulfuration, was depleted (45%, p< 0.01). In the transsulfuration pathway, cystathionine and cysteine trended upward while glutathione decreased significantly (p< 0.05). In the transmethylation pathway, levels of glycine N-methyltransferase (GNMT), the most abundant methyltransferase in the liver, decreased. The phosphatidylcholine (PC)/ phosphatidylethanolamine (PE) ratio increased significantly (p< 0.01), indicative of increased phosphatidylethanolamine methyltransferase (PEMT) activity. The protein levels of protein arginine methytransferase 1 (PRMT1) increased significantly, but its products, monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), decreased significantly. Circulating ADMA increased and approached significance (p< 0.06). Protein expression of methionine adenosyltransferase 1A, cystathionine β-synthase, γ-glutamylcysteine synthetase, betaine-homocysteine methyltransferase, and methionine synthase remained unchanged. Although gene expression of the DNA

  13. Overexpression of Hypo-Phosphorylated IκBβ at Ser313 Protects the Heart against Sepsis

    PubMed Central

    Liu, Ying-Ying; Wang, Li; Luo, Peng-Fei; Xia, Zhao-Fan

    2016-01-01

    IκBβis an inhibitor of nuclear factor kappa B(NF-κB) and participates in the cardiac response to sepsis. However, the role of the hypo-phosphorylated form of IκBβ at Ser313, which can be detected during sepsis, is unknown. Here, we examined the effects of IκBβ with a mutation at Ser313→Ala313 on cardiac damage induced by sepsis. Transgenic (Tg) mice were generated to overexpress IκBβ, in which Ser-313 is replaced with alanine ubiquitously, in order to mimic the hypo-phosphorylated form of IκBβ. Survival analysis showed that Tg mice exhibited decreased inflammatory cytokine levels and decreased rates of mortality in comparison to wild type (WT) mice, after sepsis in a cecal-ligation and puncture model (CLP). Compared to WT septic mice, sepsis in Tg mice resulted in improved cardiac functions, lower levels of troponin I and decreased rates of cardiomyocyte apoptosis, compared to WT mice. The increased formation of autophagicvacuoles detected with electron microscopy demonstrated the enhancement of cardiac autophagy. This phenomenon was further confirmed by the differential expression of genes related to autophagy, such as LC3, Atg5, Beclin-1, and p62. The increased expression of Cathepsin L(Ctsl), a specific marker for mitochondrial stress response, may be associated with the beneficial effects of the hypo-phosphorylated form of IκBβ. Our observations suggest that the hypo-phosphorylated form of IκBβ at Ser313 is beneficial to the heart in sepsis through inhibition of apoptosisand enhancement of autophagy in mutated IκBβ transgenic mice. PMID:27508931

  14. Potent homocysteine-induced ERK phosphorylation in cultured neurons depends on self-sensitization via system Xc{sup -}

    SciTech Connect

    Gu Li; Hu Xiaoling; Xue Zhanxia; Yang Jun; Wan Lishu; Ren Yan; Hertz, Leif; Peng Liang

    2010-01-15

    Homocysteine is increased during pathological conditions, endangering vascular and cognitive functions, and elevated homocysteine during pregnancy may be correlated with an increased incidence of schizophrenia in the offspring. This study showed that millimolar homocysteine concentrations in saline medium cause phosphorylation of extracellular-signal regulated kinases 1 and 2 (ERK{sub 1/2}) in cerebellar granule neurons, inhibitable by metabotropic but not ionotropic glutamate receptor antagonists. These findings are analogous to observations by , that similar concentrations cause neuronal death. However, these concentrations are much higher than those occurring clinically during hyperhomocysteinemia. It is therefore important that a approx 10-fold increase in potency occurred in the presence of the glutamate precursor glutamine, when ERK{sub 1/2} phosphorylation became inhibitable by NMDA or non-NMDA antagonists and dependent upon epidermal growth factor (EGF) receptor transactivation. However, glutamate release to the medium was reduced, suggesting that reversal of the cystine/glutamate antiporter, system X{sub c}{sup -} could be involved in potentiation of the response by causing a localized release of initially accumulated homocysteine. In agreement with this hypothesis further enhancement of ERK{sub 1/2} phosphorylation occurred in the additional presence of cystine. Pharmacological inhibition of system X{sub c}{sup -} prevented the effect of micromolar homocysteine concentrations, and U0126-mediated inhibition of ERK{sub 1/2} phosphorylation enhanced homocysteine-induced death. In conclusion, homocysteine interacts with system X{sub c}{sup -} like quisqualate (Venkatraman et al. 1994), by 'self-sensitization' with initial accumulation and subsequent release in exchange with cystine and/or glutamate, establishing high local homocysteine concentrations, which activate adjacent ionotropic glutamate receptors and cause neurotoxicity.

  15. Hypophosphorylated ASF/SF2 binds TAP and is present in messenger ribonucleoproteins.

    PubMed

    Lai, Ming-Chih; Tarn, Woan-Yuh

    2004-07-23

    Serine/arginine-rich proteins (SR proteins) function in precursor mRNA (pre-mRNA) splicing and may also act as adaptors for mRNA export. SR proteins are dynamically phosphorylated in their RS domain, and differential phosphorylation modulates their splicing activity and subcellular localization. In this study, we investigated the influence of phosphorylation on the function of SR proteins in events occurring during mRNA maturation. Immunoprecipitation experiments showed that the mRNA export receptor TAP associates preferentially with the hypophosphorylated form of shuttling SR proteins, including ASF/SF2. Overexpression of ASF induced subnuclear relocalization of TAP to SR protein-enriched nuclear speckles, suggesting their interaction in vivo. Moreover, the ASF found in a nucleoplasmic fraction rich in heterogeneous nuclear ribonucleoprotein (hnRNP) complexes is hyperphosphorylated, whereas mature messenger RNP (mRNP)-bound ASF is hypophosphorylated. Therefore, hypophosphorylation of ASF in mRNPs coincides with its higher affinity for TAP, suggesting that dephosphorylation of ASF promotes both its incorporation into mRNPs and recruitment of TAP for mRNA export. Thus, the phosphorylation state of RS domains may modulate the function of mammalian shuttling SR proteins during mRNA maturation or export. PMID:15184380

  16. The effect of subchronic supplementation with folic acid on homocysteine induced seizures.

    PubMed

    Rasic-Markovic, A; Rankov-Petrovic, B; Hrncic, D; Krstic, D; Colovic, M; Macut, Dj; Djuric, D; Stanojlovic, Olivera

    2015-06-01

    Influence of folic acid on the CNS is still unclear. Folate has a neuroprotective effect, while on the other hand excess folate can exacerbate seizures in epileptics. The aim of the present study was to examine the effect of subchronic administration of folic acid on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone induced seizures in adult rats. The activity of Na⁺/K⁺-ATPase and Mg²⁺-ATPase in different brain regions was investigated. Adult male Wistar rats were divided into groups: 1. Controls (C, 0.9% NaCl); 2. DL homocysteine-thiolactone 8.0 mmol/kg (H); 3. Subchronic supplementation with folic acid 5 mg/kg for 7 days (F) and 4. Subchronic supplementation with F + single dose of H (FH). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, three gold-plated recording electrodes were implanted into the skull. Subchronic supplementation with folic acid did not affect seizure incidence, median number of seizure episodes and severity in FH, comparison with H (p > 0.05). The majority of seizure episodes in all groups were of grade 2. There were no significant differences in lethal outcomes at 24 h upon H injection in the FH vs. H group. The activity of Na⁺/K⁺-ATPase and Mg²⁺-ATPase was significantly increased in almost all examined structures in the FH vs. H group. Subchronic folic acid administration did not exacerbate H induced seizures and completely recovered the activity of ATPases.

  17. Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: Modulation by antioxidants

    SciTech Connect

    Perez-de-Arce, Karen; Foncea, Rocio . E-mail: rfoncea@med.puc.cl; Leighton, Federico

    2005-12-16

    It has been proposed that homocysteine (Hcy)-induces endothelial dysfunction and atherosclerosis by generation of reactive oxygen species (ROS). A previous report has shown that Hcy promotes mitochondrial damage. Considering that oxidative stress can affect mitochondrial biogenesis, we hypothesized that Hcy-induced ROS in endothelial cells may lead to increased mitochondrial biogenesis. We found that Hcy-induced ROS (1.85-fold), leading to a NF-{kappa}B activation and increase the formation of 3-nitrotyrosine. Furthermore, expression of the mitochondrial biogenesis factors, nuclear respiratory factor-1 and mitochondrial transcription factor A, was significantly elevated in Hcy-treated cells. These changes were accompanied by increase in mitochondrial mass and higher mRNA and protein expression of the subunit III of cytochrome c oxidase. These effects were significantly prevented by pretreatment with the antioxidants, catechin and trolox. Taken together, our results suggest that ROS is an important mediator of mitochondrial biogenesis induced by Hcy, and that modulation of oxidative stress by antioxidants may protect against the adverse vascular effects of Hcy.

  18. Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex.

    PubMed

    Kunisawa, K; Nakashima, N; Nagao, M; Nomura, T; Kinoshita, S; Hiramatsu, M

    2015-10-01

    Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy.

  19. γ-Aminbuturic Acid A Receptor Mitigates Homocysteine-Induced Endothelial Cell Permeability

    PubMed Central

    Tyagi, Neetu; Moshal, Karni S.; Tyagi, Suresh C.; Lominadze, David

    2010-01-01

    Many cerebrovascular disorders are accompanied by an increased homocysteine (Hcy) levels. We have previously shown that acute hyperhomocysteinemia (HHcy) leads to an increased microvascular permeability in the mouse brain. Hcy competitively binds to γ -aminbuturic acid (GABA) receptors and may increase vascular permeability by acting as an excitatory neurotransmitter. However, the role of GABA-A (GABAA) receptor in Hcy-induced endothelial cell (EC) permeability remains unclear. In the present study we attempted to determine the role of GABAA receptor and the possible mechanisms involved in Hcy-induced EC layer permeability. Mouse aortic and brain ECs were grown in Transwells and treated with 50 μM Hcy in the presence or absence of GABAA-specific agonist muscimol. Role of matrix metalloproteinase-9 (MMP-9) was determined using its activity inhibitor GM-6001. Involvement of extracellular signal-regulated kinase (ERK) signaling was assessed using its kinase activity inhibitors PD98059 or U0126. EC permeability to the known content of bovine serum albumin (BSA)-conjugated with Alexa Flour-488 was assessed by measuring fluorescence intensity of the solutes in the Transwell's lower chambers. It was found that Hcy induced the formation of filamentous actin (F-actin). Hcy-induced EC permeability to BSA was significantly decreased by GABA and muscimol treatments. Presence of MMP-9 or ERK kinase activity inhibitors restored the Hcy-induced EC permeability to its baseline level. The mediation BSA leakage through the ECs was further confirmed in the experiments where Hcy-induced alterations in transendothelial electrical resistance of confluent ECs were assessed. The data suggest that Hcy increases EC layer permeability through inhibition of GABAA receptor and F-actin formation, in part, by transducing ERK and MMP-9 activation. PMID:18080868

  20. Effects of Huang Qi Decoction on Endothelial Dysfunction Induced by Homocysteine

    PubMed Central

    Wang, Li

    2016-01-01

    Vascular endothelial dysfunction can be induced by homocysteine (Hcy) through promoted oxidative stress. Huang Qi decoction (HQD) is a traditional Chinese medical formula and its components possess antioxidant effect. The study herein was therefore designed to investigate the effects of HQD at different dosage on endothelial dysfunction induced by Hcy. Tempol and apocynin were used to investigate whether antioxidant mechanisms were involved. Endothelium-dependent relaxation of rat aortas was investigated by isometric tension recordings. Reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) was determined by DHE staining. The assessment related to oxidative stress and NO bioavailability was performed by assay kits and western blot. In isometric tension experiment, HQD at the dose of 30 or 100 μg/mL, tempol, or apocynin prevented impaired endothelium-dependent relaxation in isolated aortas elicited by Hcy. In cellular experiments, substantial enhancement in NADPH oxidase and ROS generation and reduction in NO bioavailability triggered by Hcy were reversed by pretreatment of HQD at the dose of 100 μg/mL, tempol, or apocynin. The results proved that HQD at an appropriate dosage presented favorable effects on endothelial dysfunction initiated by Hcy through antioxidant mechanisms. HQD can act as a potent prescription for the treatment of endothelium related vascular complications. PMID:27725840

  1. Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies

    PubMed Central

    Han, Mingda; Serrano, Maria C.; Lastra-Vicente, Rosana; Brinez, Pilar; Acharya, Ganesh; Huhta, James C.; Chen, Ren; Linask, Kersti K.

    2009-01-01

    SUMMARY Elevated plasma homocysteine (HCy), which results from folate (folic acid, FA) deficiency, and the mood-stabilizing drug lithium (Li) are both linked to the induction of human congenital heart and neural tube defects. We demonstrated previously that acute administration of Li to pregnant mice on embryonic day (E)6.75 induced cardiac valve defects by potentiating Wnt–β-catenin signaling. We hypothesized that HCy may similarly induce cardiac defects during gastrulation by targeting the Wnt–β-catenin pathway. Because dietary FA supplementation protects from neural tube defects, we sought to determine whether FA also protects the embryonic heart from Li- or HCy-induced birth defects and whether the protection occurs by impacting Wnt signaling. Maternal elevation of HCy or Li on E6.75 induced defective heart and placental function on E15.5, as identified non-invasively using echocardiography. This functional analysis of HCy-exposed mouse hearts revealed defects in tricuspid and semilunar valves, together with altered myocardial thickness. A smaller embryo and placental size was observed in the treated groups. FA supplementation ameliorates the observed developmental errors in the Li- or HCy-exposed mouse embryos and normalized heart function. Molecular analysis of gene expression within the avian cardiogenic crescent determined that Li, HCy or Wnt3A suppress Wnt-modulated Hex (also known as Hhex) and Islet-1 (also known as Isl1) expression, and that FA protects from the gene misexpression that is induced by all three factors. Furthermore, myoinositol with FA synergistically enhances the protective effect. Although the specific molecular epigenetic control mechanisms remain to be defined, it appears that Li or HCy induction and FA protection of cardiac defects involve intimate control of the canonical Wnt pathway at a crucial time preceding, and during, early heart organogenesis. PMID:19638421

  2. Dietary intake of S-(α-carboxybutyl)-DL-homocysteine induces hyperhomocysteinemia in rats

    PubMed Central

    Strakova, Jana; Williams, Kelly T.; Gupta, Sapna; Schalinske, Kevin L.; Kruger, Warren D.; Rozen, Rima; Jiracek, Jiri; Li, Lucas; Garrow, Timothy A.

    2010-01-01

    Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(α-carboxybutyl)-DL-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed for the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an L-amino acid-defined diet either containing or devoid of CBHcy (5 mg/meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine β-synthase activity and immunodetectable protein decreased (56 and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats and S-adenosylhomocysteine levels did not change. Further, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology and plasma markers of liver damage. We conclude that CBHcy mediated BHMT inhibition causes an elevation in total plasma homocysteine that is not normalized by the folate-dependent conversion of homocysteine to methionine. Further, metabolic changes caused by BHMT inhibition affect cystathionine β-synthase and glycine N-methyltransferase activities, which further deteriorate plasma homocysteine levels. PMID:20797482

  3. Hydrogen sulfide attenuates neurodegeneration and neurovascular dysfunction induced by intracerebral-administered homocysteine in mice.

    PubMed

    Kamat, P K; Kalani, A; Givvimani, S; Sathnur, P B; Tyagi, S C; Tyagi, N

    2013-11-12

    High levels of homocysteine (Hcy), known as hyperhomocysteinemia are associated with neurovascular diseases. H2S, a metabolite of Hcy, has potent anti-oxidant and anti-inflammatory activities; however, the effect of H2S has not been explored in Hcy (IC)-induced neurodegeneration and neurovascular dysfunction in mice. Therefore, the present study was designed to explore the neuroprotective role of H2S on Hcy-induced neurodegeneration and neurovascular dysfunction. To test this hypothesis we employed wild-type (WT) males ages 8-10 weeks, WT+artificial cerebrospinal fluid (aCSF), WT+Hcy (0.5 μmol/μl) intracerebral injection (IC, one time only prior to NaHS treatment), WT+Hcy+NaHS (sodium hydrogen sulfide, precursor of H2S, 30 μmol/kg, body weight). NaHS was injected i.p. once daily for the period of 7 days after the Hcy (IC) injection. Hcy treatment significantly increased malondialdehyde, nitrite level, acetylcholinestrase activity, tumor necrosis factor-alpha, interleukin-1 beta, glial fibrillary acidic protein, inducible nitric oxide synthase, endothelial nitric oxide synthase and decreased glutathione level indicating oxidative-nitrosative stress and neuroinflammation as compared to control and aCSF-treated groups. Further, increased expression of neuron-specific enolase, S100B and decreased expression of (post-synaptic density-95, synaptosome-associated protein-97) synaptic protein indicated neurodegeneration. Brain sections of Hcy-treated mice showed damage in the cortical area and periventricular cells. Terminal deoxynucleotidyl transferase-mediated, dUTP nick-end labeling-positive cells and Fluro Jade-C staining indicated apoptosis and neurodegeneration. The increased expression of matrix metalloproteinase (MMP) MMP9, MMP2 and decreased expression of tissue inhibitor of metalloproteinase (TIMP) TIMP-1, TIMP-2, tight junction proteins (zonula occulden 1) in Hcy-treated group indicate neurovascular remodeling. Interestingly, NaHS treatment significantly

  4. Folate Deficiency Induces Neural Stem Cell Apoptosis by Increasing Homocysteine In Vitro

    PubMed Central

    Zhang, Xu-Mei; Huang, Guo-Wei; Tian, Zhi-Hong; Ren, Da-Lin; X. Wilson, John

    2009-01-01

    Cellular events for neural progenitor cells, such as proliferation and differentiation, are regulated by multiple intrinsic and extrinsic cell signals. Folate plays a central role in central nervous system development, so folate, as an extrinsic signal, may affect neural stem cell (NSC) proliferation and differentiation. In the present study, we investigated the effects of folate deficiency on the cell proliferation, cell apoptosis and homocysteine concentrations in NSCs. NSCs were isolated from fetal rats and identified as NSCs by their expression of immunoreactive nestin. Cell proliferation was quantitated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were detected and confirmed by flow cytometric analysis. We measured homocysteine concentrations in NSCs by high performance liquid chromatography and detected the expression of caspase-3 by western blot method. Folate deficiency not only decreased cell proliferation, but also increased the apoptotic rate of NSCs as demonstrated by the increased expression of early apoptotic markers such as caspase-3, compared to control group (p<0.05). Furthermore, There was a statistically significant increase in homocysteine concentration during folate deficiency in NSCs (p<0.05). These data suggest that folate affects the cell proliferation, apoptosis and homocysteine generation in NSC cells. PMID:19590702

  5. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated plasma homocysteine (Hcy) levels have been recognized as an independent risk factor for cardiovascular and cerebrovascular diseases. However, the causative mechanisms have not been delineated. Scavenger receptors such as scavenger receptor-AI/II (SR-A), CD36, and lectin-like oxidized LDL ...

  6. Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism.

    PubMed

    Martínez-Vega, Raquel; Garrido, Francisco; Partearroyo, Teresa; Cediel, Rafael; Zeisel, Steven H; Martínez-Álvarez, Concepción; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A

    2015-02-01

    Nutritional imbalance is emerging as a causative factor of hearing loss. Epidemiologic studies have linked hearing loss to elevated plasma total homocysteine (tHcy) and folate deficiency, and have shown that folate supplementation lowers tHcy levels potentially ameliorating age-related hearing loss. The purpose of this study was to address the impact of folate deficiency on hearing loss and to examine the underlying mechanisms. For this purpose, 2-mo-old C57BL/6J mice (Animalia Chordata Mus musculus) were randomly divided into 2 groups (n = 65 each) that were fed folate-deficient (FD) or standard diets for 8 wk. HPLC analysis demonstrated a 7-fold decline in serum folate and a 3-fold increase in tHcy levels. FD mice exhibited severe hearing loss measured by auditory brainstem recordings and TUNEL-positive-apoptotic cochlear cells. RT-quantitative PCR and Western blotting showed reduced levels of enzymes catalyzing homocysteine (Hcy) production and recycling, together with a 30% increase in protein homocysteinylation. Redox stress was demonstrated by decreased expression of catalase, glutathione peroxidase 4, and glutathione synthetase genes, increased levels of manganese superoxide dismutase, and NADPH oxidase-complex adaptor cytochrome b-245, α-polypeptide (p22phox) proteins, and elevated concentrations of glutathione species. Altogether, our findings demonstrate, for the first time, that the relationship between hyperhomocysteinemia induced by folate deficiency and premature hearing loss involves impairment of cochlear Hcy metabolism and associated oxidative stress.

  7. Homocysteine induces glyceraldehyde-3-phosphate dehydrogenase acetylation and apoptosis in the neuroblastoma cell line Neuro2a.

    PubMed

    Fang, M; Jin, A; Zhao, Y; Liu, X

    2016-02-01

    High plasma levels of homocysteine (Hcy) promote the progression of neurodegenerative diseases. However, the mechanism by which Hcy mediates neurotoxicity has not been elucidated. We observed that upon incubation with Hcy, the viability of a neuroblastoma cell line Neuro2a declined in a dose-dependent manner, and apoptosis was induced within 48 h. The median effective concentration (EC50) of Hcy was approximately 5 mM. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nuclear translocation and acylation has been implicated in the regulation of apoptosis. We found that nuclear translocation and acetylation of GAPDH increased in the presence of 5 mM Hcy and that higher levels of acetyltransferase p300/CBP were detected in Neuro2a cells. These findings implicate the involvement of GAPDH in the mechanism whereby Hcy induces apoptosis in neurons. This study highlights a potentially important pathway in neurodegenerative disorders, and a novel target pathway for neuroprotective therapy. PMID:26785692

  8. Homocysteine induces glyceraldehyde-3-phosphate dehydrogenase acetylation and apoptosis in the neuroblastoma cell line Neuro2a

    PubMed Central

    Fang, M.; Jin, A.; Zhao, Y.; Liu, X.

    2016-01-01

    High plasma levels of homocysteine (Hcy) promote the progression of neurodegenerative diseases. However, the mechanism by which Hcy mediates neurotoxicity has not been elucidated. We observed that upon incubation with Hcy, the viability of a neuroblastoma cell line Neuro2a declined in a dose-dependent manner, and apoptosis was induced within 48 h. The median effective concentration (EC50) of Hcy was approximately 5 mM. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) nuclear translocation and acylation has been implicated in the regulation of apoptosis. We found that nuclear translocation and acetylation of GAPDH increased in the presence of 5 mM Hcy and that higher levels of acetyltransferase p300/CBP were detected in Neuro2a cells. These findings implicate the involvement of GAPDH in the mechanism whereby Hcy induces apoptosis in neurons. This study highlights a potentially important pathway in neurodegenerative disorders, and a novel target pathway for neuroprotective therapy. PMID:26785692

  9. S-adenosyl-L-homocysteine hydrolase is necessary for aldosterone-induced activity of epithelial Na(+) channels.

    PubMed

    Stockand, J D; Zeltwanger, S; Bao, H F; Becchetti, A; Worrell, R T; Eaton, D C

    2001-09-01

    The A6 cell line was used to study the role of S-adenosyl-L-homocysteine hydrolase (SAHHase) in the aldosterone-induced activation of the epithelial Na(+) channel (ENaC). Because aldosterone increases methylation of several different molecules, and because this methylation is associated with increased Na(+) reabsorption, we tested the hypothesis that aldosterone increases the expression and activity of SAHHase protein. The rationale for this work is that general methylation may be promoted by activation of SAHHase, the only enzyme known to metabolize SAH, a potent end-product inhibitor of methylation. Although aldosterone increased SAHHase activity, steroid did not affect SAHHase expression. Antisense SAHHase oligonucleotide decreased SAHHase expression and activity. Moreover, this oligonucleotide, as well as a pharmacological inhibitor of SAHHase, decreased aldosterone-induced activity of ENaC via a decrease in ENaC open probability. The kinetics of ENaC in cells treated with antisense plus aldosterone were similar to those reported previously for the channel in the absence of steroid. This is the first report showing that active SAHHase, in part, increases ENaC open probability by reducing the transition rate from open states in response to aldosterone. Thus aldosterone-induced SAHHase activity plays a critical role in shifting ENaC from a gating mode with short open and closed times to one with longer open and closed times. PMID:11502554

  10. Homocysteine-induced apoptosis in endothelial cells coincides with nuclear NOX2 and peri-nuclear NOX4 activity.

    PubMed

    Sipkens, Jessica A; Hahn, Nynke; van den Brand, Carlien S; Meischl, Christof; Cillessen, Saskia A G M; Smith, Desirée E C; Juffermans, Lynda J M; Musters, René J P; Roos, Dirk; Jakobs, Cornelis; Blom, Henk J; Smulders, Yvo M; Krijnen, Paul A J; Stehouwer, Coen D A; Rauwerda, Jan A; van Hinsbergh, Victor W M; Niessen, Hans W M

    2013-11-01

    Apoptosis of endothelial cells related to homocysteine (Hcy) has been reported in several studies. In this study, we evaluated whether reactive oxygen species (ROS)-producing signaling pathways contribute to Hcy-induced apoptosis induction, with specific emphasis on NADPH oxidases. Human umbilical vein endothelial cells were incubated with 0.01-2.5 mM Hcy. We determined the effect of Hcy on caspase-3 activity, annexin V positivity, intracellular NOX1, NOX2, NOX4, and p47(phox) expression and localization, nuclear nitrotyrosine accumulation, and mitochondrial membrane potential (ΔΨ m). Hcy induced caspase-3 activity and apoptosis; this effect was concentration dependent and maximal after 6-h exposure to 2.5 mM Hcy. It was accompanied by a significant increase in ΔΨ m. Cysteine was inactive on these parameters excluding a reactive thiol group effect. Hcy induced an increase in cellular NOX2, p47(phox), and NOX4, but not that of NOX1. 3D digital imaging microscopy followed by image deconvolution analysis showed nuclear accumulation of NOX2 and p47(phox) in endothelial cells exposed to Hcy, but not in control cells, which coincided with accumulation of nuclear nitrotyrosine residues. Furthermore, Hcy enhanced peri-nuclear localization of NOX4 coinciding with accumulation of peri-nuclear nitrotyrosine residues, a reflection of local ROS production. p47(phox) was also increased in the peri-nuclear region. The Hcy-induced increase in caspase-3 activity was prevented by DPI and apocynin, suggesting involvement of NOX activity. The data presented in this article reveal accumulation of nuclear NOX2 and peri-nuclear NOX4 accumulation as potential source of ROS production in Hcy-induced apoptosis in endothelial cells.

  11. Homocysteine induced cardiovascular events: a consequence of long term anabolic‐androgenic steroid (AAS) abuse

    PubMed Central

    Graham, M R; Grace, F M; Boobier, W; Hullin, D; Kicman, A; Cowan, D; Davies, B; Baker, J S

    2006-01-01

    Objectives The long term effects (>20 years) of anabolic‐androgenic steroid (AAS) use on plasma concentrations of homocysteine (HCY), folate, testosterone, sex hormone binding globulin (SHBG), free androgen index, urea, creatinine, haematocrit (HCT), vitamin B12, and urinary testosterone/epitestosterone (T/E) ratio, were examined in a cohort of self‐prescribing bodybuilders. Methods Subjects (n = 40) were divided into four distinct groups: (1) AAS users still using AAS (SU; n = 10); (2) AAS users abstinent from AAS administration for 3 months (SA; n = 10); (3) non‐drug using bodybuilding controls (BC; n = 10); and (4) sedentary male controls (SC; n = 10). Results HCY levels were significantly higher in SU compared with BC and SC (p<0.01), and with SA (p<0.05). Fat free mass was significantly higher in both groups of AAS users (p<0.01). Daily energy intake (kJ) and daily protein intake (g/day) were significantly higher in SU and SA (p<0.05) compared with BC and SC, but were unlikely to be responsible for the observed HCY increases. HCT concentrations were significantly higher in the SU group (p<0.01). A significant linear inverse relationship was observed in the SU group between SHBG and HCY (r = −0.828, p<0.01), indicating a possible influence of the sex hormones in determining HCY levels. Conclusions With mounting evidence linking AAS to adverse effects on some clotting factors, the significantly higher levels of HCY and HCT observed in the SU group suggest long term AAS users have increased risk of future thromboembolic events. PMID:16488899

  12. The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats.

    PubMed

    Xie, Fang; Zhao, Yun; Ma, Jing; Gong, Jing-Bo; Wang, Shi-Da; Zhang, Liang; Gao, Xiu-Jie; Qian, Ling-Jia

    2016-09-01

    Chronic stress is a risk factor in the development of cognitive decline and even Alzheimer's disease (AD), although its underlying mechanism is not fully understood. Our previous data demonstrated that the level of homocysteine (Hcy) was significantly elevated in the plasma of stressed animals, which suggests the possibility that Hcy is a link between stress and cognitive decline. To test this hypothesis, we compared the cognitive function, plasma concentrations of Hcy, and the brain beta-amyloid (Aβ) level between rats with or without chronic unexpected mild stress (CUMS). A lower performance by rats in behavioral tests indicated that a significant cognitive decline was induced by CUMS. Stress also disturbed the normal processing of Aβ precursor protein (APP) and resulted in the accumulation of Aβ in the brains of rats, which showed a positive correlation with the hyperhomocysteinemia (HHcy) that appeared in stressed rats. Hcy-targeting intervention experiments were used to verify further the involvement of Hcy in stress-induced APP misprocessing and related cognitive decline. The results showed that diet-induced HHcy could mimic the cognitive impairment and APP misprocessing in the same manner as CUMS, while Hcy reduction by means of vitamin B complex supplements and betaine could alleviate the cognitive deficits and dysregulation of Aβ metabolism in CUMS rats. Taken together, the novel evidence from our present study suggests that Hcy is likely to be involved in chronic stress-evoked APP misprocessing and related cognitive deficits. Our results also suggested the possibility of Hcy as a target for therapy and the potential value of vitamin B and betaine intake in the prevention of stress-induced cognitive decline.

  13. The involvement of homocysteine in stress-induced Aβ precursor protein misprocessing and related cognitive decline in rats.

    PubMed

    Xie, Fang; Zhao, Yun; Ma, Jing; Gong, Jing-Bo; Wang, Shi-Da; Zhang, Liang; Gao, Xiu-Jie; Qian, Ling-Jia

    2016-09-01

    Chronic stress is a risk factor in the development of cognitive decline and even Alzheimer's disease (AD), although its underlying mechanism is not fully understood. Our previous data demonstrated that the level of homocysteine (Hcy) was significantly elevated in the plasma of stressed animals, which suggests the possibility that Hcy is a link between stress and cognitive decline. To test this hypothesis, we compared the cognitive function, plasma concentrations of Hcy, and the brain beta-amyloid (Aβ) level between rats with or without chronic unexpected mild stress (CUMS). A lower performance by rats in behavioral tests indicated that a significant cognitive decline was induced by CUMS. Stress also disturbed the normal processing of Aβ precursor protein (APP) and resulted in the accumulation of Aβ in the brains of rats, which showed a positive correlation with the hyperhomocysteinemia (HHcy) that appeared in stressed rats. Hcy-targeting intervention experiments were used to verify further the involvement of Hcy in stress-induced APP misprocessing and related cognitive decline. The results showed that diet-induced HHcy could mimic the cognitive impairment and APP misprocessing in the same manner as CUMS, while Hcy reduction by means of vitamin B complex supplements and betaine could alleviate the cognitive deficits and dysregulation of Aβ metabolism in CUMS rats. Taken together, the novel evidence from our present study suggests that Hcy is likely to be involved in chronic stress-evoked APP misprocessing and related cognitive deficits. Our results also suggested the possibility of Hcy as a target for therapy and the potential value of vitamin B and betaine intake in the prevention of stress-induced cognitive decline. PMID:27435080

  14. S phase entry causes homocysteine-induced death while ataxia telangiectasia and Rad3 related protein functions anti-apoptotically to protect neurons

    PubMed Central

    Ye, Weizhen

    2010-01-01

    A major phenotype seen in neurodegenerative disorders is the selective loss of neurons due to apoptotic death and evidence suggests that inappropriate re-activation of cell cycle proteins in post-mitotic neurons may be responsible. To investigate whether reactivation of the G1 cell cycle proteins and S phase entry was linked with apoptosis, we examined homocysteine-induced neuronal cell death in a rat cortical neuron tissue culture system. Hyperhomocysteinaemia is a physiological risk factor for a variety of neurodegenerative diseases, including Alzheimer’s disease. We found that in response to homocysteine treatment, cyclin D1, and cyclin-dependent kinases 4 and 2 translocated to the nucleus, and p27 levels decreased. Both cyclin-dependent kinases 4 and 2 regained catalytic activity, the G1 gatekeeper retinoblastoma protein was phosphorylated and DNA synthesis was detected, suggesting transit into S phase. Double-labelling immunofluorescence showed a 95% co-localization of anti-bromodeoxyuridine labelling with apoptotic markers, demonstrating that those cells that entered S phase eventually died. Neurons could be protected from homocysteine-induced death by methods that inhibited G1 phase progression, including down-regulation of cyclin D1 expression, inhibition of cyclin-dependent kinases 4 or 2 activity by small molecule inhibitors, or use of the c-Abl kinase inhibitor, Gleevec™, which blocked cyclin D and cyclin-dependent kinase 4 nuclear translocation. However, blocking cell cycle progression post G1, using DNA replication inhibitors, did not prevent apoptosis, suggesting that death was not preventable post the G1-S phase checkpoint. While homocysteine treatment caused DNA damage and activated the DNA damage response, its mechanism of action was distinct from that of more traditional DNA damaging agents, such as camptothecin, as it was p53-independent. Likewise, inhibition of the DNA damage sensors, ataxia-telangiectasia mutant and ataxia telangiectasia

  15. Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a

    PubMed Central

    Lei, Wenjing; Long, Yanjun; Li, Shuang; Liu, Ze; Zhu, Fengxin; Hou, Fan Fan; Nie, Jing

    2015-01-01

    Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production. PMID:26192994

  16. The rotamase Pin1 is up-regulated, hypophosphorylated and required for cell cycle progression in head and neck squamous cell carcinomas.

    PubMed

    Wiegand, Susanne; Dakic, Branka; Rath, Ariane F E; Makarova, Galina; Sterz, Carolina; Meissner, Wolfgang; Bette, Michael; Adamkiewicz, Jürgen; Müller-Brüsselbach, Sabine; Müller, Rolf; Werner, Jochen A; Mandic, Robert

    2009-10-01

    The peptidyl-prolyl cis/trans isomerase Pin1 has been implicated in malignant transformation in multiple studies, however, little is known about its potential impact in head and neck cancer. This study evaluates the role of Pin1 in head and neck squamous cell carcinomas (HNSCCs). Pin1 expression and level of phosphorylation was evaluated by Western blot analysis and 2D-gel-electrophoresis. Pin1 was inhibited with juglone (5-hydroxy-1,4-naphthalenedione) or Pin1 specific siRNA and its influence on cell cycle checkpoint distribution was assessed by FACS analysis. Pin1 overexpression was found in HNSCC tissues and cell lines. 2D-gel-electrophoresis data pointed to Pin1 being hypophosphorylated in HNSCC cells which is consistent with overactivation of this rotamase. Inhibition of HNSCC cells with juglone or Pin1 siRNA induced the cell cycle inhibitor p21(WAF1/Cip1) with a concomitant reduction of cells in G2/M and an increased fraction of cells with fragmented DNA. Cell death did not correlate with significant levels of apoptosis in Pin1 depleted HNSCC cells. In summary, the data shows that Pin1 is overexpressed and hypophosphorylated in HNSCC, and that inhibition of Pin1 blocks cell cycle progression and triggers tumor cell death. Pin1 therefore could represent a new target for the development of improved HNSCC targeting drugs.

  17. Effects of homocysteine on metabolic pathways in cultured astrocytes.

    PubMed

    Jin, Ying; Brennan, Lorraine

    2008-06-01

    Homocysteine is an amino acid that is an important risk factor for several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Increased homocysteine levels induce neuronal cell death in a variety of neuronal types. However, very few studies have probed the effects of homocysteine in astrocytes. The present study investigated the effects of homocysteine on primary cultures of astrocytes by exposing astrocytes to 400 microM homocysteine for 20 h. Metabolic extracts of cells were prepared following a 4-h incubation in minimum medium with 5.5 mM [U-(13)C]glucose in the presence or absence of homocysteine and analysed using (13)C NMR. The expression level of pyruvate dehydrogenase kinase isoform 2 (PDK-2), NAD(P)H levels and mitochondrial membrane potential responses were investigated following culture with homocysteine. Metabolomic analysis was performed using (1)H NMR spectroscopy and pattern recognition analysis. Following incubation with homocysteine there was a significant decrease (48%) in the ratio of flux through pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) which was due to an increased flux through PDH. In addition, homocysteine culture resulted in a significant reduction in PDK-2 protein expression. Following stimulation with glucose there was a significant increase in NAD(P)H levels and an impaired hyperpolarisation of the mitochondrial membrane in homocysteine-treated cells. Metabolomic analysis showed that the most discriminating metabolites following homocysteine treatment were choline and hypotaurine. In summary, the results demonstrated that sub-lethal concentrations of homocysteine caused significant metabolic changes and altered mitochondrial function in primary cultures of astrocytes. PMID:18417255

  18. Role of Nox inhibitors plumbagin, ML090 and gp91ds-tat peptide on homocysteine thiolactone induced blood vessel dysfunction.

    PubMed

    Smith, Renee M; Kruzliak, Peter; Adamcikova, Zuzana; Zulli, Anthony

    2015-08-01

    Antioxidants have not reduced the burden of cardiovascular disease, and current evidence suggests a beneficial role of oxidative stress, via NADPH oxidase (Nox) upregulation, in endothelial function. Homocysteine thiolactone (HcyT) induces blood vessel dysfunction and this correlates with increased vascular oxidative stress. This study aimed to determine if pharmacological inhibition of Nox could impair HcyT induced blood vessel dysfunction. Abdominal aorta were excised from New Zealand White rabbits (n = 6), cut into rings and sequentially mounted in organ baths. Rings were preincubated with 0.55 μmol/L homocysteine thiolactone for 1 h, or combinations of putative Nox inhibitors (plumbagin for Nox4, gp91ds-tat for Nox2, and ML090 for Nox1), 30 min prior to the addition of HcyT, followed by a dose response curve to acetylcholine on phenylephrine preconstricted rings. Plumbagin, ML090 + gp91ds-tat and HcyT reduced responses to acetylcholine, and Plumbagin + Hcyt caused constriction to acetylcholine, which was normalised to plumbagin by ML090. Plumbagin + ML090 or plumbagin + gp91ds-tat completely impaired the effect of acetylcholine. ML090 inhibited the effect of HcyT on reduced response to acetylcholine, whereas gp91ds-tat had no effect. This study concludes that inhibition of Nox1 prevents, whereas inhibition of Nox4 worsens, acetylcholine induced blood vessel relaxation caused by HcyT, while Nox2 inhibition has no effect. However combinations of Nox inhibitors worsen acetylcholine induced blood vessel relaxation. These results suggest that there is cross-talk between Nox isoforms during physiological and pathophysiological processes.

  19. Role of Nox inhibitors plumbagin, ML090 and gp91ds-tat peptide on homocysteine thiolactone induced blood vessel dysfunction.

    PubMed

    Smith, Renee M; Kruzliak, Peter; Adamcikova, Zuzana; Zulli, Anthony

    2015-08-01

    Antioxidants have not reduced the burden of cardiovascular disease, and current evidence suggests a beneficial role of oxidative stress, via NADPH oxidase (Nox) upregulation, in endothelial function. Homocysteine thiolactone (HcyT) induces blood vessel dysfunction and this correlates with increased vascular oxidative stress. This study aimed to determine if pharmacological inhibition of Nox could impair HcyT induced blood vessel dysfunction. Abdominal aorta were excised from New Zealand White rabbits (n = 6), cut into rings and sequentially mounted in organ baths. Rings were preincubated with 0.55 μmol/L homocysteine thiolactone for 1 h, or combinations of putative Nox inhibitors (plumbagin for Nox4, gp91ds-tat for Nox2, and ML090 for Nox1), 30 min prior to the addition of HcyT, followed by a dose response curve to acetylcholine on phenylephrine preconstricted rings. Plumbagin, ML090 + gp91ds-tat and HcyT reduced responses to acetylcholine, and Plumbagin + Hcyt caused constriction to acetylcholine, which was normalised to plumbagin by ML090. Plumbagin + ML090 or plumbagin + gp91ds-tat completely impaired the effect of acetylcholine. ML090 inhibited the effect of HcyT on reduced response to acetylcholine, whereas gp91ds-tat had no effect. This study concludes that inhibition of Nox1 prevents, whereas inhibition of Nox4 worsens, acetylcholine induced blood vessel relaxation caused by HcyT, while Nox2 inhibition has no effect. However combinations of Nox inhibitors worsen acetylcholine induced blood vessel relaxation. These results suggest that there is cross-talk between Nox isoforms during physiological and pathophysiological processes. PMID:25998981

  20. The homocysteine controversy.

    PubMed

    Smulders, Yvo M; Blom, Henk J

    2011-02-01

    Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced atherosclerotic lesions.

  1. Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance*

    PubMed Central

    Kumar, Arun; John, Lijo; Maity, Shuvadeep; Manchanda, Mini; Sharma, Abhay; Saini, Neeru; Chakraborty, Kausik; Sengupta, Shantanu

    2011-01-01

    An elevated level of homocysteine, a thiol amino acid, is associated with various complex disorders. The cellular effects of homocysteine and its precursors S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) are, however, poorly understood. We used Saccharomyces cerevisiae as a model to understand the basis of pathogenicity induced by homocysteine and its precursors. Both homocysteine and AdoHcy but not AdoMet inhibited the growth of the str4Δ strain (which lacks the enzyme that converts homocysteine to cystathionine-mimicking vascular cells). Addition of AdoMet abrogated the inhibitory effect of AdoHcy but not that of homocysteine indicating that an increase in the AdoMet/AdoHcy ratio is sufficient to overcome the AdoHcy-mediated growth defect but not that of homocysteine. Also, the transcriptomic profile of AdoHcy and homocysteine showed gross dissimilarity based on gene enrichment analysis. Furthermore, compared with homocysteine, AdoHcy treatment caused a higher level of oxidative stress in the cells. However, unlike a previously reported response in wild type (Kumar, A., John, L., Alam, M. M., Gupta, A., Sharma, G., Pillai, B., and Sengupta, S. (2006) Biochem. J. 396, 61–69), the str4Δ strain did not exhibit an endoplasmic reticulum stress response. This suggests that homocysteine induces varied response depending on the flux of homocysteine metabolism. We also observed altered expression of mitochondrial genes, defective membrane potential, and fragmentation of the mitochondrial network together with the increased expression of fission genes indicating that the imbalance in homocysteine metabolism has a major effect on mitochondrial functions. Furthermore, treatment of cells with homocysteine or AdoHcy resulted in apoptosis as revealed by annexin V staining and TUNEL assay. Cumulatively, our results suggest that elevated levels of homocysteine lead to mitochondrial dysfunction, which could potentially initiate pro-apoptotic pathways, and

  2. Disturbance of endogenous hydrogen sulfide generation and endoplasmic reticulum stress in hippocampus are involved in homocysteine-induced defect in learning and memory of rats.

    PubMed

    Li, Man-Hong; Tang, Ji-Ping; Zhang, Ping; Li, Xiang; Wang, Chun-Yan; Wei, Hai-Jun; Yang, Xue-Feng; Zou, Wei; Tang, Xiao-Qing

    2014-04-01

    Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Hydrogen sulfide (H2S) acts as an endogenous neuromodulator and neuroprotectant. It has been shown that endoplasmic reticulum (ER) stress is involved in the pathological mechanisms of the learning and memory dysfunctions and that H2S exerts its neuroprotective role via suppressing ER stress. In the present work, we explored the effects of intracerebroventricular injection of Hcy on the formation of learning and memory, the generation of endogenous H2S, and the expression of ER stress in the hippocampus of rats. We found that intracerebroventricular injection of Hcy in rats leads to learning and memory dysfunctions in the Morris water maze and novel of object recognition test and decreases in the expression of cystathionine-β-synthase, the major enzyme responsible for endogenous H2S generation, and the generation of endogenous H2S in the hippocampus of rats. We also showed that exposure of Hcy could up-regulate the expressions of glucose-regulated protein 78 (GRP78), CHOP, and cleaved caspase-12, which are the major mark proteins of ER stress, in the hippocampus of rats. Taken together, these results suggest that the disturbance of hippocampal endogenous H2S generation and the increase in ER stress in the hippocampus are related to Hcy-induced defect in learning and memory.

  3. Hydrogen Sulfide Epigenetically Attenuates Homocysteine-Induced Mitochondrial Toxicity Mediated Through NMDA Receptor in Mouse Brain Endothelial (bEnd3) Cells.

    PubMed

    Kamat, Pradip K; Kalani, Anuradha; Tyagi, Suresh C; Tyagi, Neetu

    2015-02-01

    Previously we have shown that homocysteine (Hcy) caused oxidative stress and altered mitochondrial function. Hydrogen sulfide (H2S) has potent anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, in the present study we examined whether H2S ameliorates Hcy-induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100 μM Hcy treatment in the presence or absence of 30 μM NaHS (donor of H2S) for 24 h. Hcy-activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca(2+), NADPH-oxidase-4 (NOX-4) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD-2) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5'-azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30 μM) attenuated the Hcy-induced increased expression of DNMT1, DNMT3a, Ca(2+), and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also mitigated mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy-induced LC3-I/II, CSE, Atg3/7, and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE-cadherin and ET-1 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H2S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H2S protected the cells from HHcy-induced mitochondrial toxicity and endothelial dysfunction.

  4. Hydrogen sulfide epigenetically attenuates homocysteine-induced mitochondrial toxicity mediated through NMDA receptor in mouse brain endothelial (bEnd3) cells†

    PubMed Central

    Kamat, Pradip K.; Kalani, Anuradha; Tyagi, Suresh C.; Tyagi, Neetu

    2014-01-01

    Previously we have showed that homocysteine (Hcy) caused oxidative stress and altered mitochondrial function. Hydrogen sulphide (H2S) has potent anti-inflammatory, anti-oxidative and anti-apoptotic effects. Therefore, in the present study we examined whether H2S ameliorates Hcy-induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100μM Hcy treatment in the presence or absence of 30μM NaHS (donor of H2S) for 24hrs. Hcy-activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca2+, NADPH-oxidase-4 (NOX-4) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD-2) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5′-azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30μM) attenuated the Hcy-induced increased expression of DNMT1, DNMT3a, Ca2+ and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also enhanced mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy-induced LC3-I/II, CSE, Atg3/7 and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE-Cadherin and ET-1 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H2S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H2S protected the cells from HHcy-induced mitochondrial toxicity and endothelial dysfunction. PMID:25056869

  5. Hydrogen Sulfide Epigenetically Attenuates Homocysteine-Induced Mitochondrial Toxicity Mediated Through NMDA Receptor in Mouse Brain Endothelial (bEnd3) Cells.

    PubMed

    Kamat, Pradip K; Kalani, Anuradha; Tyagi, Suresh C; Tyagi, Neetu

    2015-02-01

    Previously we have shown that homocysteine (Hcy) caused oxidative stress and altered mitochondrial function. Hydrogen sulfide (H2S) has potent anti-inflammatory, anti-oxidative, and anti-apoptotic effects. Therefore, in the present study we examined whether H2S ameliorates Hcy-induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100 μM Hcy treatment in the presence or absence of 30 μM NaHS (donor of H2S) for 24 h. Hcy-activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca(2+), NADPH-oxidase-4 (NOX-4) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD-2) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5'-azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30 μM) attenuated the Hcy-induced increased expression of DNMT1, DNMT3a, Ca(2+), and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also mitigated mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy-induced LC3-I/II, CSE, Atg3/7, and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE-cadherin and ET-1 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H2S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H2S protected the cells from HHcy-induced mitochondrial toxicity and endothelial dysfunction. PMID:25056869

  6. B vitamins and homocysteine in cardiovascular disease and aging.

    PubMed

    Wilcken, D E; Wilcken, B

    1998-11-20

    The sulfur-containing amino acid, homocysteine, is formed from the essential amino acid methionine, and a number of B vitamins are involved in methionine metabolism. Pyridoxine, vitamin B6, is a cofactor for cystathionine beta synthase, which mediates the transformation of homocysteine to cystathionine, the initial step in the transsulfuration pathway and the urinary excretion of sulfur. In a normal diet there is conservation of the carbon skeleton, and about 50% of the homocysteine formed is remethylated to methionine via steps that require folic acid and vitamin B12. A deficiency of any of these three vitamins leads to modest homocyst(e)ine elevation, as does diminished renal function, both of which are common in the elderly. It is also established that homocyst(e)ine elevation of this order is associated with increased cardiovascular risk but is also associated with most established risk factors, although it is thought to be an independent contributor. In the inborn error of metabolism homocystinuria due to cystathionine beta synthase deficiency there is greatly increased circulating homocyst(e)ine and a clear association with precocious vascular disease. In about 50% of these patients there is a vascular event before the age of 30 years. The homocysteine-induced adverse vascular changes appear to result from endothelial and smooth muscle cell effects and increased thrombogenesis. We have documented a highly significant reduction in the occurrence of vascular events during 539 patient years of treatment in 32 patients with cystathionine beta synthase deficiency (mean age 30 years, range 9-66 years) by aggressive homocyst(e)ine lowering with pyridoxine, folic acid, and B12 (p = 0.0001). The 15 pyridoxine nonresponsive patients also received oral betaine. Although a cause and effect relationship is postulated for the increased cardiovascular risk associated with mild homocysteine elevation, a common cause of this elevation is the methylenetetrahydrofolate

  7. Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons.

    PubMed

    Rodríguez-Martín, Teresa; Pooler, Amy M; Lau, Dawn H W; Mórotz, Gábor M; De Vos, Kurt J; Gilley, Jonathan; Coleman, Michael P; Hanger, Diane P

    2016-01-01

    Expression of the frontotemporal dementia-related tau mutation, P301L, at physiological levels in adult mouse brain (KI-P301L mice) results in overt hypophosphorylation of tau and age-dependent alterations in axonal mitochondrial transport in peripheral nerves. To determine the effects of P301L tau expression in the central nervous system, we examined the kinetics of mitochondrial axonal transport and tau phosphorylation in primary cortical neurons from P301L knock-in (KI-P301L) mice. We observed a significant 50% reduction in the number of mitochondria in the axons of cortical neurons cultured from KI-P301L mice compared to wild-type neurons. Expression of murine P301L tau did not change the speed, direction of travel or likelihood of movement of mitochondria. Notably, the angle that defines the orientation of the mitochondria in the axon, and the volume of individual moving mitochondria, were significantly increased in neurons expressing P301L tau. We found that murine tau phosphorylation in KI-P301L mouse neurons was diminished and the ability of P301L tau to bind to microtubules was also reduced compared to tau in wild-type neurons. The P301L mutation did not influence the ability of murine tau to associate with membranes in cortical neurons or in adult mouse brain. We conclude that P301L tau is associated with mitochondrial changes and causes an early reduction in murine tau phosphorylation in neurons coupled with impaired microtubule binding of tau. These results support the association of mutant tau with detrimental effects on mitochondria and will be of significance for the pathogenesis of tauopathies.

  8. Role of homocysteine in the development of cardiovascular disease.

    PubMed

    Ganguly, Paul; Alam, Sreyoshi Fatima

    2015-01-10

    It is well known that neuronal damage following a stroke has been attributed to the over stimulation of excitatory amino acids such as glutamate and aspartate through activation of NMDA receptors. The brain is exposed to most of the constituents of plasma including homocysteine as a result of the disruption of the blood-brain barrier after stroke, head trauma and stress. The question, therefore, arises as to whether or not homocysteine is able to selectively stimulate the release of excitatory amino acids in stroke. This review article will address the importance of homocysteine in nervous system specifically how these amino acids may trigger the release of catecholamines. Our data will thus strengthen the view that a mechanism for the association of hyperhomocysteinemia with increased brain lesion in stroke. As hypothalamus also controls the cardiac function via sympathetic system, the contractility of heart will be compromised. Homocysteine is also known to mediate cardiovascular problems by its adverse effects on cardiovascular endothelium and smooth muscle cells with resultant alterations in subclinical arterial structure and function. The present review will thus summarize both central and peripheral effects of homocysteine and will highlight some of the controversies associated with hyperhomocysteinemia-induced cardiovascular problems.

  9. Alleviation of hepatic fat accumulation by betaine involves reduction of homocysteine via up-regulation of betaine-homocysteine methyltransferase (BHMT).

    PubMed

    Ahn, Chul Won; Jun, Doo Sung; Na, Jong Deok; Choi, Yeo Jin; Kim, Young Chul

    2016-08-26

    We investigated the anti-lipogenic effect of betaine in rats fed methionine and choline-deficient diet (MCD). Intake of MCD for 3 wk resulted in a significant accumulation of hepatic lipids, which was prevented by betaine supplementation in drinking water (1%). Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein-1c (SREBP-1c), and liver kinase B1 (LKB1) was inhibited by MCD intake, and these changes were all inhibited by betaine feeding. Meanwhile, betaine supplementation reversed the reduction of methionine and S-adenosylmethionine (SAM), and the elevation of homocysteine levels in the liver, which could be attributable to the induction of betaine-homocysteine methyltransferase (BHMT) and methionine adenosyltransferase (MAT). Different cell lines were used to clarify the role of homocysteine on activation of the AMPK pathway. Homocysteine treatment decreased pAMPK, pACC, pSREBP-1c and pLKB1 in HepG2 cells. Metformin-induced activation of AMPK was also inhibited by homocysteine. Treatment with hydroxylamine, a cystathionine β-synthase inhibitor, resulted in a reduction of pAMPK, pACC and pSREBP-1c, accompanied by an elevation of intracellular homocysteine. Betaine treatment prevented the homocysteine-induced reduction of pAMPK, pACC, pSREBP-1c and pLKB1 in H4IIE cells, but not in HepG2 cells. Also the elevation of cellular homocysteine and inhibition of protein expression of BHMT were prevented by betaine only in H4IIE cells which express BHMT. The results suggest that the beneficial effect of betaine against hepatic lipid accumulation may be attributed, at least in part, to the depletion of homocysteine via up-regulation of BHMT in hepatocytes. PMID:27320863

  10. Multipotent neurogenic fate of mesenchymal stem cell is determined by Cdk4-mediated hypophosphorylation of Smad-STAT3.

    PubMed

    Kim, Dong-Young; Lee, Janet; Kang, Dongrim; Lee, Do-Hyeong; Kim, Yoon-Ja; Hwang, Sang-Gu; Kim, Dong-Ik; Lee, Chang-Woo; Lee, Kyung-Hoon

    2016-07-01

    Cyclin-dependent kinase (Cdk) in complex with a corresponding cyclin plays a pivotal role in neurogenic differentiation. In particular, Cdk4 activity acts as a signaling switch to direct human mesenchymal stem cells (MSCs) to neural transdifferentiation. However, the molecular evidence of how Cdk4 activity converts MSCs to neurogenic lineage remains unknown. Here, we found that Cdk4 inhibition in human MSCs enriches the populations of neural stem and progenitor pools rather than differentiated glial and neuronal cell pools. Interestingly, Cdk4 inhibition directly inactivates Smads and subsequently STAT3 signaling by hypophosphorylation, and both Cdk4 and Smads levels are linked during the processes of neural transdifferentiation and differentiation. In summary, our results provide novel molecular evidence in which Cdk4 inhibition leads to directing human MSCs to a multipotent neurogenic fate by inactivating Smads-STAT3 signaling. PMID:27192561

  11. Homocysteine-NMDA receptor mediated activation of extracellular-signal regulated kinase leads to neuronal cell death

    PubMed Central

    Poddar, Ranjana; Paul, Surojit

    2009-01-01

    Hyper-homocysteinemia is an independent risk factor for stroke and neurological abnormalities. However the underlying cellular mechanisms by which elevated homocysteine can promote neuronal death is not clear. In the present study we have examined the role of NMDA receptor mediated activation of the extracellular-signal regulated mitogen activated protein (ERK MAP) kinase pathway in homocysteine-dependent neurotoxicity. The study demonstrates that in neurons L-homocysteine-induced cell death is mediated through activation of NMDA receptors. The study also shows that homocysteine-dependent NMDA receptor stimulation and resultant Ca2+ influx leads to rapid and sustained phosphorylation of ERK MAP kinase. Inhibition of ERK phosphorylation attenuates homocysteine mediated neuronal cell death thereby demonstrating that activation of ERK MAP kinase signaling pathway is an intermediate step that couples homocysteine mediated NMDA receptor stimulation to neuronal death. The findings also show that cAMP response-element binding protein (CREB), a pro-survival transcription factor and a downstream target of ERK, is only transiently activated following homocysteine exposure. The sustained activation of ERK but a transient activation of CREB together suggest that exposure to homocysteine initiates a feedback loop that shuts off CREB signaling without affecting ERK phosphorylation and thereby facilitates homocysteine mediated neurotoxicity. PMID:19508427

  12. Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells.

    PubMed

    Chern, C L; Huang, R F; Chen, Y H; Cheng, J T; Liu, T Z

    2001-10-01

    Folate coenzymes are critical for de novo synthesis of purine and thymidine, and for interconversion of amino acids. Folate deficiency inhibits cellular proliferation, disturbs cell cycling, causes genetic damage and eventually results in cell death. Previously, we demonstrated that the demise of human hepatoma Hep G2 cells mediated by folate deficiency proceeded via a p53-independent apoptosis, and the perturbation of intracellular calcium homeostasis was also shown to be involved. To further delineate the mechanism associated with this observed phenomenon, Hep G2 cells were cultivated in the control or folate-deficient media (control media lacking folate, glycine, thymidine and hypoxanthine) for 4 weeks. At the end of this cultivation period, we found that TBARS (an index of lipid peroxidation) concentrations in the folate-deficient cells were drastically increased as compared to the control cells (0.04 vs 0.01 nmole/10(6) cells), indicating that a severe oxidative stress of the former cells had occurred. This phenomenon was also shown to coincide with the ability of these folate-deficient cells to elaborate increased amounts of H2O2 as compared to its folate-supplemented cells (2.87 vs 0.98 nmole/10(5) cells/h). Furthermore, the accelerated production of H2O2 by the folate-deficient cells was also closely correlated with the elevated homocysteine concentrations released in the culture medium (15.37 +/- 2.4 vs 3.58 +/- 2.4 micromole/L; P< 0.001). Finally, we demonstrated that folate deficiency was indeed capable of activating a redox-sensitive transcription factor, NF-kappaB, which is crucial in the control of a reactive oxygen species-mediated apoptosis. In summary, we show that folate deficiency-induced apoptosis is proceeded via the enhanced activation of NF-kappaB, which is the resulting form of the homocysteine-mediated overproduction of hydrogen peroxide.

  13. Emodin Inhibits Homocysteine-Induced C-Reactive Protein Generation in Vascular Smooth Muscle Cells by Regulating PPARγ Expression and ROS-ERK1/2/p38 Signal Pathway.

    PubMed

    Pang, Xiaoming; Liu, Juntian; Li, Yuxia; Zhao, Jingjing; Zhang, Xiaolu

    2015-01-01

    Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. It is known that the elevated plasma homocysteine (Hcy) level is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by inducing CRP expression in vascular smooth muscle cells (VSMCs). In the present study, we observed effect of emodin on Hcy-induced CRP expression in rat VSMCs and molecular mechanisms. The in vitro results showed that pretreatment of VSMCs with emodin inhibited Hcy-induced mRNA and protein expression of CRP in a concentration-dependent manner. The in vivo experiments displayed that emodin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further study revealed that emodin diminished Hcy-stimulated generation of reactive oxygen species (ROS), attenuated Hcy-activated phosphorylation of ERK1/2 and p38, and upregulated Hcy-inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ) in VSMCs. These demonstrate that emodin is able to inhibit Hcy-induced CRP generation in VSMCs, which is related to interfering with ROS-ERK1/2/p38 signal pathway and upregulating PPARγ expression. The present study provides new evidence for the anti-inflammatory and anti-atherosclerotic effects of emodin.

  14. Homocysteine Lowering and Cognition in CKD: The VA Homocysteine Study

    PubMed Central

    Brady, Christopher B.; Gaziano, J. Michael; Cxypoliski, Roberta A.; Guarino, Peter D.; Kaufman, James S.; Warren, Stuart R.; Hartigan, Pamela; Goldfarb, David S.; Jamison, Rex L.

    2009-01-01

    Background Individuals with advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) have high total plasma homocysteine (tHcy) levels, which may be a risk factor for cognitive impairment. Whether treatment with high dose B-vitamins to reduce high tHcy levels improves cognition in persons with kidney disease is unknown. Study Design Randomized controlled trial. Setting & Participants A substudy of 659 patients (mean age 67.3 ± 11.7 years) who participated in a randomized, double-blind, clinical trial, 5 years in duration, conducted in 36 US Department of Veterans Affairs medical centers, of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy. 236 (35.8%) were treated by dialysis (ESRD) and 423 (64.2%) had a Cockcroft-Gault estimated creatinine clearance ≤ 30 ml/min (advanced CKD). All had high tHcy levels (≥15 μmol/L) at baseline. Cognitive assessments began during the follow up period of the main trial, 3 years after treatment began; participants were subsequently retested one year later to assess cognitive change. Intervention Daily high dose B-vitamin capsule (40 mg of folic acid, 100 mg of vitamin B6, and 2 mg of vitamin B12) or placebo. Outcomes Cognitive function at initial assessment and one year later. Measurements The Telephone Interview of Cognitive Status – modified, supplemented with attention, working memory and executive function tests. Results Initial cognitive function was impaired in approximately 19% of patients, regardless of treatment assignment (vitamin or placebo) or kidney disease status (advanced CKD or ESRD). Treatment reduced tHcy levels by 26.7%. Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status one year later. Limitations Cognitive assessments began after treatment was initiated; cognitive assessment was limited. Conclusion Treatment with high daily doses of B-vitamins, which reduced tHcy levels, did not

  15. Homocysteine Metabolism in Children with Down Syndrome: In Vitro Modulation

    PubMed Central

    Pogribna, Marta; Melnyk, Stepan; Pogribny, Igor; Chango, Abalo; Yi, Ping; James, S. Jill

    2001-01-01

    The gene for cystathionine β-synthase (CBS) is located on chromosome 21 and is overexpressed in children with Down syndrome (DS), or trisomy 21. The dual purpose of the present study was to evaluate the impact of overexpression of the CBS gene on homocysteine metabolism in children with DS and to determine whether the supplementation of trisomy 21 lymphoblasts in vitro with selected nutrients would shift the genetically induced metabolic imbalance. Plasma samples were obtained from 42 children with karyotypically confirmed full trisomy 21 and from 36 normal siblings (mean age 7.4 years). Metabolites involved in homocysteine metabolism were measured and compared to those of normal siblings used as controls. Lymphocyte DNA methylation status was determined as a functional endpoint. The results indicated that plasma levels of homocysteine, methionine, S-adenosylhomocysteine, and S-adenosylmethionine were all significantly decreased in children with DS and that their lymphocyte DNA was hypermethylated relative to that in normal siblings. Plasma levels of cystathionine and cysteine were significantly increased, consistent with an increase in CBS activity. Plasma glutathione levels were significantly reduced in the children with DS and may reflect an increase in oxidative stress due to the overexpression of the superoxide dismutase gene, also located on chromosome 21. The addition of methionine, folinic acid, methyl-B12, thymidine, or dimethylglycine to the cultured trisomy 21 lymphoblastoid cells improved the metabolic profile in vitro. The increased activity of CBS in children with DS significantly alters homocysteine metabolism such that the folate-dependent resynthesis of methionine is compromised. The decreased availability of homocysteine promotes the well-established “folate trap,” creating a functional folate deficiency that may contribute to the metabolic pathology of this complex genetic disorder. PMID:11391481

  16. Dietary determinants of plasma homocysteine concentrations.

    PubMed

    Verhoef, Petra; de Groot, Lisette C P G M

    2005-05-01

    Severe hyperhomocysteinemia is typically caused by rare enzymatic defects or by renal failure. In contrast, mild to moderate hyperhomocysteinemia chiefly results from suboptimal status of nutritional factors involved in homocysteine metabolism. Low dietary intake of folate is the most important nutritional cause of elevated homocysteine (tHcy) concentrations. Folic acid is more effective than dietary folate in lowering tHcy concentrations, and a daily dose of 400 mug of folic acid is the minimum daily dose associated with the maximum tHcy-lowering effect ( approximately 20-25% reduction). Mean fasting tHcy concentrations have dropped substantially in populations with mandatory folic acid fortification, and other B-vitamins, such as vitamin B (12), are important determinants of tHcy levels in this setting. Vitamins B (2) and B (6) have little influence on fasting tHcy concentrations, although the former may be relevant in individuals with the MTHFR 677 TT-genotype, and the latter may improve tHcy catabolism in elderly individuals. Betaine and choline can lower fasting tHcy concentrations to a similar extent as folic acid, particularly in the setting of a high intake of methionine. Consumption of tea and coffee increase tHcy concentrations by up to 20%. A high-protein meal also increases tHcy, but these changes are transient, and levels return to normal after an overnight fast. Serine and cystine also influence the methionine-induced postprandial rise in tHcy concentrations. In conclusion, alteration in dietary intake or use of folic acid supplements can substantially lower tHcy concentrations. However, it is not known whether lowering tHcy levels can reduce the risk of cardiovascular disease or cognitive decline or prevent pregnancy complications or osteoporosis. PMID:16047264

  17. The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis

    PubMed Central

    Deminice, Rafael; Ribeiro, Diogo Farias; Frajacomo, Fernando Tadeu Trevisan

    2016-01-01

    Background Although studies have demonstrated that physical exercise alters homocysteine levels in the blood, meta-analyses of the effects of acute exercise and exercise training on homocysteine blood concentration have not been performed, especially regarding the duration and intensity of exercise, which could affect homocysteine levels differently. Objective The aim of this meta-analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood. Method A review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using the online databases PubMed, SPORTDiscus, and SciELO to identify relevant studies published through June 2015. Review Manager was used to calculate the effect size of acute exercise and exercise training using the change in Hcy plasmaserum concentration from baseline to post-acute exercise and trained vs. sedentary control groups, respectively. Weighted mean differences were calculated using random effect models. Results Given the abundance of studies, acute exercise trials were divided into two subgroups according to exercise volume and intensity, whereas the effects of exercise training were analyzed together. Overall, 22 studies with a total of 520 participants indicated increased plasma homocysteine concentration after acute exercise (1.18 μmol/L, 95% CI: 0.71 to 1.65, p < .01). Results of a subgroup analysis indicated that either long-term exercise of low-to-moderate intensity (1.39 μmol/L, 95% CI: 0.9 to 1.89, p < .01) or short-term exercise of high intensity (0.83 μmol/L, 95% CI: 0.19 to 1.40, p < .01) elevated homocysteine levels in the blood. Increased homocysteine induced by exercise was significantly associated with volume of exercise, but not intensity. By contrast, resistance training reduced plasma homocysteine concentration (-1.53 μmol/L, 95% CI: -2.77 to -0.28, p = .02), though aerobic training did not. The cumulative

  18. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death

    SciTech Connect

    Hemendinger, Richelle A. Armstrong, Edward J.; Brooks, Benjamin Rix

    2011-03-15

    Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS). Information on the toxicity of homocysteine in motor neurons is limited and few studies have examined how this toxicity can be modulated. In NSC-34D cells (a hybrid cell line derived from motor neuron-neuroblastoma), homocysteine induces apoptotic cell death in the millimolar range with a TC{sub 50} (toxic concentration at which 50% of maximal cell death is achieved) of 2.2 mM, confirmed by activation of caspase 3/7. Induction of apoptosis was independent of short-term reactive oxygen species (ROS) generation. Methyl Vitamin B12 (MeCbl) and methyl tetrahydrofolate (MTHF), used clinically to treat elevated homocysteine levels, were tested for their ability to reverse homocysteine-mediated motor neuron cell death. MeCbl in the micromolar range was able to provide neuroprotection (2 h pretreatment prior to homocysteine) and neurorescue (simultaneous exposure with homocysteine) against millimolar homocysteine with an IC{sub 50} (concentration at which 50% of maximal cell death is inhibited) of 0.6 {mu}M and 0.4 {mu}M, respectively. In contrast, MTHF (up to 10 {mu}M) had no effect on homocysteine-mediated cell death. MeCbl inhibited caspase 3/7 activation by homocysteine in a time- and dose-dependent manner, whereas MTHF had no effect. We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron-neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS.

  19. Mercury/homocysteine ligation-induced ON/OFF-switching of a T-T mismatch-based oligonucleotide molecular beacon.

    PubMed

    Stobiecka, Magdalena; Molinero, Anthony A; Chałupa, Agata; Hepel, Maria

    2012-06-01

    A molecular beacon (MB) with stem-loop (hairpin) DNA structure and with attached fluorophore-quencher pair at the ends of the strand has been applied to study the interactions of Hg(2+) ions with a thymine-thymine (T-T) mismatch in Watson-Crick base-pairs and the ligative disassembly of MB·Hg(2+) complex by Hg(2+) sequestration with small biomolecule ligands. In this work, a five base-pair stem with configuration 5'-GGTGG...CCTCC-3' for self-hybridization of MB has been utilized. In this configuration, the four GC base-pair binding energy is not sufficient to hybridize fully at intermediate temperatures and to form a hairpin MB conformation. The T-T mismatch built-in into the stem area can effectively bind Hg(2+) ions creating a bridge, T-Hg-T. We have found that the T-Hg-T bridge strongly enhances the ability of MB to hybridize, as evidenced by an unusually large MB melting temperature shift observed on bridge formation, ΔT(m) = +15.1 ± 0.5 °C, for 100 nM MB in MOPS buffer. The observed ΔT(m) is the largest of the ΔT(m) found for other MBs and dsDNA structures. By fitting the parameters of the proposed model of reversible MB interactions to the experimental data, we have determined the T-Hg-T bridge formation constant at 25 °C, K(1) = 8.92 ± 0.42 × 10(17) M(-1) from mercury(II) titration data and K(1) = 1.04 ± 0.51 × 10(18) M(-1) from the bridge disassembly data; ΔG° = -24.53 ± 0.13 kcal/mol. We have found that the biomarker of oxidative stress and cardiovascular disease, homocysteine (Hcys), can sequester Hg(2+) ions from the T-Hg-T complex and withdraw Hg(2+) ions from MB in the form of stable Hg(Hcys)(2)H(2) complexes. Both the model fitting and independent (1)H NMR results on the thymidine-Hg-Hcys system indicate also the high importance of 1:1 complexes. The high value of K(1) for T-Hg-T bridge formation enables analytical determinations of low concentrations of Hg(2+) (limit of detection LOD = 19 nM or 3.8 ppb, based on 3σ method) and Hcys

  20. Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression.

    PubMed

    Bhatia, Pankaj; Singh, Nirmal

    2015-12-01

    Homocysteine (Hcy) is a nonproteogenic sulfur containing amino acid derived from dietary methionine through demethylation. Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia. Hcy excess decreases the S-adenosylmethionine (SAM)-dependent synthesis of catecholamines, viz. dopamine, norepinephrine, epinephrine, and noncatecholamine, viz. serotonin (5-HT), due to genetic alteration in key enzyme MTHFR in the homocysteine metabolism pathway that leads to depression. Thus, hyperhomocysteinemia (HHcy)-induced SAM level is influenced by the single nucleotide polymorphism (SNP) MTHFR C677T. Furthermore, HHcy leads to production of precarious neurotoxic product homocysteic acid (HCA) and cysteine sulfinic acid (CSA) which acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has neurotoxic effects on dopaminergic neurons. In the current review, an attempt has been made to discuss the neurotoxic effects of HHcy in the pathogenesis of depression. PMID:26376956

  1. Homocysteine Homeostasis and Betaine-Homocysteine S-Methyltransferase Expression in the Brain of Hibernating Bats

    PubMed Central

    Zhang, Yijian; Zhu, Tengteng; Wang, Lina; Pan, Yi-Hsuan; Zhang, Shuyi

    2013-01-01

    Elevated homocysteine is an important risk factor that increases cerebrovascular and neurodegenerative disease morbidity. In mammals, B vitamin supplementation can reduce homocysteine levels. Whether, and how, hibernating mammals, that essentially stop ingesting B vitamins, maintain homocysteine metabolism and avoid cerebrovascular impacts and neurodegeneration remain unclear. Here, we compare homocysteine levels in the brains of torpid bats, active bats and rats to identify the molecules involved in homocysteine homeostasis. We found that homocysteine does not elevate in torpid brains, despite declining vitamin B levels. At low levels of vitamin B6 and B12, we found no change in total expression level of the two main enzymes involved in homocysteine metabolism (methionine synthase and cystathionine β-synthase), but a 1.85-fold increase in the expression of the coenzyme-independent betaine-homocysteine S-methyltransferase (BHMT). BHMT expression was observed in the amygdala of basal ganglia and the cerebral cortex where BHMT levels were clearly elevated during torpor. This is the first report of BHMT protein expression in the brain and suggests that BHMT modulates homocysteine in the brains of hibernating bats. BHMT may have a neuroprotective role in the brains of hibernating mammals and further research on this system could expand our biomedical understanding of certain cerebrovascular and neurodegenerative disease processes. PMID:24376891

  2. Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration.

    PubMed

    Can, Cenk; Cinar, Mehtap G; Koşay, Sezen; Evinç, Akgün

    2002-06-14

    We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model. PMID:12044840

  3. High levels of homocysteine results in cerebral amyloid angiopathy in mice.

    PubMed

    Li, Jian-Guo; Praticò, Domenico

    2015-01-01

    High levels of homocysteine is a risk factor for developing Alzheimer's disease (AD), and the effect that this amino acid has on amyloid-β (Aβ) protein precursor metabolism is considered one of the potential mechanism(s) involved in this effect. However, despite consistent literature indicating that this condition results in brain parenchyma amyloidosis, no data are available on whether it may also influence the amount of Aβ deposited in the vasculature. To test this hypothesis, we implemented a model of diet-inducing high homocysteinemia in AD transgenic mice, 3xTg, and assessed them for the development of cerebral amyloid angiopathy (CAA). Compared with controls, mice with high homocysteine showed a significant increase in the amount of Aβ deposited in the brain vasculature, which was not associated with histological evidence of microhemorrhage occurrence. Mice with high homocysteine had a significant reduction in steady state level of the apolipoprotein E, which is a main Aβ chaperon protein, but no changes in its receptor, the low-density-lipoprotein-receptor-1. Our data demonstrate that a diet-induced high homocysteine level favors the development of CAA via a reduction of Aβ clearance and transport within the brain. Therapeutic approaches aimed at restoring brain apolipoprotein E levels should be considered in individuals carrying this environmental risk factor in order to reduce the incidence of homocysteine-dependent CAA. PMID:25061050

  4. Homocysteine and migraine. A narrative review.

    PubMed

    Lippi, Giuseppe; Mattiuzzi, Camilla; Meschi, Tiziana; Cervellin, Gianfranco; Borghi, Loris

    2014-06-10

    Recent evidence suggests that migraine is associated with an increased risk of cardiovascular disorders, so that it is increasingly hypothesized that this primary form of headache may be linked to thrombotic diseases by some biological pathways and risk factors. Homocysteine, a sulfur-containing molecule, is now recognized as an independent risk factor for a variety of thrombotic disorders, especially ischemic heart disease and stroke. This article is hence aimed to provide an overview of epidemiological evidence about the association between homocysteine and migraine published in cross-sectional, prospective or interventional studies. Overall, the evidence gathered from cross-sectional studies that measured plasma homocysteine levels suggests that the epidemiological link between the plasma concentration of this biomarker and migraine is very weak, at best. Contradictory evidence emerged from interventional studies, in which treatment of hyperhomocysteinemia with folic acid or vitamin B supplementation was effective to lower plasma homocysteine and decrease frequency and/or severity of migraine. The association remains largely speculative, however, since it could not be clearly demonstrated that these two biological effects were directly linked. The only study that has assessed homocysteine in cerebrospinal fluid reported that the concentration of this biomarker in migraine patients was significantly increased compared to controls. Although this evidence must be obviously confirmed in larger trials, some putative mechanisms may support a causal link between increased generation of homocysteine in the brain environment and migraine.

  5. Reversal by Growth Hormone of Homocysteine-induced Epithelial-to-Mesenchymal Transition through Membrane Raft-Redox Signaling in Podocytes

    PubMed Central

    Li, Cai-Xia; Xia, Min; Han, Wei-Qing; Li, Xiao-Xue; Zhang, Chun; Boini, Krishna M.; Liu, Xiao-Cheng; Li, Pin-Lan

    2011-01-01

    Epithelial-to-Mesenchymal Transition (EMT) is an important pathogenic mechanism mediating glomerular injury or sclerosis in a variety of renal and systemic diseases such as hyperhomocysteinemia (hHcys). The present study was designed to test whether Hcys-induced EMT in podocytes is reversed by growth hormone (GH), a hormone regulating cell differentiation and growth and to explore the cellular and molecular mechanism mediating its action. It was found that Hcys induced significant EMT in podocytes, as shown by marked decreases in slit diaphragm-associated protein P-cadherin and zonula occludens-1 as epithelial markers and by dramatic increases in the expression of mesenchymal markers, fibroblast specific protein-1 and α-smooth muscle actin, which were detected by all examinations via immunocytochemistry, real time RT-PCR and Western blot analysis. When podocytes were treated with GH at 25 ng/mL, however, Hcys failed to induce podocyte EMT. Using electromagnetic spin resonance spectrometry, Hcys-induced superoxide (O2.−) production via NADPH oxidase was found to be significantly inhibited by GH (66%). Functionally, GH was shown to substantially inhibit Hcys-induced increases in the permeability of podocyte monolayers and to block the decrease in podocin expression in these cells. In addition, NADPH oxidase subunit, gp91phox and GH receptors aggregated in membrane raft clusters, which produced O2.− in response to Hcys and could be blocked by GH, membrane raft disruptors filipin and MCD or NADPH oxidase inhibitor, apocynin. It is concluded that Hcys-induced podocyte EMT is associated with transmembrane membrane raft-redox signaling and that GH reverses this Hcys-induced EMT protecting podocytes from functional disturbance. PMID:21691087

  6. Hypophosphorylation of ribosomal protein S6 is a molecular mechanism underlying ischemic tolerance induced by either hibernation or preconditioning.

    PubMed

    Miyake, Shin-ichi; Wakita, Hideaki; Bernstock, Joshua D; Castri, Paola; Ruetzler, Christl; Miyake, Junko; Lee, Yang-Ja; Hallenbeck, John M

    2015-12-01

    Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) have an extraordinary capacity to withstand prolonged and profound reductions in blood flow and oxygen delivery to the brain without incurring any cellular damage. As such, the hibernation torpor of I. tridecemlineatus provides a valuable model of tolerance to ischemic stress. Herein, we report that during hibernation torpor, a marked reduction in the phosphorylation of the ribosomal protein S6 (rpS6) occurs within the brains of I. tridecemlineatus. Of note, rpS6 phosphorylation was shown to increase in the brains of rats that underwent an occlusion of the middle cerebral artery. However, such an increase was attenuated after the implementation of an ischemic preconditioning paradigm. In addition, cultured cortical neurons treated with the rpS6 kinase (S6K) inhibitors, D-glucosamine or PF4708671, displayed a decrease in rpS6 phosphorylation and a subsequent increase in tolerance to oxygen/glucose deprivation, an in vitro model of ischemic stroke. Collectively, such evidence suggests that the down-regulation of rpS6 signal transduction may account for a substantial part of the observed increase in cellular tolerance to brain ischemia that occurs during hibernation torpor and after ischemic preconditioning. Further identification and characterization of the mechanisms used by hibernating species to increase ischemic tolerance may eventually clarify how the loss of homeostatic control that occurs during and after cerebral ischemia in the clinic can ultimately be minimized and/or prevented. Mammalian hibernation provides a valuable model of tolerance to ischemic stress. Herein, we demonstrate that marked reductions in the phosphorylation of ribosomal protein S6 (rpS6), extracellular signal-regulated kinase family of mitogen-activated protein (MAP) kinase p44/42 (p44/42MAPK) and ribosomal protein S6 kinase (S6K) occur within the brains of both hibernating squirrels and rats, which have undergone an ischemic preconditioning paradigm. We therefore propose that the down-regulation of rpS6 signal transduction may account for a substantial part of the observed increase in cellular tolerance to brain ischemia that occurs during hibernation torpor and after ischemic preconditioning, via a suppression of protein synthesis and/or energy consumption.

  7. Interactions Between Nuclear receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice

    PubMed Central

    Tsuchiya, Hiroyuki; da Costa, Kerry-Ann; Lee, Sangmin; Renga, Barbara; Jaeschke, Hartmut; Yang, Zhihong; Orena, Stephen J.; Goedken, Michael J.; Zhang, Yuxia; Kong, B; Lebofsky, Margitta; Rudraiah, Swetha; Smalling, Rana; Guo, Grace; Fiorucci, Stefano; Zeisel, Steven H.; Wang, Li

    2015-01-01

    BACKGROUND & AIMS Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. METHODS We studied mice with disruptions in Nr0b2 (called SHP-null mice) Bhmt, or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (the NIAAA binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%), or high-fat diets (60%). Serum and livers were collected over a 24 hr light–dark cycle and analyzed by RNA-seq, metabolomic, and quantitative PCR, immunoblot, and chromatin immunoprecipitation assays. RESULTS SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism, compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and Cth by FOXA1. Expression of Bhmt and Cth was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control but not SHP-null mice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice. CONCLUSIONS Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and Cth

  8. Changes in plasma methionine and total homocysteine levels in patients receiving methotrexate infusions.

    PubMed

    Broxson, E H; Stork, L C; Allen, R H; Stabler, S P; Kolhouse, J F

    1989-11-01

    Methotrexate reduces intracellular pools of 5-methyltetrahydrofolate and could result in reduced conversion of homocysteine to methionine by methionine synthetase. This study was designed to investigate the effects of moderate dose to very high dose methotrexate on methionine and total homocysteine as reflections of methotrexate induced intracellular events. Methionine and total homocysteine were measured prior to, during, and following twenty-six 24-h i.v. infusions of 33.6 g/m2 methotrexate (very high dose methotrexate) in 16 children with acute lymphocytic leukemia and seven 4-h i.v. infusions of 8 g/m2 methotrexate (high dose methotrexate) in 5 children with osteogenic sarcoma. Amino acids were measured by gas chromatography/mass spectrophotometry. Mean methionine levels decreased by 70.0 +/- 3.1% (SE) with very high dose methotrexate and 72.6 +/- 5.9% with high dose methotrexate at 24 and 4.5 h, respectively, after beginning methotrexate infusions. Mean total homocysteine levels increased by 61.7 +/- 3.1% with very high dose methotrexate and 55.6 +/- 17.5% with high dose methotrexate at 36 and 24 h, respectively, after beginning methotrexate infusions. No consistent or significant changes were noted in levels of total cysteine, leucine, isoleucine, or valine. Similar changes did not occur in patients receiving prednisone, vincristine, daunomycin, and intrathecal methotrexate as therapy for acute lymphocytic leukemia. These changes in homocysteine and methionine may reflect biological effects of methotrexate that may predict cytotoxicity of methotrexate.

  9. Liver-X-receptor activator prevents homocysteine-induced production of IgG antibodies from murine B lymphocytes via the ROS-NF-{kappa}B pathway

    SciTech Connect

    Chang Lina; Zhang, Zhenmin; Li Wenjing; Dai Jing; Guan Youfei; Wang Xian . E-mail: xwang@bjmu.edu.cn

    2007-06-08

    Our previous study showed that homosysteine (Hcy) promotes proliferation of mouse splenic B lymphocytes. In this study, we investigated whether Hcy could stimulate the production of IgG antibodies. Hcy significantly increased the production of IgG antibodies from resting B lymphocytes. B lymphocytes from ApoE-knockout mice with hyperhomocysteinemia showed elevated IgG secretion at either the basal Hcy level or in response to lipopolysaccharide. Hcy promoted reactive oxygen species (ROS) formation, and free radical scavengers, MnTMPyP decreased Hcy-induced IgG secretion. The inhibitor of NF-{kappa}B (MG132) also significantly reduced Hcy-induced IgG secretion. Furthermore, Hcy-induced formation of ROS, activation of NF-{kappa}B, and secretion of IgG could be inhibited by the liver-X-receptor (LXR) agonist TO 901317. Thus, our data provide strong evidence that HHcy induces IgG production from murine splenic B lymphocytes both in vitro and in vivo. The mechanism might be through the ROS-NF-{kappa}B pathway and can be attenuated by the activation of LXR.

  10. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine.

    PubMed

    Wang, H; Yoshizumi, M; Lai, K; Tsai, J C; Perrella, M A; Haber, E; Lee, M E

    1997-10-01

    Although hyperhomocysteinemia has been recognized recently as a prevalent risk factor for myocardial infarction and stroke, the mechanisms by which it accelerates arteriosclerosis have not been elucidated, mostly because the biological effects of homocysteine can only be demonstrated at very high concentrations and can be mimicked by cysteine, which indicates a lack of specificity. We found that 10-50 microM of homocysteine (a range that overlaps levels observed clinically) but not cysteine inhibited DNA synthesis in vascular endothelial cells (VEC) and arrested their growth at the G1 phase of the cell cycle. Homocysteine in this same range had no effect on the growth of vascular smooth muscle cells (VSMC) or fibroblasts. Homocysteine decreased carboxyl methylation of p21(ras) (a G1 regulator whose activity is regulated by prenylation and methylation in addition to GTP-GDP exchange) by 50% in VEC but not VSMC, a difference that may be explained by the ability of homocysteine to dramatically increase levels of S-adenosylhomocysteine, a potent inhibitor of methyltransferase, in VEC but not VSMC. Moreover, homocysteine-induced hypomethylation in VEC was associated with a 66% reduction in membrane-associated p21(ras) and a 67% reduction in extracellular signal-regulated kinase 1/2, which is a member of the mitogen-activated protein (MAP) kinase family. Because the MAP kinases have been implicated in cell growth, the p21(ras)-MAP kinase pathway may represent one of the mechanisms that mediates homocysteine's effect on VEC growth. VEC damage is a hallmark of arteriosclerosis. Homocysteine-induced inhibition of VEC growth may play an important role in this disease process.

  11. Alcohol consumption and plasma homocysteine.

    PubMed

    Sakuta, Hidenari; Suzuki, Takashi

    2005-10-01

    A few reports show that consumption of spirits and of wine correlate with elevated plasma total homocysteine (tHcy), which is associated with the risk of cardiovascular disease. We analyzed the relation between tHcy and current daily ethanol consumption cross-sectionally in middle-aged Japanese men (n = 974, age 51-59 years). Plasma tHcy was positively associated with consumption of whiskey but not with consumption of shochu (Japanese spirits), sake, beer, or wine. Odds ratios of an increase in daily intake of 30 ml ethanol (approximately 1 standard deviation) for hyperhomocysteinemia (>14.0 micromol/l) were 2.58 (95% confidence interval, 1.29-5.14) for whiskey, 1.08 (0.78-1.50) for shochu, 0.99 (0.59-1.66) for sake, 0.98 (0.58-1.63) for beer, and 1.70 (0.31-9.50) for wine in a multivariate logistic regression analysis adjusted for the daily number of cigarettes smoked, physical activity, vegetable consumption, and serum creatinine levels. After inclusion of plasma folate and vitamin B12 in the multivariate analysis model, the association between whiskey ethanol consumption and hyperhomocysteinemia remained significant with odds ratio of 2.79 (1.36-5.72). These results suggest that whiskey consumption correlates with hyperhomocysteinemia independently of plasma folate or vitamin B12 or lifestyle factors in the population studied.

  12. Alcohol consumption and plasma homocysteine.

    PubMed

    Sakuta, Hidenari; Suzuki, Takashi

    2005-10-01

    A few reports show that consumption of spirits and of wine correlate with elevated plasma total homocysteine (tHcy), which is associated with the risk of cardiovascular disease. We analyzed the relation between tHcy and current daily ethanol consumption cross-sectionally in middle-aged Japanese men (n = 974, age 51-59 years). Plasma tHcy was positively associated with consumption of whiskey but not with consumption of shochu (Japanese spirits), sake, beer, or wine. Odds ratios of an increase in daily intake of 30 ml ethanol (approximately 1 standard deviation) for hyperhomocysteinemia (>14.0 micromol/l) were 2.58 (95% confidence interval, 1.29-5.14) for whiskey, 1.08 (0.78-1.50) for shochu, 0.99 (0.59-1.66) for sake, 0.98 (0.58-1.63) for beer, and 1.70 (0.31-9.50) for wine in a multivariate logistic regression analysis adjusted for the daily number of cigarettes smoked, physical activity, vegetable consumption, and serum creatinine levels. After inclusion of plasma folate and vitamin B12 in the multivariate analysis model, the association between whiskey ethanol consumption and hyperhomocysteinemia remained significant with odds ratio of 2.79 (1.36-5.72). These results suggest that whiskey consumption correlates with hyperhomocysteinemia independently of plasma folate or vitamin B12 or lifestyle factors in the population studied. PMID:16584970

  13. [Mechanisms that protect against homocysteine toxicity].

    PubMed

    Zimny, Jarosław

    2008-01-01

    Elevated concentrations of homocysteine (Hcy) in human tissues have been correlated with some diseases, such as cardio-vascular, neurodegenerative, and kidney disorders. Hcy occurs in human blood in several forms. The most reactive is homocysteine thiolactone (HcyTl). It spontaneously homocysteinylates proteins impairing their functions. As has been evidenced recently, organisms developed protective mechanisms against the HcyTl toxicity. The first mechanism discovered was the calcium-dependent enzyme occurring in mammalian sera, known till then as paraoxonase, which hydrolyzes HcyTl to Hcy. Chronologically second mechanism discovered was urinary excretion of HcyTl. The third protective mechanism is the HcyTl hydrolysis catalyzed by intracellular enzyme known as bleomycin hydrolase. This review outlines current knowledge of the Hcy toxicity and of the three aforementioned protective mechanisms, emphasizing the role of bleomycin hydrolase/ homocysteine-thiolactonase. PMID:18610586

  14. Homocysteine thiolactone affects protein ubiquitination in yeast.

    PubMed

    Bretes, Ewa; Zimny, Jarosław

    2013-01-01

    The formation of homocysteine thiolactone (HcyTl) from homocysteine occurs in all examined so far organisms including bacteria, yeast, and humans. Protein N-homocysteinylation at the ε-amino group of lysine is an adverse result of HcyTl accumulation. Since tagging of proteins by ubiquitination before their proteasomal degradation takes place at the same residue, we wondered how N-homocysteinylation may affect the ubiquitination of proteins. We used different yeast strains carrying mutations in genes involved in the homocysteine metabolism. We found positive correlation between the concentration of endogenous HcyTl and the concentration of ubiquitinated proteins. This suggests that N-homocysteinylation of proteins apparently does not preclude but rather promotes their decomposition. PMID:24051443

  15. Constitutive hypophosphorylation of extracellular signal-regulated kinases-1/2 and down-regulation of c-Jun in human gastric adenocarcinoma

    SciTech Connect

    Wu, William Ka Kei; Sung, Joseph Joe Yiu; Yu Le; Li Zhijie; Chu, Kent Man; Cho, C.H.

    2008-08-22

    Hyperphosphorylation of extracellular signal-regulated protein kinases-1/2 (ERK1/2) is known to promote cancer cell proliferation. We therefore investigated the constitutive phosphorylation levels of ERK1/2 and the expression of its downstream targets c-Fos, c-Jun, and cyclooxygenase-2 (COX-2) in biopsied human gastric cancer tissues. Results showed that ERK1/2 phosphorylation and c-Jun expression were significantly lowered in gastric cancer compared with the non-cancer adjacent tissues. The expression of c-Fos, however, was not altered while COX-2 was significantly up-regulated. To conclude, we demonstrate that hypophosphorylation of ERK1/2 may occur in gastric cancer. Such discovery may have implication in the application of pathway-directed therapy for this malignant disease.

  16. BODIPY-based azamacrocyclic ensemble for selective fluorescence detection and quantification of homocysteine in biological applications.

    PubMed

    Li, Zan; Geng, Zhi-Rong; Zhang, Cui; Wang, Xiao-Bo; Wang, Zhi-Lin

    2015-10-15

    Considering the significant role of plasma homocysteine in physiological processes, two ensembles (F465-Cu(2+) and F508-Cu(2+)) were constructed based on a BODIPY (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene) scaffold conjugated with an azamacrocyclic (1,4,7-triazacyclononane and 1,4,7,10-tetraazacyclododecane) Cu(2+) complex. The results of this effort demonstrated that the F465-Cu(2+) ensemble could be employed to detect homocysteine in the presence of other biologically relevant species, including cysteine and glutathione, under physiological conditions with high selectivity and sensitivity in the turn-on fluorescence mode, while the F508-Cu(2+) ensemble showed no fluorescence responses toward biothiols. A possible mechanism for this homocysteine-specific specificity involving the formation of a homocysteine-induced six-membered ring sandwich structure was proposed and confirmed for the first time by time-dependent fluorescence spectra, ESI-MS and EPR. The detection limit of homocysteine in deproteinized human serum was calculated to be 241.4 nM with a linear range of 0-90.0 μM and the detection limit of F465 for Cu(2+) is 74.7 nM with a linear range of 0-6.0 μM (F508, 80.2 nM, 0-7.0 μM). We have demonstrated the application of the F465-Cu(2+) ensemble for detecting homocysteine in human serum and monitoring the activity of cystathionine β-synthase in vitro. PMID:25951084

  17. Public health significance of elevated homocysteine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of two pathways: remethylation, which requires folic acid and vitamin B12 coenzymes; and transsulfuration, which requires pyridoxal-5'-phosphate, the vitamin B6 coenzyme. Data from a number of laboratories suggest that m...

  18. B Vitamins, Homocysteine and Bone Health

    PubMed Central

    Fratoni, Valentina; Brandi, Maria Luisa

    2015-01-01

    Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn. PMID:25830943

  19. B vitamins, homocysteine and bone health.

    PubMed

    Fratoni, Valentina; Brandi, Maria Luisa

    2015-03-30

    Nutrition is one of the most important modifiable factors involved in the development and maintenance of good bone health. Calcium and Vitamin D have confirmed and established roles in the maintenance of proper bone health. However, other nutritional factors could also be implicated. This review will explore the emerging evidence of the supporting role of certain B Vitamins as modifiable factors associated with bone health. Individuals with high levels of homocysteine (hcy) exhibit reduced bone mineral density (BMD), alteration in microarchitecture and increased bone fragility. The pathophysiology caused by high serum homocysteine is not completely clear regarding fractures, but it may involve factors, such as bone mineral density, bone turnover, bone blood flow and collagen cross-linking. It is uncertain whether supplementation with B Vitamins, such as folate, Vitamin B1, and Vitamin B6, could decrease hip fracture incidence, but the results of further clinical trials should be awaited before a conclusion is drawn.

  20. Homocysteine and Familial Longevity: The Leiden Longevity Study

    PubMed Central

    Wijsman, Carolien A.; van Heemst, Diana; Rozing, Maarten P.; Slagboom, P. Eline; Beekman, Marian; de Craen, Anton J. M.; Maier, Andrea B.; Westendorp, Rudi G. J.; Blom, Henk J.; Mooijaart, Simon P.

    2011-01-01

    Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity. PMID:21408159

  1. Homocysteine-Mediated Modulation of Mitochondrial Dynamics in Retinal Ganglion Cells

    PubMed Central

    Ganapathy, Preethi S.; Perry, Richard L.; Tawfik, Amany; Smith, Robert M.; Perry, Elizabeth; Roon, Penny; Bozard, B. Renee; Ha, Yonju

    2011-01-01

    Purpose. To evaluate the effect of excess homocysteine on the regulation of retinal ganglion cell mitochondrial dynamics. Methods. Mice deficient in cystathionine-β-synthase (cbs) were used as a model of hyperhomocysteinemia. Gene and protein expression analyses of Opa1 and Fis1 were performed on cbs+/−neural retinas. Mitochondria within retinal ganglion cell axons underwent systematic ultrastructural analysis to measure area, length, width, and the distance between the mitochondria and the axon wall. Primary mouse ganglion cells were cultured, treated with homocysteine, and assessed for levels of Opa1 and Fis1 protein, the number of mitochondria per length of neurite, and levels of cleaved caspase-3. Results. Opa1 and Fis1 protein levels in cbs+/− neural retinas were elevated to 191.00% ± 26.40% and 226.20% ± 4.57%, respectively, compared with wild-type. Mitochondria of cbs+/− retinas were smaller in all parameters studied, including area (0.32 ± 0.01μm2 vs. 0.42 ± 0.02 μm2), compared with wild-type. Primary ganglion cells treated with homocysteine had elevations in Opa1 and Fis1 proteins, a significantly higher number of mitochondria per length of neurite (0.1781 ± 0.017 vs. 0.1156 ± 0.012), and significantly higher levels of cleaved caspase-3 compared with control. Conclusions. This study provides the first evidence that homocysteine-induced ganglion cell loss involves the dysregulation of mitochondrial dynamics, both in vivo and in vitro. The present data suggest increased mitochondrial fission as a novel mechanism of homocysteine toxicity to neurons. Of particular relevance are glaucoma and Alzheimer's disease, neurodegenerative diseases that are associated with hyperhomocysteinemia and, more recently, have implicated increased mitochondrial fission in their pathogeneses. PMID:21642619

  2. Preparation of CuO/ZnO nanocomposite and its application as a cysteine/homocysteine colorimetric and fluorescence detector.

    PubMed

    Šimšíková, Michaela; Čechal, Jan; Zorkovská, Anna; Antalík, Marián; Šikola, Tomáš

    2014-11-01

    Cysteine and homocysteine play a crucial role in many biological functions but abnormal levels of these amino acids may lead to various forms of pathogenesis. Therefore, selective and easy-to-use methods for the detection of cysteine and homocysteine are essential for the early diagnosis of developing diseases. In this paper we report on a rapid, straightforward and highly selective method for the detection of cysteine (Cys) and homocysteine (Hcy) which uses a CuO/ZnO nanocomposite as a dual colorimetric and fluorometric assay. The presence of Cys and Hcy in a solution of these nanorods (NRs) induces a change in its color from light blue to dark grey which is visible to the naked eye. This is accompanied by a blue shift in the absorption spectra from 725 nm to 650 nm and a decrease in the intensity of CuO/ZnO nanocomposite emission. These changes are ascribed to the reduction of Cu(II) to Cu(0), and the oxidation of cysteine (homocysteine) and subsequent formation of the disulfide bond. This novel assay method does not respond to any other amino-acid which is present in living organisms; therefore the selective determination of cysteine (homocysteine) with a lower analyte limit of 40 μM (4.8 μg mL(-1)) can be carried out in aqueous solutions without the need for any sophisticated instrumentation, fluorophore molecules or complicated procedures.

  3. Preparation of CuO/ZnO nanocomposite and its application as a cysteine/homocysteine colorimetric and fluorescence detector.

    PubMed

    Šimšíková, Michaela; Čechal, Jan; Zorkovská, Anna; Antalík, Marián; Šikola, Tomáš

    2014-11-01

    Cysteine and homocysteine play a crucial role in many biological functions but abnormal levels of these amino acids may lead to various forms of pathogenesis. Therefore, selective and easy-to-use methods for the detection of cysteine and homocysteine are essential for the early diagnosis of developing diseases. In this paper we report on a rapid, straightforward and highly selective method for the detection of cysteine (Cys) and homocysteine (Hcy) which uses a CuO/ZnO nanocomposite as a dual colorimetric and fluorometric assay. The presence of Cys and Hcy in a solution of these nanorods (NRs) induces a change in its color from light blue to dark grey which is visible to the naked eye. This is accompanied by a blue shift in the absorption spectra from 725 nm to 650 nm and a decrease in the intensity of CuO/ZnO nanocomposite emission. These changes are ascribed to the reduction of Cu(II) to Cu(0), and the oxidation of cysteine (homocysteine) and subsequent formation of the disulfide bond. This novel assay method does not respond to any other amino-acid which is present in living organisms; therefore the selective determination of cysteine (homocysteine) with a lower analyte limit of 40 μM (4.8 μg mL(-1)) can be carried out in aqueous solutions without the need for any sophisticated instrumentation, fluorophore molecules or complicated procedures. PMID:25465753

  4. Homocysteine levels in vegetarians versus omnivores.

    PubMed

    Krajcovicová-Kudlácková, M; Blazícek, P; Kopcová, J; Béderová, A; Babinská, K

    2000-01-01

    Vitamin B(12), folate, and vitamin B(6) are the main determinants of homocysteinemia. The vegan diet provides no vitamin B(12), but also less strict forms of alternative nutrition may suffer from a deficit of this vitamin. The plasma homocysteine level was measured in alternative nutrition groups of adults (lacto- and lactoovovegetarians, n = 62; vegans, n = 32) and compared with the levels in a group consuming traditional diet (n = 59), omnivores). In the group of vegetarians the average homocysteine level is 13.18 vs. 10.19 micromol/l in omnivores; the frequency of hyperhomocysteinemia is 29 vs. 5% in omnivores. In the group of vegans the average homocysteine value is 15.79 micromol/l (53% of the individual values exceeded 15 micromol/l). Omnivores consume the recommended amount of methionine; however, in individuals consuming an alternative diet, the intake of methionine is deficient (assessed by food frequency questionnaire; lower content of methionine in plant proteins). Under conditions of lower methionine availability the remethylation pathway prevails; therefore, vitamin B(12) and folate were evaluated in relation to the homocysteine level. The serum vitamin B(12) levels are significantly lower in the alternative nutrition groups (214.8 pmol/l in vegetarians, 140.1 pmol/l in vegans vs. 344.7 pmol/l in omnivores); a deficit (<179.0 pmol/l) was found in 26% of the vegetarians and in 78% of the vegans vs. 0% in omnivores. The serum folate levels were within the range of reference values in all groups; however, they were significantly lower in omnivores. The results show that the mild hyperhomocysteinemia in alternative nutrition is a consequence of vitamin B(12) deficiency.

  5. Homocysteine, B Vitamins, and Cognitive Impairment.

    PubMed

    Smith, A David; Refsum, Helga

    2016-07-17

    Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia. Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process. Homocysteine may interact with both risk factors and protective factors, thereby identifying people at risk but also providing potential strategies for early intervention. Public health steps to slow cognitive decline should be promoted in individuals who are at risk of dementia, and more trials are needed to see if simple interventions with nutrients can prevent progression to dementia. PMID:27431367

  6. Impact of homocysteine-thiolactone on plasma fibrin networks.

    PubMed

    Genoud, Valeria; Lauricella, Ana María; Kordich, Lucía C; Quintana, Irene

    2014-11-01

    Epidemiologic studies have shown that hyperhomocysteinemia is an independent risk factor for vascular disease. Homocysteine (Hcy) circulates as different species, mostly protein bound, and approximately 1% as its reduced form and the cyclic thioester homocysteine-thiolactone (HTL). Despite the level of plasma thiolactone being markedly low, detrimental effects are related to its high reactivity. HTL reacts with proteins by acylation of free basic amino groups; in particular, the epsilon-amino group of lysine residues forms adducts and induces structural and functional changes in plasma proteins. In order to assess the effects of HTL on plasma fibrin networks, a pool of normal plasma incubated with HTL (100, 500 and 1,000 μmol/L, respectively) was evaluated by global coagulation tests and fibrin formation kinetic assays, and the resulting fibrin was observed by scanning electron microscopy. HTL significantly prolonged global coagulation tests in a concentration-dependent manner with respect to control, and increases were up to 14.5%. Fibrin formation kinetic parameters displayed statistically significant differences between HTL-treated plasma and control in a concentration-dependent way, showing higher lag phase and lower maximum reaction velocity and final network optical density. Electron microscopy analysis of HTL plasma networks revealed a compact architecture, with more branches and shorter fibers than control. We can conclude that HTL induced a slower coagulation process, rendering more tightly packed fibrin clots. Since these features of the networks have been related to impaired fibrinolysis, the N-homocysteinylation reactions would be involved in the prothrombotic effects associated to hyperhomocysteinemia.

  7. Increased CSF Homocysteine in Pathological Gamblers Compared with Healthy Controls

    ERIC Educational Resources Information Center

    Nordin, Conny; Sjodin, Ingemar

    2009-01-01

    Neurocognitive disturbances suggesting a frontal lobe dysfunction have been observed in pathological gamblers and alcohol dependents. Given that a high homocysteine level has been suggested to be a mediating factor in alcohol-related cognitive decline, we have determined homocysteine and cobalamine in cerebrospinal fluid (CSF) obtained from 11…

  8. Genetic variation in homocysteine metabolism, cognition, and white matter lesions.

    PubMed

    de Lau, Lonneke M L; van Meurs, Joyce B J; Uitterlinden, André G; Smith, A David; Refsum, Helga; Johnston, Carole; Breteler, Monique M B

    2010-11-01

    Several studies have shown an association between homocysteine concentration and cognitive performance or cerebral white matter lesions. However, variations in genes encoding for enzymes and other proteins that play a role in homocysteine metabolism have hardly been evaluated in relation to these outcome measures. In the population-based Rotterdam Scan Study, we examined the association of seven polymorphisms of genes involved in homocysteine metabolism (MTHFR 677C>T, MTHFR 1298A>C, RFC 80G>A, TC 776C>G, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68) with plasma total homocysteine, cognitive performance, and cerebral white matter lesions among 1011 non-demented elderly participants. Of all the studied polymorphisms, only MTHFR 677C>T was associated with homocysteine concentration. No significant relationship was observed for any of the polymorphisms with cognitive performance or severity of cerebral white matter lesions.

  9. Specific potassium ion interactions facilitate homocysteine binding to betaine-homocysteine S-methyltransferase.

    PubMed

    Mládková, Jana; Hladílková, Jana; Diamond, Carrie E; Tryon, Katherine; Yamada, Kazuhiro; Garrow, Timothy A; Jungwirth, Pavel; Koutmos, Markos; Jiráček, Jiří

    2014-10-01

    Betaine-homocysteine S-methyltransferase (BHMT) is a zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. This reaction supports S-adenosylmethionine biosynthesis, which is required for hundreds of methylation reactions in humans. Herein we report that BHMT is activated by potassium ions with an apparent K(M) for K⁺ of about 100 µM. The presence of potassium ions lowers the apparent K(M) of the enzyme for homocysteine, but it does not affect the apparent K(M) for betaine or the apparent k(cat) for either substrate. We employed molecular dynamics (MD) simulations to theoretically predict and protein crystallography to experimentally localize the binding site(s) for potassium ion(s). Simulations predicted that K⁺ ion would interact with residues Asp26 and/or Glu159. Our crystal structure of BHMT bound to homocysteine confirms these sites of interaction and reveals further contacts between K⁺ ion and BHMT residues Gly27, Gln72, Gln247, and Gly298. The potassium binding residues in BHMT partially overlap with the previously identified DGG (Asp26-Gly27-Gly28) fingerprint in the Pfam 02574 group of methyltransferases. Subsequent biochemical characterization of several site-specific BHMT mutants confirmed the results obtained by the MD simulations and crystallographic data. Together, the data herein indicate that the role of potassium ions in BHMT is structural and that potassium ion facilitates the specific binding of homocysteine to the active site of the enzyme.

  10. Homocysteine and Raynaud's phenomenon: a review.

    PubMed

    Lazzerini, Pietro Enea; Capecchi, Pier Leopoldo; Bisogno, Stefania; Cozzalupi, Mauro; Rossi, Pier Carlo; Pasini, Franco Laghi

    2010-01-01

    Raynaud's phenomenon, categorized as primary and secondary when occurring isolated or in association with an underlying disease, respectively, is a paroxysmal and recurrent acral ischemia resulting from an abnormal arterial vasospastic response to cold or emotional stress. The key issue in the pathogenesis of Raynaud's phenomenon is presumed to be a dysregulation in the mechanisms of vascular motility resulting in an imbalance between vasodilatation and vasoconstriction. Homocysteine, a non-protein forming sulphured amino acid proposed as an independent risk factor for atherothrombosis in the general population, clearly demonstrated to produce vascular damage through mechanisms also including endothelial injury and modifications in circulating mediators of vasomotion. The rationale for homocysteine involvement in the pathogenesis of Raynaud's phenomenon led some authors to investigate the possible association between mild hyperhomocysteinemia and such a vascular disturbance, particularly in the course of connective tissue disease. Here we review data regarding this putative association and the supposed mechanisms involved, also discussing the emblematic case of a patient with new-onset severe Raynaud's phenomenon and markedly elevated homocysteinemia.

  11. [Gastrointestinal disease with elevated plasma homocysteine level].

    PubMed

    Coll, P; Guttormsen, A B; Berstad, A

    1999-10-10

    Elevated plasma homocystein (tHcy) is a marker for functional deficiency of folate and/or cobalamin. Malabsorption of these vitamins occurs in various gastroenterologic diseases. A frequent mutation (C677T) in the gene coding for the enzyme methyltetrahydrofolate reductase (MTHFR) is often associated with elevated values of tHcy. We have investigated 24 patients with tHcy > 40 mumol/l for gastrointestinal disease that can contribute to such elevation. Of these, 19 were homozygous for mutated MTHFR, four were heterozygous and one was normal. We found two cases of probable celiac disease, one case of Crohn's disease and one case of ulcerative colitis. These four were homozygous for the C667T mutation. Furthermore, we found eight persons who were anacidic; four homozygous, three heterozygous and one normal. All had gastritis histologically, six had serum gastrin > 50 pmol/l, and four were already on treatment with cobalamin injections. Helicobacter pylori-infection was found in nine out of 22 persons. Gastrointestinal disease occurs frequently in patients with tHcy > 40 mumol/l, but with the exception of conditions resulting in serious deficiency of cobalamin, these diseases alone do not seem sufficient to cause such high levels. We suggest that a reasonable approach to patients with homocystein values above 40 mumol/l is to exclude cobalamin deficiency, and that further investigations should be based upon thorough anamnesis and symptoms. PMID:10563175

  12. [Plasma homocysteine levels in patients with ischemic heart disease].

    PubMed

    Márk, L; Erdei, F; Márki-Zay, J; Nagy, E; Kondacs, A; Katona, A

    2001-07-29

    In the latest years it became clear that beside traditional cardiovascular risk factors the high plasma homocysteine level increases the risk of atherosclerotic diseases too. Metaanalysis of 27 papers found that 10% of population's coronary risk is attributable to homocysteine and a 5 mumol/l increase in its plasma level elevates the coronary risk by as much as 0.5 mumol/l cholesterol increase. Recent studies have shown an inverse relation between the levels of plasma homocysteine and that of folic acid, vitamin B6, vitamin B12. The latters are cofactors and substrates of the homocysteine and methionin metabolism. The plasma total cholesterol, HDL-cholesterol, triglyceride, lipoprotein(a), Apo A1, Apo B and homocysteine concentrations were examined in 39 patients suffering from coronary artery disease treated in the Cardiac Rehabilitation Department of our hospital. Twenty of them were treated by folic acid and vitamin B6 for a three week period. The mean (+/- SD) plasma homocysteine concentration was 15.60 +/- 6.14 mumol/l. In the treated subgroup the mean (+/- SD) plasma homocysteine concentration was 17.3 +/- 7.00 mumol/l, the mean (+/- SD) plasma folic acid level was 8.58 +/- 4.6 mumol/l. After the three week treatment period (folic acid and vitamin B6) the plasma homocysteine level decreased by 26.5% (p = 0.012), that of folic acid increased by 68.7% (p = 0.002). From the plasma lipids the level of total- and LDL-cholesterol decreased significantly (6.7% and 10.4%, P < 0.05), caused by the strict diet during hospital treatment. As for the genetic polymorphism of the V677 gen of the metylenetetrahydrofolate-reductase (MTHFR) enzyme there was a significant correlation with homocysteine level (r = 0.436, p = 0.010), and a negative, but not significant correlation with the folic acid level (r = -0.354).

  13. Relationship between homocysteine and intraocular pressure in men and women

    PubMed Central

    Leibovitzh, Haim; Cohen, Eytan; levi, Amos; Kramer, Michal; Shochat, Tzippy; Goldberg, Elad; Krause, Ilan

    2016-01-01

    Abstract The relationship between homocysteine levels and glaucoma has been questioned in previous studies without conclusive results. In the current study, we assessed the relationship between homocysteine levels and intraocular pressure which is one of the main factors in the development of glaucoma in men and women. A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 11,850 subjects, within an age range 20 to 80 years. The relationship between homocysteine and intraocular pressure has been investigated by comparing intraocular pressure in subjects with elevated and normal homocysteine and by comparing homocysteine levels in subjects with elevated and normal intraocular pressure. In addition, we compared the levels of homocysteine in subjects with and without a confirmed diagnosis of glaucoma. The mean IOP (±SD) in subjects with normal homocysteine levels(≤15 μmol/L) was 13.2 ± 2.3 mm Hg and 13.4 ± 2.4 mm Hg in those with high homocysteine levels (>15 μmol/L) (P < 0.008, 95% confidence interval [CI] 0.3–0.09).Nonetheless, after multivariate adjustment for age, gender, vitamin B12, and folic acid statistical significance was no longer demonstrated (P = 0.37). Mean homocysteine levels (±SD) in subjects with normal intraocular pressure of ≤ 21 mm Hg was 11.7 ± 5.5 μmol/L and 12.09 ± 3.43 μmol/L in those with elevated intraocular pressure (P = 0.4, 95%CI 1.1–1.8). Mean homocysteine levels (±SD) in subjects with glaucoma were 11.2 ± 3.5 μmol/L compared to 11.7 ± 5.5 μmol/L in subjects without glaucoma and normal intraocular pressure ≤ 21 mm Hg (P = 0.4, 95% CI 1.2–2.1). The current study displays no clinical correlation between the homocysteine level and the intraocular pressure. Homocysteine may not be used as a predictive parameter to recognize those subjects prone to develop elevated intraocular pressure. PMID:27661027

  14. Organotypic tissue culture investigation of homocysteine thiolactone cardiotoxic effect.

    PubMed

    Lopatina, Ekaterina V; Kipenko, A V; Penniyaynen, V A; Pasatetskaya, N A; Djuric, D; Krylov, B V

    2015-06-01

    Homocysteine thiolactone was demonstrated to inhibit the growth of 10-12-day-old chicken embryo cardiac tissue explants at 7 × 10⁻⁹ -1 × 10⁻³ M concentrations in a dose-dependent manner. The maximal cardiotoxic effect of homocysteine thiolactone was detected at 1 × 10⁻³ M, which corresponds to severe hyperhomocysteinemia. The results of experiments on culturing of cardiac tissue explants in the medium containing homocysteine thiolactone (1 × 10⁻³ M) and ouabain at concentrations regulating the signal-transducing (1 × 10⁻¹⁰ M) and pumping (1 × 10⁻⁸ M) functions of Na⁺,K⁺ -ATPase indicate that the cardiotoxic effect of homocysteine thiolactone is supposed to result from inhibition of the Na⁺,K⁺ -ATPase pumping function.

  15. Homocysteine and Cognitive Performance in Elders with Self-Neglect

    NASA Technical Reports Server (NTRS)

    Burnett, J.; Smith, S.M.; Aung, K.; Dyer, C.

    2009-01-01

    Elevated plasma homocysteine has been associated with altered cognitive performance in older adults. Elders referred to Adult Protective Services (APS) for self-neglect have been reported to have elevated plasma homocysteine levels and to suffer from cognitive impairment. This study assesses the association, if any, between plasma homocysteine and cognitive performance among elders with self-neglect. Methods: Sixty-five community-living adults, 65 years of age and older, reported to Adult Protective Services for self-neglect and 55 matched controls (matched for age, ethnicity, gender and socio-economic status) consented and participated in this study. The research team conducted in-home comprehensive geriatric assessments which included the mini-mental state exam (MMSE), the 15-item geriatric depression scale (GDS), the Wolf-Klein Clock Drawing Tests (CDT) and a comprehensive nutritional biochemistry panel, which included plasma homocysteine. Student s t tests and Pearson correlations were conducted to assess for bivariate associations. Results: Elders with self-neglect had significantly higher plasma homocysteine levels (M=12.68umol/L, sd=4.4) compared to the controls (M=10.40umol/L, sd=3.61;t=3.21, df=127, p=.002). There were no statistically significant associations between cognitive performance and plasma homocysteine in the self-neglect group, however there was a significant correlation between plasma homocysteine and the CDT among the controls (r=-.296, p=.022). Conclusion: Mean plasma homocysteine levels were significantly higher in elders with self-neglect, however, they do not appear to be related to cognitive performance, indicating that cognitive impairment in elder self-neglect involve mechanisms other than hyperhomocysteinemia. These findings warrant further investigation

  16. A Protein Extract from Chicken Reduces Plasma Homocysteine in Rats

    PubMed Central

    Lysne, Vegard; Bjørndal, Bodil; Vik, Rita; Nordrehaug, Jan Erik; Skorve, Jon; Nygård, Ottar; Berge, Rolf K.

    2015-01-01

    The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP. PMID:26053618

  17. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed

    Kocer, Bilge; Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia. PMID:27493964

  18. Homocysteine injures vascular endothelial cells by inhibiting mitochondrial activity

    PubMed Central

    Yang, Fengyong; Qi, Xiujing; Gao, Zheng; Yang, Xingju; Zheng, Xingfeng; Duan, Chonghao; Zheng, Jian

    2016-01-01

    The aim of the present study was to investigate the role of homocysteine (Hcy) in the pathogenesis of pulmonary embolism (PE) and the associated molecular mechanisms in human umbilical vein endothelial cells (HUVECs). Hcy contents were detected with high-performance liquid chromatography. Apoptosis was detected by flow cytometry using Annexin-V staining. Cytochrome c oxidase (COX) activity was assessed with an enzyme activity assay, and the expression levels of COX 17 were determined by western blot analysis. Intracellular reactive oxygen species levels were measured using a microplate reader with a fluorescence probe. The results demonstrated that, compared with the control group, the serum Hcy levels were significantly elevated in the PE group, suggesting that Hcy may be an indicator for PE. Following treatment with Hcy, the apoptosis rate was markedly elevated in HUVECs. Moreover, Hcy decreased COX activity and downregulated the expression of COX 17 in HUVECs. Furthermore, Hcy increased the ROS levels in these endothelial cells. However, all the above-mentioned physiopathological changes induced by Hcy in HUVECs could be restored by folic acid. In conclusion, the results of the present study demonstrated that Hcy inhibited COX activity, downregulated COX 17 expression, increased intracellular ROS levels and enhanced apoptosis in endothelial cells.

  19. Acute homocysteine administration impairs memory consolidation on inhibitory avoidance task and decreases hippocampal brain-derived neurotrophic factor immunocontent: prevention by folic acid treatment.

    PubMed

    Matté, C; Pereira, L O; Dos Santos, T M; Mackedanz, V; Cunha, A A; Netto, C A; Wyse, A T S

    2009-11-10

    In the present study, we first investigated the effect of single homocysteine administration on consolidation of short- and long-term memories of inhibitory avoidance task in Wistar rats. We also measured brain-derived neurotrophic factor levels in the hippocampus and parietal cortex of rats. The influence of pretreatment with folic acid on behavioral and biochemical effects elicited by homocysteine was also studied. Wistar rats were subjected to a folic acid or saline pretreatment from their 22(nd) to 28(th) day of life; 12 h later they were submitted to a single administration of homocysteine or saline. For motor activity and memory evaluation we performed open-field and inhibitory avoidance tasks. Hippocampus and parietal cortex were obtained for brain-derived neurotrophic factor immunocontent determination. Results showed that homocysteine impaired short- and long-term memories and reduced brain-derived neurotrophic factor levels in the hippocampus. Pretreatment with folic acid prevented both the memory deficit and the reduction in the brain-derived neurotrophic factor immunocontent induced by homocysteine injection. Further studies are required to determine the entire mechanism by which folic acid acts and its potential therapeutic use for memory impairment prevention in homocystinuric patients.

  20. Plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate treatment in pediatric patients with acute lymphoblastic leukemia or Burkitt lymphoma: association with hepatotoxicity.

    PubMed

    Kubota, Masaru; Nakata, Rieko; Adachi, Souichi; Watanabe, Ken-Ichiro; Heike, Toshio; Takeshita, Yasufumi; Shima, Midori

    2014-07-01

    This study aimed to investigate: (i) changes of plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate (HD-MTX) treatment and (ii) the correlation of these sulfur-containing amino acids with MTX-induced hepatotoxicity. Fifteen pediatric patients with acute lymphoblastic leukemia and one patient with Burkitt lymphoma, with a total of 26 treatment courses of HD-MTX, were enrolled. Homocysteine levels increased at 24 h after HD-MTX treatment, and showed marginal decreases at 48 and 72 h. Methionine levels showed a biphasic pattern, i.e. an initial decrease at 24 h followed by increases at 48 and 72 h. S-adenosylhomocysteine exhibited a marginal decrease at 24 h. Changes of homocysteine exhibited significant correlation only with a maximum increase of alanine aminotransferase or total bilirubin from baseline. This study has demonstrated, for the first time, simultaneous changes of plasma homocysteine, methionine and S-adenosylhomocysteine following HD-MTX. The potential of homocysteine as a marker of hepatotoxicity is also presented.

  1. Homocysteine lowering interventions for preventing cardiovascular events

    PubMed Central

    Martí-Carvajal, Arturo J; Solà, Ivan; Lathyris, Dimitrios; Salanti, Georgia

    2014-01-01

    Background Cardiovascular disease such as coronary artery disease, stroke and congestive heart failure, is a leading cause of death worldwide. A postulated risk factor is elevated circulating total homocysteine (tHcy) levels which is influenced mainly by blood levels of cyanocobalamin (vitamin B12), folic acid (vitamin B9) and pyridoxine (vitamin B6). There is uncertainty regarding the strength of association between tHcy and the risk of cardiovascular disease. Objectives To assess the clinical effectiveness of homocysteine-lowering interventions (HLI) in people with or without pre-existing cardiovascular disease. Search methods We searched The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (issue 3 2008), MEDLINE (1950 to August 2008), EMBASE (1988 to August 2008), and LILACS (1982 to September 2, 2008). We also searched in Allied and Complementary Medicine (AMED; 1985 to August 2008), ISI Web of Science (1993 to August 2008), and the Cochrane Stroke Group Specialised Register (April 2007). We hand searched pertinent journals and the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. Selection criteria We included randomised clinical trials (RCTs) assessing the effects of HLI for preventing cardiovascular events with a follow-up period of 1 year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. Data collection and analysis We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using I2. We used a random-effects model to synthesise the findings. Main results We included eight RCTs involving 24,210 participants with a low risk of bias in general terms. HLI did not reduce the risk of non-fatal or fatal myocardial infarction, stroke, or

  2. [Disturbances of folic acid and homocysteine metabolism in alcohol abuse].

    PubMed

    Cylwik, Bogdan; Chrostek, Lech

    2011-04-01

    Chronic alcohol abuse leads to malnutrition, and thus to the deficiency of many nutrients, including vitamins and trace elements. Most often comes to the deficiency of all vitamins, however because the clinical implications, the most important is folic acid (vitamin B9) deficiency. Biochemical effect of folate deficiency is elevated homocysteine concentration in the blood, named "cholesterol of XXI. century". In the paper, the folate and homocysteine metabolism in alcohol abuse was discussed. Mechanisms of alcohol action on folate homeostasis in the human body have been indicated. Chronic alcohol consumption leads to deficiency of this vitamin due to their dietary inadequacy, intestinal malabsorption, decreased hepatic uptake and increased body excretion, mainly via urine. The decreased concentration of serum folic acid may occur in 80% of alcoholics. The cause of elevated concentrations of homocysteine in the serum of alcohol abusers is also a deficiency of vitamins involved such as vitamin B12 and pyridoxal phosphate. Disturbance of folic acid and homocysteine metabolism in alcohol abusers can lead to serious clinical consequences. Folic acid deficiency leads inter alia to macrocytic and megaloblastic anemia and neurological disorders. Megaloblastic anemia occurs in about half of alcohol abusers with chronic liver diseases. In turn, high level of homocysteine in blood is associated with an inreased risk of cardiovascular diseases. Hyperhomocysteinemia is an independent risk factor that favors the occurrence of acute coronary syndromes in patients with coronary heart disease.

  3. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CA...

  4. Hypophosphorylation of the architectural chromatin protein DEK in death-receptor-induced apoptosis revealed by the isotope coded protein label proteomic platform.

    PubMed

    Tabbert, Anja; Kappes, Ferdinand; Knippers, Rolf; Kellermann, Josef; Lottspeich, Friedrich; Ferrando-May, Elisa

    2006-11-01

    During apoptosis nuclear morphology changes dramatically due to alterations of chromatin architecture and cleavage of structural nuclear proteins. To characterize early events in apoptotic nuclear dismantling we have performed a proteomic study of apoptotic nuclei. To this end we have combined a cell-free apoptosis system with a proteomic platform based on the differential isotopic labeling of primary amines with N-nicotinoyloxy-succinimide. We exploited the ability of this system to produce nuclei arrested at different stages of apoptosis to analyze proteome alterations which occur prior to or at a low level of caspase activation. We show that the majority of proteins affected at the onset of apoptosis are involved in chromatin architecture and RNA metabolism. Among them is DEK, an architectural chromatin protein which is linked to autoimmune disorders. The proteomic analysis points to the occurrence of multiple PTMs in early apoptotic nuclei. This is confirmed by showing that the level of phosphorylation of DEK is decreased following apoptosis induction. These results suggest the unexpected existence of an early crosstalk between cytoplasm and nucleus during apoptosis. They further establish a previously unrecognized link between DEK and cell death, which will prove useful in the elucidation of the physiological function of this protein.

  5. Plasma homocysteine concentration changes after renal transplantation in children.

    PubMed

    Merouani, Aicha; Delvin, Edgar E; Genest, Jacques; Rozen, Rima; Lambert, Marie

    2002-07-01

    Hyperhomocysteinemia, a risk factor for vascular disease, is found in children as well as in 80% of adult patients with end-stage renal disease. The aim of this study was to assess the changes in plasma homocysteine concentrations after renal transplantation (RT). Plasma homocysteine, vitamin B(12), and folate concentrations were prospectively measured in six patients at three points, before and post transplantation (6 months, 4 years), and compared with controls using standardized scores (Z score) for each of these parameters. Folic acid supplementation was introduced after the evaluation at 6 months. Patients had elevated median plasma homocysteine Z scores during dialysis (4.12). When assessed at 6 months and 4 years, median plasma homocysteine Z scores were, respectively, 2.35 and 0.29. Median folate Z scores were 1.89 during dialysis, -0.26 at 6 months, and 3.26 at 4 years post RT. Median vitamin B(12) Z score was 2.12 during dialysis, 0.58 at 6 months, and -0.07 at 4 years post RT. Glomerular filtration rate (GFR) improved after RT, with median GFR of 84.5 ml/min per 1.73 m(2) at 6 months. This stabilized to a value of 70.5 ml/min per 1.73 m(2) at 4 years. When comparing values before and after RT at 6 months, changes were observed only for GFR ( P<0.03) and vitamin B(12) ( P<0.05). There were no changes in plasma homocysteine, folate, and serum albumin. At 4 years, a significant decrease in plasma homocysteine was observed ( P<0.05) with increased GFR ( P<0.03). No significant changes were observed in plasma albumin, folate, and vitamin B(12) concentrations. In conclusion, elevated plasma homocysteine in children during dialysis persists after RT despite a significant improvement in renal function. However, normalization was attained when patients were supplemented with folic acid. Further controlled studies are required to evaluate the determinants and treatment of elevated plasma homocysteine in pediatric transplant patients. PMID:12172766

  6. Homocysteine, B-vitamins and CVD.

    PubMed

    McNulty, Helene; Pentieva, Kristina; Hoey, Leane; Ward, Mary

    2008-05-01

    There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21%) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B12 and B6. Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10% of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored. PMID:18412997

  7. Copper and homocysteine in cardiovascular diseases.

    PubMed

    Kang, Y James

    2011-03-01

    High blood copper (Cu) and homocysteine (Hcy) concentrations have been independently reported as risk factors for cardiovascular diseases. When they are simultaneously measured, a concomitant increase in both parameters in association with vascular dysfunction has been observed. Cu chelator penicillamine can significantly diminish the inhibitory effect of Hcy on endothelial function, which has led to the interpretation that Cu mediates the deleterious effect of Hcy. However, Cu itself has been shown to be beneficial to the cardiovascular system. In particular, Cu promotion of angiogenesis has been well documented. Cu stimulates endothelial cell proliferation and differentiation and promotes microtubule formation in cultured saphenous veins. High levels of Hcy do not affect the process of microtubule formation, but the combination of Cu and Hcy leads to a significant inhibitory effect. Under other conditions, Cu does not affect, but Hcy inhibits, the endothelium-dependent relaxation of blood vessels and the combination of both augments the inhibition. Why does Cu produce adverse effects when it co-exists with Hcy? Cu forms complexes with Hcy and the Cu-Hcy complexes possess a deleterious potential due to their redox properties. Cu chelation can remove Cu from the Cu-Hcy complexes, but leaves behind high levels of Hcy and produces Cu deficiency. An alternative approach should focus on the reduction of Hcy, but maintenance of Cu, making detrimental Cu beneficial. A comprehensive understanding of Cu speciation and a development of selective modulation of Cu coordination to Cu-binding molecules to avoid Cu-Hcy complex formation would effectively improve the condition of cardiovascular disease.

  8. Daily rhythms in plasma levels of homocysteine

    PubMed Central

    Lavie, Lena; Lavie, Peretz

    2004-01-01

    Background There is accumulated evidence that plasma concentration of the sulfur-containing amino-acid homocysteine (Hcy) is a prognostic marker for cardiovascular morbidity and mortality. Both fasting levels of Hcy and post methionine loading levels are used as prognostic markers. The aim of the present study was to investigate the existence of a daily rhythm in plasma Hcy under strictly controlled nutritional and sleep-wake conditions. We also investigated if the time during which methionine loading is performed, i.e., morning or evening, had a different effect on the resultant plasma Hcy concentration. Methods Six healthy men aged 23–26 years participated in 4 experiments. In the first and second experiments, the daily rhythm in Hcy as well as in other amino acids was investigated under a normal or an inverse sleep-wake cycle. In the third and fourth, Hcy concentrations were investigated after a morning and evening methionine loading. To standardize food consumption in the first two experiments, subjects received every 3 hours 150 ml of specially designed low-protein liquid food (Ensure® formula). Results In both the first and second experiments there was a significant daily rhythm in Hcy concentrations with a mid-day nadir and a nocturnal peak. Strikingly different 24-h patterns were observed in methionine, leucine, isoleucine and tyrosine. In all, the 24-h curves revealed a strong influence of both the sleep-wake cycle and the feeding schedule. Methionine loading resulted in increased plasma Hcy levels during both morning and evening experiments, which were not significantly different from each other. Conclusions There is a daily rhythm in plasma concentration of the amino acid Hcy, and this rhythm is independent of sleep-wake and food consumption. In view of the fact that increased Hcy concentrations may be associated with increased cardiovascular risks, these findings may have clinical implications for the health of rotating shift workers. PMID:15347422

  9. Lack of embryotoxicity of homocysteine thiolactone in mouse embryos in vitro.

    PubMed

    Hansen, D K; Grafton, T F; Melnyk, S; James, S J

    2001-01-01

    Recent work from humans and chick embryos has suggested that homocysteine may play a role in producing neural tube defects (NTDs). In an effort to determine if homocysteine is able to produce NTDs in mammalian embryos, mouse embryos were explanted on GD 8 and cultured for 44 h. When either homocysteine or homocysteine thiolactone was added to the culture medium, treated embryos developed as well as controls and had closed neural tubes. Homocysteine thiolactone was also microinjected into the amniotic sac of mouse embryos. Again, development proceeded normally with no significant increase in the number of embryos with open neural tubes at the end of the culture period. HPLC analysis of embryonic thiols 24 h after microinjection revealed a significant increase in embryonic cystathionine levels. These data suggest that homocysteine does not produce NTDs in mouse embryos cultured in vitro and that early organogenesis-stage embryos are able to metabolize homocysteine.

  10. L-Cysteine/D,L-homocysteine-regulated ileum motility via system L and B°(,+) transporter: Modification by inhibitors of hydrogen sulfide synthesis and dietary treatments.

    PubMed

    Yamane, Satoshi; Nomura, Ryouya; Yanagihara, Madoka; Nakamura, Hiroyuki; Fujino, Hiromichi; Matsumoto, Kenjiro; Horie, Syunji; Murayama, Toshihiko

    2015-10-01

    Previous studies including ours demonstrated that L-cysteine treatments decreased motility in gastrointestinal tissues including the ileum via hydrogen sulfide (H2S), which is formed from sulfur-containing amino acids such as L-cysteine and L-homocysteine. However, the amino acid transport systems involved in L-cysteine/L-homocysteine-induced responses have not yet been elucidated in detail; therefore, we investigated these systems pharmacologically by measuring electrical stimulation (ES)-induced contractions with amino acids in mouse ileum preparations. The treatments with L-cysteine and D,L-homocysteine inhibited ES-induced contractions in ileum preparations from fasted mice, and these responses were decreased by the treatment with 2-aminobicyclo[2.2.1]heptane-2-carboxylate (BCH), an inhibitor of systems L and B°(,+). The results obtained using ileum preparations and a model cell line (PC12 cells) with various amino acids and BCH showed that not only L-cysteine, but also aminooxyacetic acid and D,L-propargylglycine, which act as H2S synthesis inhibitors, appeared to be taken up by these preparations/cells in L and B°(,+) system-dependent manners. The L-cysteine and D,L-homocysteine responses were delayed and abolished, respectively, in ileum preparations from fed mice. Our results suggested that the regulation of ileum motility by L-cysteine and D,L-homocysteine was dependent on BCH-sensitive systems, and varied depending on feeding in mice. Therefore, the effects of aminooxyacetic acid and D,L-propargylglycine on transport systems need to be considered in pharmacological analyses.

  11. Increased plasma homocysteine levels in shift working bus drivers

    PubMed Central

    Martins, P; D'Almeida, V; Vergani, N; Perez, A; Tufik, S

    2003-01-01

    Background: Previous studies have indicated an association between shift work and cardiovascular disease. There is also considerable epidemiological evidence that hyperhomocysteinemia is an independent risk factor for cardiovascular disorders. Aims: To analyse plasma homocysteine levels in shift work bus drivers, and to investigate possible relations with sleep parameters and other biochemical factors. Methods: Blood samples were collected from 30 male shift working long-haul bus drivers in a Brazilian sample and analysed for plasma levels of homocysteine, folic acid, vitamin B12, and serum lipids. A group of 22 daytime workers, matched for age and body mass index served as controls. The incidence of mutations in the gene coding for methylene tetrahydrofolate, an enzyme which is related to hyperhomocysteinemia, was also assessed. Polysomnographic recordings were obtained from the target group. Results: Bus drivers showed significantly higher levels of plasma homocysteine than the control group (18.57 v 9.43 µM). Most of the other biochemical, behavioural, and molecular parameters did not differ between groups. Likewise, sleep parameters appeared to be within the normal range. Conclusions: The significantly increased plasma homocysteine levels in long-haul bus drivers did not appear to be secondary to other biochemical or behavioural problems in this group. These results suggest that hyperhomocysteinemia may be involved in the increased incidence of cardiovascular diseases observed in shift workers. PMID:12937187

  12. Effects of Alcohol, Lithium, and Homocysteine on Nonmuscle Myosin-II in the Mouse Placenta and Human Trophoblasts

    PubMed Central

    HAN, Mingda; NEVES, Ana Luisa; SERRANO, Maria; BRINEZ, Pilar; HUHTA, James C.; ACHARYA, Ganesh; LINASK, Kersti K.

    2012-01-01

    Mouse embryonic exposure to alcohol, lithium, and homocysteine results in intrauterine growth restriction (IUGR) and cardiac defects. Our present study focuses on the placental effects. Objectives We analyzed the hypothesis that expression of nonmuscle myosin (NMM)-II isoforms involved in cell motility, mechanosensing, and extracellular matrix assembly, are altered by the three factors in human trophoblast (HTR8/SVneo) cells in vitro and in the mouse placenta in vivo. Study Design After exposure during gastrulation to alcohol, homocysteine, or lithium, ultrasonography defined embryos exhibiting abnormal placental blood flow. Results NMM-IIA /NMM-IIB are differentially expressed in trophoblasts and in mouse placental vascular endothelial cells under pathological conditions. Misexpression of NMM-IIA/ NMM-IIB in the affected placentas continued stably to mid-gestation, but can be prevented by folate and myo-inositol supplementation. Conclusions It is concluded that folate and myo-inositol initiated early in mouse pregnancy can restore NMM-II expression, permit normal placentation/embryogenesis, and prevent IUGR induced by alcohol, lithium, and homocysteine. PMID:22704764

  13. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    SciTech Connect

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae

    2012-04-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  14. Elevated plasma homocysteine is associated with increased brain atrophy rates in older subjects with mild hypertension.

    PubMed

    Narayan, Sunil K; Firbank, Michael J; Saxby, Brian K; Stansby, Gerard; Hansrani, Monica; O'Brien, John T; Ford, Gary A

    2011-01-01

    We determined using serial MR imaging whether raised plasma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 ± 0.48% per year, mean ± SD) were significantly correlated with homocysteine (β = 0.46, p = 0.001 homocysteine; β = 0.44, p = 0.007 homocysteine/folate/B12 models) but not with folate or B12 levels. Progression of WML (0.08 ± 0.16%) was not associated with homocysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine levels are associated with increased rates of whole-brain atrophy but not WML progression.

  15. Homocysteine Serum Levels in Diabetic Patients with Non Proliferative, Proliferative and without Retinopathy

    PubMed Central

    Gagliano, Caterina; Giordano, Maria; Vacante, Marco; Caraci, Filippo; Drago, Filippo; Avitabile, Teresio; Motta, Massimo

    2014-01-01

    Homocysteine has been associated with extracellular matrix changes. The diabetic retinopathy is a neurovascular complication of diabetes mellitus and it is the leading cause of vision loss among working adults worldwide. In this study, we evaluate the role of homocysteine in diabetic retinopathy analyzing the plasma levels of homocysteine in 63 diabetic type 2 patients with nonproliferative retinopathy (NPDR), 62 patients with proliferative diabetic retinopathy (PDR), 50 healthy subjects used as control group, and 75 randomly selected patients. PMID:24877066

  16. Homocysteine serum levels in diabetic patients with non proliferative, proliferative and without retinopathy.

    PubMed

    Malaguarnera, Giulia; Gagliano, Caterina; Giordano, Maria; Salomone, Salvatore; Vacante, Marco; Bucolo, Claudio; Caraci, Filippo; Reibaldi, Michele; Drago, Filippo; Avitabile, Teresio; Motta, Massimo

    2014-01-01

    Homocysteine has been associated with extracellular matrix changes. The diabetic retinopathy is a neurovascular complication of diabetes mellitus and it is the leading cause of vision loss among working adults worldwide. In this study, we evaluate the role of homocysteine in diabetic retinopathy analyzing the plasma levels of homocysteine in 63 diabetic type 2 patients with nonproliferative retinopathy (NPDR), 62 patients with proliferative diabetic retinopathy (PDR), 50 healthy subjects used as control group, and 75 randomly selected patients. PMID:24877066

  17. Homocysteine: cardiovascular risk factor in children and adolescents?

    PubMed

    Leal, Adriana Amorim De Farias; Palmeira, Astrid Camêlo; Castro, Gabriella Menezes Almeida De; Simões, Mônica Oliveira Da Silva; Ramos, Alessandra Teixeira; Medeiros, Carla Campos Muniz

    2013-01-01

    The aim of this study was to identify publications in literature that investigated Homocysteine (He) as a risk factor for CVD among children and adolescents. An active search for information in LILACS, IBECS, Science Direct, Medline and Cochrane Library databases was conducted using the following combination of keywords "homocysteine", "cardiovascular diseases", "child" and "adolescent". Fifteen articles were analyzed showing direct relationship with increasing age (8 studies) and male gender (10 studies), and an inverse relationship with serum vitamins B6, B12 and folate levels. Thus, the results suggest that more research must be carried through in order to determine in a more coherent way the causes of the hiperhomocisteinemia in the pediatric population, guiding for an adequate diet, rich in nutrients necessary to favor the metabolism of the He. PMID:24182942

  18. Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.

    PubMed

    Kim, Sungeun; Nho, Kwangsik; Ramanan, Vijay K; Lai, Dongbing; Foroud, Tatiana M; Lane, Katie; Murrell, Jill R; Gao, Sujuan; Hall, Kathleen S; Unverzagt, Frederick W; Baiyewu, Olusegun; Ogunniyi, Adesola; Gureje, Oye; Kling, Mitchel A; Doraiswamy, P Murali; Kaddurah-Daouk, Rima; Hendrie, Hugh C; Saykin, Andrew J

    2015-01-01

    Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration.

  19. Homocystein as a Risk Factor for Developing Complications in Chronic Renal Failure

    PubMed Central

    Jakovljevic, Biljana; Gasic, Branislav; Kovacevic, Pedja; Rajkovaca, Zvezdana; Kovacevic, Tijana

    2015-01-01

    Aim: Cardiovascular diseases are leading cause of death in patients with chronic renal failure. The aim of our study was to establish connection between levels of homocysteine and traditional and nontraditional risk factors for developing cardiovascular diseases in dialysis and pre dialysis patients. Methods: We included 33 pre dialysis (23 in stage three and 10 in stage four of chronic kidney disease) and 43 patients receiving hemodialysis longer than six months. Besides standard laboratory parameters, levels of homocysteine and blood pressure were measured in all patients. Glomerular filtration rate was measured in pre dialysis patients and dialysis quality parameters in dialysis patients. Results: Homocysteine levels were elevated in all patients (19±5.42mmol/l). The connection between homocysteine levels and other cardiovascular diseases risk factors was not established in pre dialysis patients. In patients treated with hemodialysis we found negative correlation between homocysteine levels and patients’ age (p<0.05) and positive correlation between homocysteine levels and length of dialysis (p<0.01) as well as between homocysteine and anemia parameters (erythrocytes, hemoglobin), (p<0.01). Homocysteine and LDL (and total cholesterol) were in negative correlation (p<0.01). Conclusion: Homocysteine, as one of nontraditional cardiovascular diseases risk factors, is elevated in all patients with chronic renal failure and it’s positive correlation with some other risk factors was found. PMID:26005384

  20. Plasma Homocysteine is Not Related to the Severity of Microangiopathy in Secondary Raynaud Phenomenon

    PubMed Central

    Jacomella, Vincenzo; Wasila, Monika; Husmann, Marc; Gitzelmann, Gabriela; Meier, Thomas; Amann-Vesti, Beatrice

    2011-01-01

    Introduction: The role of elevated homocysteine in primary and secondary Raynaud phenomenon (RP) and in patients with atherosclerosis has been reported controversially. In secondary RP due to connective tissue disease specific alterations of nailfold capillaries might be present. An association between these microvascular changes and homocysteine has been suggested. Aim: The aim of this study was to determine whether homocysteine level differs between patients with primary and secondary RP and to test the hypothesis that homocysteine or other cardiovascular risk factors are associated with specific features of microangiopathy in secondary RP. Patients and Methods Eighty-one consecutive patients with RP referred for vascular assessment were studied by nailfold capillaroscopy. Homocysteine, C-reactive protein and cholesterol were measured and other cardiovascular risk factors and comorbidities assessed. Results: Homocysteine, C-reactive-protein and cholesterol levels did not differ between patients with primary (n=60) and secondary RP (n=21). Likewise, no differences in the prevalence of cardiovascular risk factors and comorbidities were found. In secondary RP no correlation was found between microvascular involvement and homocysteine or C-reactive protein. Conclusion: Plasma homocysteine is not different in patients with either primary or secondary RP and is therefore not a marker for the distinction of these diseases. The extent of microvascular involvement in secondary RP does not correlate with plasma homocysteine. PMID:22216066

  1. IMPAIRED HOMOCYSTEINE TRANSSULFURATION IS AN INDICATOR OF ALCOHOLIC LIVER DISEASE

    PubMed Central

    Medici, Valentina; M.Peerson, Janet; Stabler, Sally P.; French, Samuel W.; Gregory, Jesse F.; Virata, Maria Catrina; Albanese, Antony; Bowlus, Christopher L.; Devaraj, Sridevi; Panacek, Edward A.; Rahim, Nazir; Richards, John R.; Rossaro, Lorenzo; Halsted, Charles H.

    2010-01-01

    Background & Aims Although abnormal hepatic methionine metabolism plays a central role in the pathogenesis of experimental alcoholic liver disease (ALD), its relationship to the risk and severity of clinical ALD is not known. The aim of this clinical study was to determine the relationship between serum levels of methionine metabolites in chronic alcoholics and the risk and pathological severity of ALD. Methods Serum levels of liver function biochemical markers, vitamin B6, vitamin B12, folate, homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, α-aminobutyrate, glycine, serine, and dimethylglycine were measured in 40 ALD patients, of whom 24 had liver biopsies, 26 were active drinkers without liver disease, and 28 were healthy subjects. Results Serum homocysteine was elevated in all alcoholics, whereas ALD patients had low vitamin B6 with elevated cystathionine and decreased α-aminobutyrate/cystathionine ratios, consistent with decreased activity of vitamin B6 dependent cystathionase. The α-aminobutyrate/cystathionine ratio predicted the presence of ALD, while cystathionine correlated with the stage of fibrosis in all ALD patients. Conclusions The predictive role of the α- aminobutyrate/cystathionine ratio for the presence of ALD and the correlation between cystathionine serum levels with the severity of fibrosis point to the importance of the homocysteine transsulfuration pathway in ALD and may have important diagnostic and therapeutic implications. PMID:20561703

  2. Relationship between paraoxonase and homocysteine: crossroads of oxidative diseases

    PubMed Central

    2012-01-01

    Homocysteine (Hcy) is an accepted independent risk factor for several major pathologies including cardiovascular disease, birth defects, osteoporosis, Alzheimer's disease, and renal failure. Interestingly, many of the pathologies associated with homocysteine are also linked to oxidative stress. The enzyme paraoxonase (PON1) – so named because of its ability to hydrolyse the toxic metabolite of parathion, paraoxon – was also shown early after its identification to manifest arylesterase activity. Although the preferred endogenous substrate of PON1 remains unknown, lactones comprise one possible candidate class. Homocysteine-thiolactone can be disposed of by enzymatic hydrolysis by the serum Hcy-thiolactonase/paraoxonase carried on high-density lipoprotein (HDL). In this review, Hcy and the PON1 enzyme family were scrutinized from different points of view in the literature and the recent articles on these subjects were examined to determine whether these two molecular groups are related to each other like a coin with two different sides, so close and yet so different and so opposite. PMID:22457688

  3. Serum homocysteine level in vegetarians in District Tharparker, Sindh

    PubMed Central

    Kapoor, Aneel; Zuberi, Nudrat Anwar; Rathore, M. Imran; Baig, Mukhtiar

    2015-01-01

    Objectives: The aim of present study was to investigate serum homocysteine levels in apparently healthy vegetarians and ominvores in Mithi, district Tharparker, Sindh, Pakistan. Methods: This study was conducted in the Department of Biochemistry, Basic Medical Sciences Institute (BMSI), Jinnah Postgraduate Medical Center (JPMC), Karachi and blood samples were collected from Mithi, district Tharparker, Sindh, Pakistan, in 2012. One hundred vegetarian and one hundred omnivores (age ranging from 20-40 years) were enrolled for this study. Serum homocysteine levels were measured by the chemiluminescence enzyme immunoassay method. Results: Serum homocysteine (Hcy) level was considerably higher (p<0.001) in vegetarian group compared to omnivores. We further grouped and analyzed our study subjects according to their gender and according to Hcy level (greater than or lower than 15µmol/L). A considerable number of vegetarian subjects 30% were having Hcy >15µmol/L compared to omnivores 6%, (p<0.001). Gender-wise comparison showed that 27.02% male and 38.46% females had >15µmol/L serum Hcy level in vegetarian group and 6.9% male and 3.5% females had >15µmol/L serum Hcy level in omnivores group, but the difference was not significant in any group. Conclusion: Vegetarians are more prone to develop hyperhomocysteinemia, so they are at high risk to develop cardiovascular disease. PMID:25878628

  4. Plasma homocysteine concentration in children with chronic renal failure.

    PubMed

    Merouani, A; Lambert, M; Delvin, E E; Genest, J; Robitaille, P; Rozen, R

    2001-10-01

    Hyperhomocysteinemia, a risk factor for vascular disease, is commonly found in adult patients with end-stage renal disease. Major determinants of elevated plasma homocysteine levels in these patients include deficiencies in folate and vitamin B12, methylenetetrahydrofolate reductase (MTHFR) genotype and renal function. Little information is available for children with chronic renal failure (CRF). The prevalence and the factors that affect plasma homocysteine concentration were determined in children. Twenty-nine children with various degrees of CRF (15 were dialyzed, 14 were not dialyzed) were compared with 57 age- and sex-matched healthy children. Homocysteine concentrations were higher in patients than controls (17.3 micromol/l vs 6.8 micromol/l, P<0.0001) and hyperhomocysteinemia (>95th percentile for controls: 14.0 micromol/l) was seen in 62.0% of patients and 5.2% of controls. Folate concentrations were lower in patients (9.9 nmol/l) than controls (13.5 nmol/l), P<0.01. Vitamin B12 was similar in patients (322 pmol/l) and controls (284 pmol/l). Dialyzed patients have a higher prevalence of hyperhomocysteinemia than nondialyzed patients (87% vs 35%). Dialyzed patients with MTHFR mutation have higher plasma homocysteine (28.5 micromol/l) than nondialyzed patients with the mutation (10.7 micromol/l), P<0.002. In our study, differences between controls and patients in plasma homocysteine concentrations are observed when age is greater then 92 months, folate less than 21.6 nmol/l and vitamin B12 less than 522 pmol/l. Our study shows that hyperhomocysteinemia is common in children with CRF and is associated with low folate and normal vitamin B12 status, compared to normal children. Among the patients, the dialyzed patients with the MTHFR mutation are particularly at risk for hyperhomocysteinemia. Further studies are needed to investigate therapeutic interventions and the potential link with vascular complications in these patients. PMID:11605787

  5. The methionine-homocysteine cycle and its effects on cognitive diseases.

    PubMed

    Miller, Alan L

    2003-02-01

    Homocysteine, a sulfur-containing amino acid, is a metabolite of the essential amino acid methionine, and exists at a critical biochemical intersection in the methionine cycle - between S-adenosylmethionine, the indispensable ubiquitous methyl donor, and vitamins B12 and folic acid. High blood levels of homocysteine signal a breakdown in this vital process, resulting in far-reaching biochemical and life consequences. The link between homocysteine and cardiovascular disease is well established, and decreasing plasma total homocysteine by providing nutritional cofactors for its metabolism has been shown to reduce the risk of cardiovascular events. Information has been emerging regarding a connection between homocysteine metabolism and cognitive function, from mild cognitive decline (age-related memory loss) to vascular dementia and Alzheimer's disease. Significant deficiencies in the homocysteine re-methylation cofactors cobalamin (B12) and folate, as well as the trans-sulfuration cofactor vitamin B6, are commonly seen in the elderly population, with a resultant increase in homocysteine with advancing age. Hyperhomocysteinemia has been shown to be an independent risk factor for cognitive dysfunction. Indirect and direct vascular damage can be caused by homocysteine, which has been implicated in vascular dementia, with an increased risk of multiple brain infarcts and dementia as homocysteine levels rise. A significant correlation has been found between risk of Alzheimer's disease and high plasma levels of homocysteine, as well as low levels of folic acid, and vitamins B6 and B12. All of these disease associations are thought to be interrelated via increased homocysteine and S-adenosylhomocysteine and subsequent hypomethylation of numerous substances, including DNA and proteins, that render vascular structures and neurons more susceptible to damage and apoptosis. Providing the nutritional cofactors for proper functioning of the methionine cycle may improve methylation

  6. S-homoadenosyl-L-cysteine and S-homoadenosyl-L-homocysteine. Synthesis and binding studies of hon-hydrolyzed substrate analogues with S-adenosyl-L-homocysteine hydrolase.

    PubMed

    Miles, Robert W; Nielsen, Lars P C; Ewing, Gregory J; Yin, Daniel; Borchardt, Ronald T; Robins, Morris J

    2002-11-15

    Treatment of homoadenosine [9-(5-deoxy-beta-D-ribo-hexofuranosyl)adenine] with thionyl chloride and pyridine in acetonitrile gave 6'-chloro-6'-deoxyhomoadenosine, which underwent nucleophilic displacement with L-cysteine or L-homocysteine to give homologated analogues of S-adenosyl-L-homocysteine. Each amino acid in aqueous sodium hydroxide at 60 degrees C gave excellent conversion from the chloronucleoside, and adsorption on Amberlite XAD-4 resin provided more convenient isolation than prior methods. Weak binding of these non-hydrolyzed analogues to S-adenosyl-L-homocysteine hydrolase was observed.

  7. Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin.

    PubMed

    Kwon, Bumsup; Querfurth, Henry W

    2015-11-01

    Excessive saturated free fatty acids (SFFAs; e.g. palmitate) in blood are a pathogenic factor in diabetes, obesity, cardiovascular disease and liver failure. In contrast, monounsaturated free fatty acids (e.g. oleate) prevent the toxic effect of SFFAs in various types of cells. The mechanism is poorly understood and involvement of the mTOR complex is untested. In the present study, we demonstrate that oleate preconditioning, as well as coincubation, completely prevented palmitate-induced markers of inflammatory signaling, insulin resistance and cytotoxicity in C2C12 myotubes. We then examined the effect of palmitate and/or oleate on the mammalian target of rapamycin (mTOR) signal path and whether their link is mediated by AMP-activated protein kinase (AMPK). Palmitate decreased the phosphorylation of raptor and 4E-BP1 while increasing the phosphorylation of p70S6K. Palmitate also inhibited phosphorylation of AMPK, but did not change the phosphorylated levels of mTOR or rictor. Oleate completely prevented the palmitate-induced dysregulation of mTOR components and restored pAMPK whereas alone it produced no signaling changes. To understand this more, we show activation of AMPK by metformin also prevented palmitate-induced changes in the phosphorylations of raptor and p70S6K, confirming that the mTORC1/p70S6K signaling pathway is responsive to AMPK activity. By contrast, inhibition of AMPK phosphorylation by Compound C worsened palmitate-induced changes and correspondingly blocked the protective effect of oleate. Finally, metformin modestly attenuated palmitate-induced insulin resistance and cytotoxicity, as did oleate. Our findings indicate that palmitate activates mTORC1/p70S6K signaling by AMPK inhibition and phosphorylation of raptor. Oleate reverses these effects through a metformin-like facilitation of AMPK. PMID:26344902

  8. Are dietary choline and betaine intakes determinants of total homocysteine concentration?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated homocysteine concentrations are associated with an increased risk of cardiovascular disease and a decline in cognitive function. Intakes of choline and betaine, as methyl donors, may affect homocysteine concentrations. The objective was to examine whether choline and betaine intakes, assess...

  9. Central cardiovascular actions of L-homocysteine microinjected into ventrolateral medullary autonomic areas of the rat.

    PubMed

    Takemoto, Yumi

    2016-09-01

    Elevated L-homocysteine concentrations in the plasma and cerebrospinal fluid are related to cardiovascular and neuronal diseases, and could contribute to disease development. However, the central cardiovascular actions of L-homocysteine in two important autonomic regulating areas remain unknown: the rostral ventrolateral medulla (RVLM), including pre-sympathetic neurons, and the caudal ventrolateral medulla (CVLM), including interneurons projecting to pre-sympathetic neurons in the RVLM. Therefore, the aim of the current study was to examine the influence of L-homocysteine microinjected into the RVLM and CVLM areas on changes in arterial blood pressure (ABP) and heart rate (HR) of anesthetized rats, as well as the influence of ionotropic excitatory amino acid (iEAA) receptors on the central actions of L-homocysteine. L-Homocysteine solutions were microinjected into the RVLM and CVLM, which were defined according to pressor and depressor responses to L-glutamate microinjections, respectively. ABP and HR increased in the RVLM and decreased in the CVLM after microinjection with L-homocysteine, similar to L-glutamate, in a dose-dependent manner, suggesting mediation of EAA receptors. Prior microinjection of the N-methyl-D-aspartate (NMDA) iEAA receptor antagonist MK801, but not the non-NMDA receptor antagonist CNQX, abolished the observed responses to L-homocysteine in both the RVLM and CVLM. These results indicate the central cardiovascular actions of L-homocysteine via MK801-sensitive receptors of the medullary autonomic neurons in the rat RVLM and CVLM. It remains unknown if the central cardiovascular actions are related to cardiovascular diseases after endogenously and locally augmented L-homocysteine production by disordered metabolism. Further studies on functional significance of L-homocysteine may provide some clue to understand its toxic mechanism. PMID:27178024

  10. Central cardiovascular actions of L-homocysteine microinjected into ventrolateral medullary autonomic areas of the rat.

    PubMed

    Takemoto, Yumi

    2016-09-01

    Elevated L-homocysteine concentrations in the plasma and cerebrospinal fluid are related to cardiovascular and neuronal diseases, and could contribute to disease development. However, the central cardiovascular actions of L-homocysteine in two important autonomic regulating areas remain unknown: the rostral ventrolateral medulla (RVLM), including pre-sympathetic neurons, and the caudal ventrolateral medulla (CVLM), including interneurons projecting to pre-sympathetic neurons in the RVLM. Therefore, the aim of the current study was to examine the influence of L-homocysteine microinjected into the RVLM and CVLM areas on changes in arterial blood pressure (ABP) and heart rate (HR) of anesthetized rats, as well as the influence of ionotropic excitatory amino acid (iEAA) receptors on the central actions of L-homocysteine. L-Homocysteine solutions were microinjected into the RVLM and CVLM, which were defined according to pressor and depressor responses to L-glutamate microinjections, respectively. ABP and HR increased in the RVLM and decreased in the CVLM after microinjection with L-homocysteine, similar to L-glutamate, in a dose-dependent manner, suggesting mediation of EAA receptors. Prior microinjection of the N-methyl-D-aspartate (NMDA) iEAA receptor antagonist MK801, but not the non-NMDA receptor antagonist CNQX, abolished the observed responses to L-homocysteine in both the RVLM and CVLM. These results indicate the central cardiovascular actions of L-homocysteine via MK801-sensitive receptors of the medullary autonomic neurons in the rat RVLM and CVLM. It remains unknown if the central cardiovascular actions are related to cardiovascular diseases after endogenously and locally augmented L-homocysteine production by disordered metabolism. Further studies on functional significance of L-homocysteine may provide some clue to understand its toxic mechanism.

  11. Dissecting the Catalytic Mechanism of Betaine-Homocysteine S-Methyltransferase Using Intrinsic Tryptophan Fluorescence and Site-Directed Mutagenesis

    SciTech Connect

    Castro, C.; Gratson, A.A.; Evans, J.C.; Jiracek, J.; Collinsova, M.; Ludwig, M.L.; Garrow, T.A.

    2010-03-05

    Betaine-homocysteine S-methyltransferase (BHMT) is a zinc-dependent enzyme that catalyzes the transfer of a methyl group from glycine betaine (Bet) to homocysteine (Hcy) to form dimethylglycine (DMG) and methionine (Met). Previous studies in other laboratories have indicated that catalysis proceeds through the formation of a ternary complex, with a transition state mimicked by the inhibitor S-({delta}-carboxybutyl)-l-homocysteine (CBHcy). Using changes in intrinsic tryptophan fluorescence to determine the affinity of human BHMT for substrates, products, or CBHcy, we now demonstrate that the enzyme-substrate complex reaches its transition state through an ordered bi-bi mechanism in which Hcy is the first substrate to bind and Met is the last product released. Hcy, Met, and CBHcy bind to the enzyme to form binary complexes with K{sub d} values of 7.9, 6.9, and 0.28 {micro}M, respectively. Binary complexes with Bet and DMG cannot be detected with fluorescence as a probe, but Bet and DMG bind tightly to BHMT-Hcy to form ternary complexes with K{sub d} values of 1.1 and 0.73 {micro}M, respectively. Mutation of each of the seven tryptophan residues in human BHMT provides evidence that the enzyme undergoes two distinct conformational changes that are reflected in the fluorescence of the enzyme. The first is induced when Hcy binds, and the second, when Bet binds. As predicted by the crystal structure of BHMT, the amino acids Trp44 and Tyr160 are involved in binding Bet, and Glu159 in binding Hcy. Replacing these residues by site-directed mutagenesis significantly reduces the catalytic efficiency (V{sub max}/K{sub m}) of the enzyme. Replacing Tyr77 with Phe abolishes enzyme activity.

  12. DACH-LIGA homocystein (german, austrian and swiss homocysteine society): consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases: guidelines and recommendations.

    PubMed

    Stanger, Olaf; Herrmann, Wolfgang; Pietrzik, Klaus; Fowler, Brian; Geisel, Jürgen; Dierkes, Jutta; Weger, Martin

    2003-11-01

    About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and getting larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B12, and vitamin B6 deficiencies and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10% of total risk. Elevated plasma homocysteine levels (>12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10% of the general population and in up to 40% of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence over-proportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial anti-thrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stress. Especially when acting as direct or indirect antagonists of cofactors and enzyme

  13. Impaired homocysteine metabolism in patients with alcoholic liver disease in Taiwan.

    PubMed

    Chien, Yi-Wen; Chen, Ya-Ling; Peng, Hsiang-Chi; Hu, Jui-Ting; Yang, Sien-Sing; Yang, Suh-Ching

    2016-08-01

    ​Impaired homocysteine metabolism plays an important role in alcoholic liver disease (ALD); however, there are limited data about its relationship with the risk and severity of patients with ALD in Taiwan. To understand plasma homocysteine and related vitamin concentrations in patients with ALD in Taiwan, we recruited 50 male patients with ALD from Cathay General Hospital, with 49 age-and gender-matched healthy adults as the control group. The Institutional Review Board for Human Studies approved the study, and informed consent was obtained from all patients prior to blood collection. Significantly higher plasma homocysteine concentrations but lower folate concentrations were obtained from patients with ALD. In addition, patients with ALD showed a significant lower erythrocyte reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio but higher plasma thiobarbituric acid-reactive substance (TBARS) concentration, which indicated that oxidative stress was occurring in patients with ALD. A negative correlation between plasma folate and homocysteine was observed in all subjects. There was also a negative correlation between plasma homocysteine and the erythrocyte GSH/GSSG ratio which indicated impaired homocysteine metabolism may have disrupted the antioxidative status. In addition, patients in Child-Pugh Class B and C showed higher plasma vitamin B12 concentrations than did patients without cirrhosis and patients in Child-Pugh Class A. These findings show that impaired homocysteine metabolism was observed in patients with ALD in Taiwan. In addition, the plasma vitamin B12 concentration may reflect the degree of liver injury. PMID:27565754

  14. The relationship between plasma homocysteine level and different treatment modalities in patients with ankylosing spondylitis.

    PubMed

    Capkin, Erhan; Karkucak, Murat; Akyüz, Ayşe; Alver, Ahmet; Turkyilmaz, Aysegul Kucukali; Zengin, Elif

    2012-08-01

    To determine plasma homocysteine levels in ankylosing spondylitis (AS) and their correlation with disease activity measurements. To examine the effects of different treatment modalities on homocysteine levels. One hundred eight patients diagnosed with AS according to New York criteria and 65 healthy individuals matched in terms of age and gender were enrolled in the study. Patients were given detailed physical examinations. The Bath AS Disease Activity Index (BASDAI) was used for disease activity, the Bath AS Metrology Index (BASMI) for spinal mobility, the Bath AS Functional Index (BASFI) to determine functional status and the Bath AS Radiological Index (BASRI) for radiological analysis. Sedimentation rate (ESR) and C reactive protein (CRP) levels, acute phase reactants, were measured. Plasma homocysteine levels, serum interleukin (IL) -6 and serum tumor necrosis factor- α (TNF- α) levels were investigated using the enzyme-linked immunosorbent assay (ELISA) method. Plasma homocysteine levels in AS patients were statistically significantly lower compared with those in the healthy control group (P = 0.0001). There was no significant difference among sub-groups established on the basis of medical treatments and disease activity (BASDAI ≤4 and >4). No statistically significant correlation was determined between homocysteine level and disease activity parameters, radiological score and functional indices. A significant negative correlation was, however, established between age and homocysteine level in the AS group (P < 0.05, r = -0.426). Plasma homocysteine was lower in AS patients compared with the control group. This is not correlated with disease activation and medical treatment employed.

  15. Protective Effects of Acetylation on the Pathological Reactions of the Lens Crystallins with Homocysteine Thiolactone

    PubMed Central

    Moafian, Zeinab; Khoshaman, Kazem; Oryan, Ahmad; Kurganov, Boris I.; Yousefi, Reza

    2016-01-01

    Various post-translational lens crystallins modifications result in structural and functional insults, contributing to the development of lens opacity and cataract disorders. Lens crystallins are potential targets of homocysteinylation, particularly under hyperhomocysteinemia which has been indicated in various eye diseases. Since both homocysteinylation and acetylation primarily occur on protein free amino groups, we applied different spectroscopic methods and gel mobility shift analysis to examine the possible preventive role of acetylation against homocysteinylation. Lens crystallins were extensively acetylated in the presence of acetic anhydride and then subjected to homocysteinylation in the presence of homocysteine thiolactone (HCTL). Extensive acetylation of the lens crystallins results in partial structural alteration and enhancement of their stability, as well as improvement of α-crystallin chaperone-like activity. In addition, acetylation partially prevents HCTL-induced structural alteration and aggregation of lens crystallins. Also, acetylation protects against HCTL-induced loss of α-crystallin chaperone activity. Additionally, subsequent acetylation and homocysteinylation cause significant proteolytic degradation of crystallins. Therefore, further experimentation is required in order to judge effectively the preventative role of acetylation on the structural and functional insults induced by homocysteinylation of lens crystallins. PMID:27706231

  16. Relationship between homocysteine and intraocular pressure in men and women: A population-based study.

    PubMed

    Leibovitzh, Haim; Cohen, Eytan; Levi, Amos; Kramer, Michal; Shochat, Tzippy; Goldberg, Elad; Krause, Ilan

    2016-09-01

    The relationship between homocysteine levels and glaucoma has been questioned in previous studies without conclusive results. In the current study, we assessed the relationship between homocysteine levels and intraocular pressure which is one of the main factors in the development of glaucoma in men and women.A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 11,850 subjects, within an age range 20 to 80 years. The relationship between homocysteine and intraocular pressure has been investigated by comparing intraocular pressure in subjects with elevated and normal homocysteine and by comparing homocysteine levels in subjects with elevated and normal intraocular pressure. In addition, we compared the levels of homocysteine in subjects with and without a confirmed diagnosis of glaucoma.The mean IOP (±SD) in subjects with normal homocysteine levels(≤15 μmol/L) was 13.2 ± 2.3 mm Hg and 13.4 ± 2.4 mm Hg in those with high homocysteine levels (>15 μmol/L) (P < 0.008, 95% confidence interval [CI] 0.3-0.09).Nonetheless, after multivariate adjustment for age, gender, vitamin B12, and folic acid statistical significance was no longer demonstrated (P = 0.37). Mean homocysteine levels (±SD) in subjects with normal intraocular pressure of ≤ 21 mm Hg was 11.7 ± 5.5 μmol/L and 12.09 ± 3.43 μmol/L in those with elevated intraocular pressure (P = 0.4, 95%CI 1.1-1.8). Mean homocysteine levels (±SD) in subjects with glaucoma were 11.2 ± 3.5 μmol/L compared to 11.7 ± 5.5 μmol/L in subjects without glaucoma and normal intraocular pressure ≤ 21 mm Hg (P = 0.4, 95% CI 1.2-2.1).The current study displays no clinical correlation between the homocysteine level and the intraocular pressure. Homocysteine may not be used as a predictive parameter to recognize those subjects prone to develop elevated intraocular pressure. PMID:27661027

  17. A colorimetric, ratiometric and water-soluble fluorescent probe for simultaneously sensing glutathione and cysteine/homocysteine.

    PubMed

    Dai, Xi; Wang, Zhao-Yang; Du, Zhi-Fang; Cui, Jie; Miao, Jun-Ying; Zhao, Bao-Xiang

    2015-11-01

    A chlorinated coumarin-aldehyde was developed as a colorimetric and ratiometric fluorescent probe for distinguishing glutathione (GSH), cystenine (Cys) and homocysteine (Hcy). The GSH-induced substitution-cyclization and Cys/Hcy-induced substitution-rearrangement cascades lead to the corresponding thiol-coumarin-iminium cation and amino-coumarin-aldehyde with distinct photophysical properties. The probe can be used to simultaneously detect GSH and Cys/Hcy by visual determination based on distinct different colors - red and pale-yellow in PBS buffer solution by two reaction sites. From the linear relationship of fluorescence intensity and biothiols concentrations, it was determined that the limits of detection for GSH, Hcy and Cys are 0.08, 0.09 and 0.18 μM, respectively. Furthermore, the probe was successfully used in living cell imaging with low cell toxicity. PMID:26572845

  18. Homocysteine activates T cells by enhancing endoplasmic reticulum-mitochondria coupling and increasing mitochondrial respiration.

    PubMed

    Feng, Juan; Lü, Silin; Ding, Yanhong; Zheng, Ming; Wang, Xian

    2016-06-01

    Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by increasing proliferation and stimulating cytokine secretion in T cells. However, whether homocysteine (Hcy)-mediated T cell activation is associated with metabolic reprogramming is unclear. Here, our in vivo and in vitro studies showed that Hcy-stimulated splenic T-cell activation in mice was accompanied by increased levels of mitochondrial reactive oxygen species (ROS) and calcium, mitochondrial mass and respiration. Inhibiting mitochondrial ROS production and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell interferon γ (IFN-γ) secretion and proliferation. Hcy also enhanced endoplasmic reticulum (ER) stress in T cells, and inhibition of ER stress with 4-phenylbutyric acid blocked Hcy-induced T-cell activation. Mechanistically, Hcy increased ER-mitochondria coupling, and uncoupling ER-mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial reprogramming, IFN-γ secretion and proliferation in T cells, suggesting that juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell activation by increasing ER-mitochondria coupling and regulating metabolic reprogramming.

  19. A turn-on fluorescent sensor for the discrimination of cystein from homocystein and glutathione.

    PubMed

    Niu, Li-Ya; Guan, Ying-Shi; Chen, Yu-Zhe; Wu, Li-Zhu; Tung, Chen-Ho; Yang, Qing-Zheng

    2013-02-14

    We report a turn-on fluorescent sensor based on nitrothiophenolate boron dipyrromethene (BODIPY) derivatives for the discrimination of cystein (Cys) from homocystein (Hcy) and glutathione (GSH). The sensor was applied for detection of Cys in living cells. PMID:23295243

  20. A turn-on fluorescent sensor for the discrimination of cystein from homocystein and glutathione.

    PubMed

    Niu, Li-Ya; Guan, Ying-Shi; Chen, Yu-Zhe; Wu, Li-Zhu; Tung, Chen-Ho; Yang, Qing-Zheng

    2013-02-14

    We report a turn-on fluorescent sensor based on nitrothiophenolate boron dipyrromethene (BODIPY) derivatives for the discrimination of cystein (Cys) from homocystein (Hcy) and glutathione (GSH). The sensor was applied for detection of Cys in living cells.

  1. [Determination of homocysteine by tandem mass spectrometry with chemical ionization].

    PubMed

    Miroshnichenko, I I; Platova, A I; Safarova, T P; Iakovleva, O B

    2014-01-01

    Homocysteine (Hcy) is an intermediate of methionine metabolism. High plasma Hcy concentrations are an independent risk factor for stroke, peripheral vascular disease, deep venous thrombosis, coronary disease, and cognitive deficiency. Apparently, it is a great importance to measure Hcy levels in human blood. A new method for the quantification of Hcy by means of reversed-phase LC/atmospheric pressure chemical ionization mass spectrometry has been developed. The MRM ion transition, m/z 136.0 ® 90.0 was used for Hcy quantification. The limit of detection was 0.4 mM, quantification was performed from 1 mM to 40 mM with coefficient of determination of R2=0,997. The method was applied successfully to Hcy determination in human blood.

  2. Association between Plasma Homocysteine Levels and Neuronal Injury in HIV Infection

    PubMed Central

    Ahlgren, Erika; Hagberg, Lars; Fuchs, Dietmar; Andersson, Lars-Magnus; Nilsson, Staffan; Zetterberg, Henrik; Gisslén, Magnus

    2016-01-01

    Objective To investigate the role of homocysteine in neuronal injury in HIV infection. Methods Using a cross-sectional design and archived samples, we compared concentrations of plasma homocysteine and cerebrospinal fluid (CSF) neurofilament light protein (NFL), a sensitive marker of neuronal injury, in 83 HIV-1-infected subjects without antiretroviral treatment. We also analyzed plasma vitamin B12, serum folate, CSF, and plasma HIV RNA, the immune activation marker neopterin in CSF and serum, and albumin ratio as a marker of blood-brain barrier integrity. Twenty-two subjects provided a second sample median of 12.5 months after antiretroviral treatment initiation. Results A significant correlation was found between plasma homocysteine and CSF NFL concentrations in untreated individuals (r = 0.52, p < 0.0001). As expected, there was a significant inverse correlation between homocysteine and B12 (r = –0.41, p < 0.001) and folate (r = –0.40, p = < 0.001) levels. In a multiple linear regression analysis homocysteine stood out as an independent predictor of CSF NFL in HIV-1-infected individuals. The correlation of plasma homocysteine and CSF NFL was also present in the group receiving antiretroviral therapy (r = 0.51, p = 0.016). Conclusion A correlation between plasma homocysteine and axonal injury, as measured by CSF NFL, was found in both untreated and treated HIV. While this study is not able to prove a causal link, homocysteine and functional B12/folate deficiency appear to play a role in neural injury in HIV-infected individuals. PMID:27441551

  3. ACP Broadsheet No 152: March 1998. Clinical implications of plasma homocysteine measurement in cardiovascular disease.

    PubMed Central

    Still, R A; McDowell, I F

    1998-01-01

    Plasma homocysteine is emerging as an important risk factor for cardiovascular disease. Measurement in clinical laboratories is feasible by several techniques, including HPLC. Of particular importance is the potential for treatment by dietary modification and vitamin supplements, particularly folic acid. The outcome of vitamin intervention on cardiovascular events is awaited with interest. If the role of homocysteine is confirmed then it may rival cholesterol in importance as a cardiovascular risk factor. Images PMID:9659257

  4. Associations between Serum 25-hydroxyvitamin D and Lipids, Lipoprotein Cholesterols, and Homocysteine

    PubMed Central

    Glueck, Charles J.; Jetty, Vybhav; Rothschild, Matan; Duhon, Gregory; Shah, Parth; Prince, Marloe; Lee, Kevin; Goldenberg, Michael; Kumar, Ashwin; Goldenberg, Naila; Wang, Ping

    2016-01-01

    Background: Serum 25(OH) vitamin D levels are inversely associated with cardiovascular disease (CVD) mortality, mediated in part by independent positive relationships with high-density lipoprotein cholesterol (HDLC) and inverse relationships with low-density lipoprotein cholesterol (LDLC), triglyceride, and homocysteine. Aims: In this study, we assessed relationships between fasting serum vitamin D and lipids, lipoprotein cholesterols, and homocysteine. Materials and Methods: We studied 1534 patients sequentially referred to our center from 2007 to 2016. Fasting serum total 25(OH) vitamin D, plasma cholesterol, triglyceride, HDLC, LDLC, and homocysteine were measured. Stepwise regression models were used with total cholesterol, triglyceride, HDLC, LDLC, and homocysteine as dependent variables and explanatory variables age, race, gender, body mass index (BMI), and serum vitamin D levels. Relationships between quintiles of serum vitamin D and triglycerides, HDLC, LDLC, and homocysteine were assessed after covariance adjusting for age, race, gender, and BMI. Results: Fasting serum vitamin D was positively correlated with age, HDLC, and White race, and was inversely correlated with BMI, total and LDL cholesterol, triglyceride, and fasting serum homocysteine (P ≤ 0.0001 for all). Serum vitamin D was a significant independent inverse explanatory variable for total cholesterol, triglyceride, and LDL cholesterol, and accounted for the largest amount of variance in serum total cholesterol (partial R2 =3.6%), triglyceride (partial R2 =3.1%), and LDLC (partial R2 =2.9%) (P < 0.0001 for all). Serum vitamin D was a significant positive explanatory variable for HDLC (partial R2 = 1.4%, P < 0.0001), and a significant inverse explanatory variable for homocysteine (partial R2 = 6.0–12.6%). Conclusions: In hyperlipidemic patients, serum vitamin D was a significant independent inverse determinant of total cholesterol, LDLC, triglyceride, and homocysteine, and a significant

  5. Sex Difference in the Association between Serum Homocysteine Level and Non-Alcoholic Fatty Liver Disease

    PubMed Central

    Won, Bo-Youn; Lee, Soo-Hyun; Yun, Sung-Hwan; Kim, Moon-Jong; Park, Kye-Seon; Kim, Young-Sang; Haam, Ji-Hee; Kim, Hyung-Yuk; Kim, Hye-Jung; Park, Ki-Hyun

    2016-01-01

    Background The relationship between serum homocysteine levels and non-alcoholic fatty liver disease is poorly understood. This study aims to investigate the sex-specific relationship between serum homocysteine level and non-alcoholic fatty liver disease in the Korean population. Methods This cross-sectional study included 150 men and 132 women who participated in medical examination programs in Korea from January 2014 to December 2014. Patients were screened for fatty liver by abdominal ultrasound and patient blood samples were collected to measure homocysteine levels. Patients that consumed more than 20 grams of alcohol per day were excluded from this study. Results The homocysteine level (11.56 vs. 8.05 nmol/L) and the proportion of non-alcoholic fatty liver disease (60.7% vs. 19.7%) were significantly higher in men than in women. In men, elevated serum homocysteine levels were associated with a greater prevalence of non-alcoholic fatty liver disease (quartile 1, 43.6%; quartile 4, 80.6%; P=0.01); however, in females, there was no significant association between serum homocysteine levels and the prevalence of non-alcoholic fatty liver disease. In the logistic regression model adjusted for age and potential confounding parameters, the odds ratio for men was significantly higher in the uppermost quartile (model 3, quartile 4: odds ratio, 6.78; 95% confidential interval, 1.67 to 27.56); however, serum homocysteine levels in women were not associated with non-alcoholic fatty liver disease in the crude model or in models adjusted for confounders. Conclusion Serum homocysteine levels were associated with the prevalence of non-alcoholic fatty liver disease in men. PMID:27468343

  6. Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores.

    PubMed

    Hung, Chien-Jung; Huang, Po-Chao; Lu, Shao-Chun; Li, Yi-Hwei; Huang, Hsien-Bin; Lin, Bi-Fong; Chang, Sue-Joan; Chou, Hsu-Fang

    2002-02-01

    Mild hyperhomocysteinemia is an independent risk factor for cardiovascular disease and may result from a deficiency of folate, vitamin B-6 or vitamin B-12. Because vitamin B-12 deficiency is often associated with vegetarianism, this study was designed to examine the effect of Taiwanese vegetarian diets on B-vitamin status and plasma homocysteine levels. Female Buddhist lacto-vegetarians (n = 45; 31-45 y) and matched omnivores (n = 45) recruited in Hualien, Taiwan, were investigated. Taiwanese vegetarians consumed normal amount of folate, but only 21% of Taiwan Recommended Daily Nutrient Allowances (RDNA) values of vitamin B-12. Compared with the omnivores, the vegetarians had significantly higher levels of plasma folate (14.79 +/- 7.70 vs. 11.98 +/- 8.29 nmol/L), but lower levels of vitamin B-12 (207.7 +/- 127.1 vs. 403.5 +/- 138.9 pmol/L). Fasting plasma homocysteine levels were significantly higher in vegetarians than in omnivores (mean: 11.20 +/- 4.27 vs. 8.64 +/- 2.06 micromol/L; median: 10.5 vs. 8.5 micromol/L). Fasting plasma homocysteine was inversely correlated with plasma folate and vitamin B-12 in the vegetarian group. Multiple regression analysis revealed that plasma folate, vitamin B-12 and creatinine were independent determinants of homocysteine variation and contributed to 38.6% of homocysteine variation in the vegetarians. Compared with the omnivores, vegetarians also had significantly lower serum levels of valine, isoleucine, leucine, lysine, alanine and arginine, but higher levels of glycine. In the vegetarian group, fasting plasma homocysteine correlated negatively with serum threonine, lysine, histidine, arginine and cystine, and these amino acids contributed to 38.7% of homocysteine variation. In conclusion, the Buddhist nuns who consumed a lacto-vegetarian diet had mildly elevated fasting plasma homocysteine levels presumably due to lower levels of plasma vitamin B-12.

  7. Homocysteine and its nutritional determinants in two ethnic groups of Slovakia.

    PubMed

    Krajcovicová-Kudlácková, M; Blazícek, P; Ginter, E; Valachicová, M

    2004-12-01

    Determinants of total homocysteine involve demographic (age, sex, ethnic origin), genetic (enzymatic defects of metabolic homocysteine pathways) and acquired factors (deficiency of B-group vitamins, state of health, lifestyle). Plasma levels of total homocysteine and serum levels of vitamin B12, folic acid, vitamin B6 were measured in adult apparently healthy Romany minority subjects (n=119) and compared with those levels in apparently healthy subjects of majority Slovak population (n=146). Mean homocysteine level was similar in both groups (9.92 micromol/l in the Romany vs. 9.61 micromol/l in majority group). Hyperhomocysteinemia was only observed in 3% of both ethnic probands. Vitamin B12 level was equal (301 micromol/l in the Romany and 311 micromol/ in majority group). Deficient levels were found in 4% of the Romany subjects and 9% of the majority subjects. Folic acid level was significantly lower in Romany group (11.3 nmol/l vs. 14.8 nmol/l) with deficiency in 42% of the Romany subjects vs. 28% in the majority subjects. This finding is a consequence of lower consumption of fruit, vegetables, pulses and whole grain products in the Romany group. Vitamin B6 deficiency was found in 68% of the Romany subjects and 40% of majority subjects. This vitamin is homocysteine determinant under excessive methionine intake (overnutrition with predominance of animal protein intake). As was demonstrated in a dietetic questionnaires, the Romany subjects are more frequent consumers of meat and eggs. This nutrition regime should indicate an increased homocysteine level under vitamin B6 deficiency. The results of normal homocysteine levels in the Romany population under condition of higher folic acid and vitamin B6 deficiencies, smoking and higher alcohol consumption may suggest a more effective homocysteine metabolism in relation to different ethnic origin.

  8. Serum homocysteine level in patients with ankylosing spondylitis.

    PubMed

    Başkan, Bedriye Mermerci; Sivas, Filiz; Aktekin, Lale Akbulut; Doğan, Yasemin Pekin; Ozoran, Kürşat; Bodur, Hatice

    2009-10-01

    In this study serum homocystein (Hcy) level was measured and its relationship with disease activity criteria and treatment protocols was investigated in ankylosing spondylitis (AS) patients. Ninety-two AS patients and 58 healthy individuals were recruited. Erythrocyte sedimentation rate and serum C-reactive protein were determined. Bath AS disease activity index and Bath AS functional index were calculated. Serum Hcy levels >15 micromol/l were considered as hyperhomocysteinemia. The mean serum homocysteine levels were 14.40 and 12.60 micromol/l in patients with AS and the control group, respectively, and the difference between two groups was significant. While there was no significant difference between the sulfasalazine (SSZ) group with 14.25 micromol/l mean Hcy level and the methotrexate (MTX)/SSZ group with 16.05 micromol/l, there was a statistically significant difference between the Hcy levels of these two groups and Hcy level of 12.15 micromol/l of the non-steroidal anti-inflammatory drugs group, and 12.60 micromol/l Hcy level of the control group. Mean serum Hcy level was 13.65 micromol/l in patients with active AS and 14.60 micromol/l in patients with inactive AS, and there was no significant difference between the groups. In our study serum Hcy level was found to be significantly higher in patients with AS than in healthy control subjects. Especially for the AS patients receiving MTX and SSZ treatment without folic acid supplementation, addition of folic acid to their therapy may decrease the risk of cardiovascular disease which in turn decreases the mortality in these patients, but further prospective studies are needed for supporting these results. PMID:19288264

  9. Stroke: roles of B vitamins, homocysteine and antioxidants.

    PubMed

    Sánchez-Moreno, Concepción; Jiménez-Escrig, Antonio; Martín, Antonio

    2009-06-01

    In the present review concerning stroke, we evaluate the roles of B vitamins, homocysteine and antioxidant vitamins. Stroke is a leading cause of death in developed countries. However, current therapeutic strategies for stroke have been largely unsuccessful. Several studies have reported important benefits on reducing the risk of stroke and improving the post-stroke-associated functional declines in patients who ate foods rich in micronutrients, including B vitamins and antioxidant vitamins E and C. Folic acid, vitamin B6 and vitamin B12 are all cofactors in homocysteine metabolism. Growing interest has been paid to hyperhomocysteinaemia as a risk factor for CVD. Hyperhomocysteinaemia has been linked to inadequate intake of vitamins, particularly to B-group vitamins and therefore may be amenable to nutritional intervention. Hence, poor dietary intake of folate, vitamin B6 and vitamin B12 are associated with increased risk of stroke. Elevated consumption of fruits and vegetables appears to protect against stroke. Antioxidant nutrients have important roles in cell function and have been implicated in processes associated with ageing, including vascular, inflammatory and neurological damage. Plasma vitamin E and C concentrations may serve as a biological marker of lifestyle or other factors associated with reduced stroke risk and may be useful in identifying those at high risk of stroke. After reviewing the observational and intervention studies, there is an incomplete understanding of mechanisms and some conflicting findings; therefore the available evidence is insufficient to recommend the routine use of B vitamins, vitamin E and vitamin C for the prevention of stroke. A better understanding of mechanisms, along with well-designed controlled clinical trials will allow further progress in this area.

  10. Vitamin supplementation reduces the level of homocysteine in the urine of autistic children.

    PubMed

    Kałużna-Czaplińska, Joanna; Michalska, Monika; Rynkowski, Jacek

    2011-04-01

    Significant differences in homocysteine levels in the urine of autistic children are observed. We hypothesized that vitamin supplementation might reduce the level of urinary homocysteine. To rationalize such a hypothesis, analyses were performed using the gas chromatography/mass spectrometry method. The homocysteine level in the urine of autistic children was measured twice: (1) before vitamin supplementation (group C, 30 autistic children) and (2) after supplementation, with either folic acid and vitamins B(6) and B(12) (group A1, 24 autistic children) or vitamins B(6) and B(12) alone (group A2, 6 autistic children). The homocysteine level in the urine of autistic children before vitamin supplementation was 2.41 ± 1.10 mmol/mol creatinine (mean ± SD difference). After treatment, the homocysteine level was reduced to 1.13 ± 0.44 and 1.33 ± 0.39 mmol/mol creatinine for A1 and A2 groups, respectively. The intake of vitamins B(6) and B(12), together with folic acid, was found to be more effective in lowering the levels of urinary homocysteine than the intake of vitamins B(6) and B(12) alone. Our findings may lead to the recommendation of including vitamins B(6) and B(12) together with folic acid supplementation in the diets of children with autism.

  11. The diagnostic value of serum homocysteine concentration as a risk factor for coronary artery disease.

    PubMed

    Dierkes, J; Bissé, E; Nauck, M; Orth, M; Mayer, H; Luley, C; Wieland, H

    1998-06-01

    Hyperhomocysteinemia is now regarded as an established risk factor for coronary artery disease and is present frequently in the general population. However, the diagnostic value of this risk factor relative to others has only occasionally been investigated. We compared the diagnostic value of classic risk factors and of homocysteine in a retrospective case-control study in 191 cases with angiographically established coronary artery disease and 231 healthy controls. Life style habits were assessed by a detailed questionnaire. Laboratory parameters including lipoproteins and blood lipids, homocysteine, folate, and vitamin B12 were measured and their diagnostic value compared with each other by use of receiver-operator characteristic analysis. Comparison of the receiver-operator characteristic curves revealed that homocysteine significantly discriminated between cases and control subjects. High-density-lipoprotein cholesterol, triglycerides and non-esterified fatty acids also had an area under the curve significantly different from 0.5 (the area under the curve representing no discrimination). Homocysteine was weakly related to folate, vitamin B12, age and serum creatinine concentration. We conclude that hyperhomocysteinemia is at least as important as conventional risk factors for coronary artery disease and that receiver operator characteristic analysis of homocysteine is suitable to determine patients at the highest risk for coronary artery disease. Clinical trials testing the effect of homocysteine lowering by vitamin supplementation in the prevention of coronary artery disease are needed.

  12. Elevated plasma homocysteine level is possibly associated with skin sclerosis in a series of Japanese patients with systemic sclerosis.

    PubMed

    Motegi, Sei-Ichiro; Toki, Sayaka; Yamada, Kazuya; Uchiyama, Akihiko; Ishikawa, Osamu

    2014-11-01

    Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease (PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon (RP), digital ulcers (DU) in systemic sclerosis (SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis (AO) and interstitial lung disease (ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness (IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO.

  13. Homocysteine levels in schizophrenia and affective disorders—focus on cognition

    PubMed Central

    Moustafa, Ahmed A.; Hewedi, Doaa H.; Eissa, Abeer M.; Frydecka, Dorota; Misiak, Błażej

    2014-01-01

    Although homocysteine (Hcy) has been widely implicated in the etiology of various physical health impairments, especially cardiovascular diseases, overwhelming evidence indicates that Hcy is also involved in the pathophysiology of schizophrenia and affective disorders. There are several mechanisms linking Hcy to biological underpinnings of psychiatric disorders. It has been found that Hcy interacts with NMDA receptors, initiates oxidative stress, induces apoptosis, triggers mitochondrial dysfunction and leads to vascular damage. Elevated Hcy levels might also contribute to cognitive impairment that is widely observed among patients with affective disorders and schizophrenia. Supplementation of vitamins B and folic acid has been proved to be effective in lowering Hcy levels. There are also studies showing that this supplementation strategy might be beneficial for schizophrenia patients with respect to alleviating negative symptoms. However, there are no studies addressing the influence of add-on therapies with folate and vitamins B on cognitive performance of patients with schizophrenia and affective disorders. In this article, we provide an overview of Hcy metabolism in psychiatric disorders focusing on cognitive correlates and indicating future directions and perspectives. PMID:25339876

  14. Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1alpha.

    PubMed

    Li, Siming; Arning, Erland; Liu, Chang; Vitvitsky, Victor; Hernandez, Carlos; Banerjee, Ruma; Bottiglieri, Teodoro; Lin, Jiandie D

    2009-03-01

    Plasma homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Hcy is a nonprotein amino acid derivative that is generated from the methionine cycle, which provides the methyl group for essentially all biological methylation reactions. Although plasma Hcy levels are elevated in patients with cardiovascular disease, the mechanisms that regulate Hcy homeostasis remain poorly defined. In this study, we found that the expression of key enzymes involved in Hcy metabolism is induced in the liver in response to fasting. This induction coincides with increased expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a transcriptional coactivator that regulates hepatic gluconeogenesis and mitochondrial function. PGC-1alpha stimulates the expression of genes involved in Hcy metabolism in cultured primary hepatocytes as well as in the liver. Adenoviral-mediated expression of PGC-1alpha in vivo leads to elevated plasma Hcy levels. In contrast, mice deficient in PGC-1alpha have lower plasma Hcy concentrations. These results define a novel role for the PGC-1alpha coactivator pathway in the regulation of Hcy homeostasis and suggest a potential pathogenic mechanism that contributes to hyperhomocysteinemia.

  15. Vitamin B(12) deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid.

    PubMed

    Vaes, Bart L T; Lute, Carolien; Blom, Henk J; Bravenboer, Nathalie; de Vries, Teun J; Everts, Vincent; Dhonukshe-Rutten, Rosalie A; Müller, Michael; de Groot, Lisette C P G M; Steegenga, Wilma T

    2009-05-01

    The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B(12) deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B(12), Hcy, and MMA on differentiation and activity of bone cells. B(12) deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B(12) deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B(12), Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B(12) did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B(12) deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels.

  16. Association of serum calcium concentrations with fibrinogen and homocysteine in nondiabetic Korean subjects

    PubMed Central

    Cho, Hyun Sun; Lee, Sung Won; Shin, Juyoung; Moon, Sung Dae; Han, Je Ho; Cha, Bong Yun; Kim, Eun Sook

    2016-01-01

    Abstract Considerable evidence shows that increased serum calcium levels are associated with metabolic disorders, cardiovascular disease, and increased mortality. This study investigated whether serum calcium, within a normal range, is significantly associated with serum fibrinogen and homocysteine, markers of increased cardiovascular disease risk in nondiabetic Korean subjects. A cross-sectional analysis was performed on 1096 subjects (mean age, 55.1 ± 11.1 years; 36.1% women) undergoing a general health checkup. Serum biochemistry was analyzed including serum albumin-corrected calcium (Cac), insulin resistance (IR, using homeostasis model assessment [HOMA]), fibrinogen, and homocysteine. Compared with patients within the lowest Cac quartile, those with higher Cac levels had increased fibrinogen and homocysteine levels as well as an increased proportion of smoking, dyslipidemia, and HOMA-IR. Correlation analyses revealed linear relationships for Cac with fibrinogen and homocysteine in both genders. After adjustment for confounding factors, serum Cac was significantly associated with high fibrinogen (odds ratio [OR] for the highest vs the lowest quartile = 1.76, 95% confidence interval [CI] = 1.09–2.83, P = 0.02) and homocysteine (OR = 1.83, 95% CI = 1.07–3.11, P = 0.027). Multivariate regression models showed that Cac was linearly associated with fibrinogen (standardized β = 0.14, P < 0.001) and homocysteine (standardized β = 0.07, P = 0.009). High normal calcium concentrations were independently associated with increased levels of fibrinogen and homocysteine. Further investigation is needed to validate whether slightly increased calcium levels within the normal range indicate a higher risk of cardiovascular disease. PMID:27310988

  17. Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis

    PubMed Central

    Yajnik, Chittaranjan S; Chandak, Giriraj R; Joglekar, Charudatta; Katre, Prachi; Bhat, Dattatray S; Singh, Suraj N; Janipalli, Charles S; Refsum, Helga; Krishnaveni, Ghattu; Veena, Sargoor; Osmond, Clive; Fall, Caroline HD

    2014-01-01

    Background: Disturbed one-carbon (1-C) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established. Methods: We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study (PMNS, Pune, India) and Parthenon Cohort Study (Mysore, India). We tested for evidence of causality within a Mendelian randomization framework, using a methylenetetrahydrofolatereductase (MTHFR) gene variant rs1801133 (earlier known as 677C→T) by instrumental variable and triangulation analysis, separately and using meta-analysis. Results: Median (IQR) homocysteine concentration and mean (SD) birthweight were 8.6 µmol/l (6.7,10.8) and 2642 g (379) in the PMNS and 6.0 µmol/l (5.1,7.1) and 2871 g (443) in the Parthenon study. Offspring birthweight was inversely related to maternal homocysteine concentration—PMNS: –22 g/SD [95% confidence interval (CI): (–50, 5), adjusted for gestational age and offspring gender]; Parthenon: –57 g (–92, –21); meta-analysis: –40 g (–62, –17)]. Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [PMNS: 0.30 SD/allele (0.14, 0.46); Parthenon: 0.21 SD (0.02, 0.40); meta-analysis: 0.26 SD (0.14, 0.39)]; and lower birthweight [PMNS: –46 g (–102, 11, adjusted for gestational age, offspring gender and rs1801133 genotype); Parthenon: –78 g (–170, 15); meta-analysis: –61 g (–111, –10)]. Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight. Conclusions: Our findings suggest a causal role for maternal homocysteine (1-C metabolism) in fetal growth. Reducing maternal homocysteine concentrations may improve fetal growth. PMID:25052622

  18. The impact of intratracheally instilled carbon black on the cardiovascular system of rats: elevation of blood homocysteine and hyperactivity of platelets.

    PubMed

    Kim, Hwa; Oh, Seok-Jeong; Kwak, Hui-Chan; Kim, Jong-Kyu; Lim, Cheol-Hong; Yang, Jeong-Sun; Park, Kwangsik; Kim, Sang-Kyum; Lee, Moo-Yeol

    2012-01-01

    Carbon black (CB) is an industrial chemical with high potential for human exposure. Although the relationship between exposure to particulate matter (PM) and cardiovascular disease is well documented, the risk of adverse cardiovascular effects attributed to CB particles has not been clearly characterized. This study was performed to (1) investigate the effects of CB on cardiovascular system and (2) identify the target tissue or potential biomarkers. Carbon black with a distinct particle size, N330 (ultrafine particle) and N990 (fine particle), was intratracheally instilled into rats at a doses of 1, 3, or 10 mg/kg. Measurements of thrombotic activity and determination of plasma homocysteine levels, cardiac functionality, and inflammatory responses were conducted at 24-h and 1-wk time points. Exposure to N330 accelerated platelet-dependent blood clotting at 10 mg/kg, the highest exposure tested. Unexpectedly, both N330 and N990 led to prolongation of activated partial thromboplastin time (aPTT), whereas these CB particles failed to affect prothrombin time (PT). N990 produced a significant elevation in the level of plasma homocysteine, a well-established etiological factor in cardiovascular diseases. Both N330 and N990 induced apparent inflammation in the lungs; however, both particles failed to initiate systemic inflammation. Neither CB particle produced observable cardiac symptoms as detected by electrocardiography. Taken together, data show CB exposure enhanced the cardiovascular risk by inducing hyperhomocysteinemia and platelet hyperactivity, although these effects may be variable depending on particle size and exposure duration. Homocysteine may be a potential biomarker for cardiovascular toxicity following CB exposure.

  19. Comparative Assessment of Vitamin-B12, Folic Acid and Homocysteine Levels in Relation to p53 Expression in Megaloblastic Anemia

    PubMed Central

    Yadav, Manish K.; Manoli, Nandini M.

    2016-01-01

    Background Megaloblastic anemia (MBA), also known as macrocytic anemia, is a type of anemia characterized by decreased number of RBCs as well as the presence of unusually large, abnormal and poorly developed erythrocytes (megaloblasts), which fail to enter blood circulation due to their larger size. Lack of vitamin-B12 (VB12) and / or folate (Vitamin-B9, VB9) with elevated homocysteine is the key factor responsible for megaloblastic anemia. Prior studies have demonstrated the induction of apoptosis in these abnormal under-developed erythrocytes. However, it is not clear whether this apoptosis induction is due to elevated p53 level or due to any other mechanism. Furthermore, it is also not fully known whether decreased vitamin-B12 and / or folate are responsible for apoptosis induction mediated by p53 in pre-erythroblasts. Methods Levels of serum VB9, VB12 and homocysteine in 50 patients suffering from MBA were compared with 50 non-megaloblastic anemia control subjects, who were referred by the clinicians for bone marrow examination for medical conditions other than MBA. Next, we have measured the p53 expression in the paraffin embedded blocks prepared from bone marrow biopsy, using immunohistochemistry, and the expression levels correlated with VB9 and VB12 levels. Results Out of 50 MBA patients 40 (80%) and 44 (88%) subjects had very low VB12 and VB9 levels respectively. In contrast, only 2 (4%) and 12 (24%) non-megaloblastic anemia controls, out of 50 subjects, had low VB12 and VB9 respectively. Correlating with low vitamin B9 and B12, the homocysteine levels were high in 80% cases. But, only 20% non-megaloblastic controls exhibited high homocysteine in plasma. Immunohistochemical analysis for p53 expression showed a significantly high level of expression in MBA cases and no—or very low—expression in control subjects. Our correlation studies comparing the VB12 and VB9 levels with p53 expression concludes unusually high p53 levels in patients suffering from VB

  20. A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma

    PubMed Central

    Xuan, Yang; Li, Xiao-Hong; Hu, Zhong-Qian; Teng, Zhi-Mei; Hu, Dao-Jun

    2016-01-01

    Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs). PMID:27126524

  1. Homocysteine Metabolism in ZDF (Type 2) Diabetic Rats

    PubMed Central

    Wijekoon, Enoka P.; Hall, Beatrice; Ratnam, Shobhitha; Brosnan, Margaret E.; Zeisel, Steven H.; Brosnan, John T.

    2008-01-01

    Mild hyperhomocysteinemia is a risk factor for many diseases, including cardiovascular disease. We determined the effects of insulin resistance and of type 2 diabetes on homocysteine (Hcy) metabolism using Zucker diabetic fatty rats (ZDF/Gmi fa/fa and ZDF/Gmi fa/?). Plasma total Hcy was reduced in ZDF fa/fa rats by 24% in the pre-diabetic insulin-resistant stage, while in the frank diabetic stage there was a 59% reduction. Hepatic activities of several enzymes that play a role in the removal of Hcy: cystathionine β-synthase (CBS), cystathionine γ-lyase, and betaine:Hcy methyltransferase (BHMT) were increased as was methionine adenosyltransferase. CBS and BHMT mRNA levels and the hepatic level of S-adenosylmethionine were also increased in the ZDF fa/fa rats. Studies with primary hepatocytes showed that Hcy export and the transsulfuration flux in cells from ZDF fa/fa rats were particularly sensitive to betaine. Interestingly, liver betaine concentration was found to be significantly lower in the ZDf fa/fa rats at both 5 and 11 weeks. These results emphasize the importance of betaine metabolism in determining plasma Hcy levels in type 2 diabetes. PMID:16249451

  2. Protective mechanisms against homocysteine toxicity: the role of bleomycin hydrolase.

    PubMed

    Zimny, Jaroslaw; Sikora, Marta; Guranowski, Andrzej; Jakubowski, Hieronim

    2006-08-11

    Homocysteine (Hcy) editing by methionyl-tRNA synthetase results in the formation of Hcy-thiolactone and initiates a pathway that has been implicated in human disease. In addition to being cleared from the circulation by urinary excretion, Hcy-thiolactone is detoxified by the serum Hcy-thiolactonase/paraoxonase carried on high density lipoprotein. Whether Hcy-thiolactone is detoxified inside cells was unknown. Here we show that Hcy-thiolactone is hydrolyzed by an intracellular enzyme, which we have purified to homogeneity from human placenta and identified by proteomic analyses as human bleomycin hydrolase (hBLH). We have also purified an Hcy-thiolactonase from the yeast Saccharomyces cerevisiae and identified it as yeast bleomycin hydrolase (yBLH). BLH belongs to a family of evolutionarily conserved cysteine aminopeptidases, and its only known biologically relevant function was deamidation of the anticancer drug bleomycin. Recombinant hBLH or yBLH, expressed in Escherichia coli, exhibits Hcy-thiolactonase activity similar to that of the native enzymes. Active site mutations, C73A for hBLH and H369A for yBLH, inactivate Hcy-thiolactonase activities. Yeast blh1 mutants are deficient in Hcy-thiolactonase activity in vitro and in vivo, produce more Hcy-thiolactone, and exhibit greater sensitivity to Hcy toxicity than wild type yeast cells. Our data suggest that BLH protects cells against Hcy toxicity by hydrolyzing intracellular Hcy-thiolactone. PMID:16769724

  3. Higher homocysteine associated with thinner cortical gray matter in 803 ADNI subjects

    PubMed Central

    Madsen, Sarah K.; Rajagopalan, Priya; Joshi, Shantanu H.; Toga, Arthur W.; Thompson, Paul M.

    2014-01-01

    A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor – high homocysteine levels in the blood – is known to increase risk for Alzheimer’s disease and vascular disorders. Here we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, surface area) computed from brain MRI in 803 elderly subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital and right temporal regions; and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex, and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, mild cognitive impairment, or Alzheimer’s disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels. PMID:25444607

  4. A Sensitive Ratiometric Long-Wavelength Fluorescent Probe for Selective Determination of Cysteine/Homocysteine.

    PubMed

    Manibalan, Kesavan; Chen, Sin-Ming; Mani, Veerappan; Huang, Tsung-Tao; Huang, Sheng-Tung

    2016-07-01

    The development of sensitive fluorescence probes to detect biothiols such as cysteine and homocysteine has attracted great attention in recent times. Herein, we described the design and synthesis of coumarin based long-wavelength fluorescence probe, Bromo-2-benzothiazolyl-3-cyano-7-hydroxy coumarin (BBCH, 2) for selective detections of cysteine and homocysteine. The probe is rationally designed in such a way that both sulfhydryl and adjacent amino groups of thiols are involved in sensing process. Only cysteine/homocysteine able to react with BBCH to release fluorescence reporter (BCH, 1); while, glutathione and other amino acids unable to react with BBCH due to the absence of adjacent amino groups. In presence of cysteine, the color of BBCH is turns from colorless to red and thus BBCH is a naked eye fluorescence indicator for cysteine. Besides, BBCH can discriminate cysteine and homocysteine based on color changes and different reaction rates. The described sensing platform showed good sensing performances to detect cysteine and homocysteine with detection limits of 0.87 and 0.19 μM, respectively. Practical applicability was verified in biological and pharmaceutical samples. PMID:27290640

  5. What is the influence of hormone therapy on homocysteine and crp levels in postmenopausal women?

    PubMed Central

    Lakryc, Eli Marcelo; Machado, Rogério Bonassi; Soares, José Maria; Fernandes, César Eduardo; Baracat, Edmund Chada

    2015-01-01

    OBJECTIVE: To evaluate the influence of estrogen therapy and estrogen-progestin therapy on homocysteine and C-reactive protein levels in postmenopausal women. METHODS: In total, 99 postmenopausal women were included in this double-blind, randomized clinical trial and divided into three groups: Group A used estrogen therapy alone (2.0 mg of 17β-estradiol), Group B received estrogen-progestin therapy (2.0 mg of 17 β-estradiol +1.0 mg of norethisterone acetate) and Group C received a placebo (control). The length of treatment was six months. Serum measurements of homocysteine and C-reactive protein were carried out prior to the onset of treatment and following six months of therapy. RESULTS: After six months of treatment, there was a 20.7% reduction in homocysteine levels and a 100.5% increase in C-reactive protein levels in the group of women who used estrogen therapy. With respect to the estrogen-progestin group, there was a 12.2% decrease in homocysteine levels and a 93.5% increase in C-reactive protein levels. CONCLUSION: Our data suggested that hormone therapy (unopposed estrogen or estrogen associated with progestin) may have a positive influence on decreasing cardiovascular risk due to a significant reduction in homocysteine levels. PMID:25789519

  6. Molecular Targeting of Proteins by l-Homocysteine: Mechanistic Implications for Vascular Disease

    PubMed Central

    Glushchenko, Alla V.; Jacobsen, Donald W.

    2010-01-01

    Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, complications of pregnancy, cognitive impairment, and osteoporosis. That elevated homocysteine leads to vascular dysfunction may be the linking factor between these apparently unrelated pathologies. Although a growing body of evidence suggests that homocysteine plays a causal role in atherogenesis, specific mechanisms to explain the underlying pathogenesis have remained elusive. This review focuses on chemistry unique to the homocysteine molecule to explain its inherent cytotoxicity. Thus, the high pKa of the sulfhydryl group (pKa, 10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Studies in this laboratory have identified albumin, fibronectin, transthyretin, and metallothionein as targets for homocysteinylation. In the case of albumin, the mechanism of targeting has been elucidated. Homocysteinylation of the cysteine residues of fibronectin impairs its ability to bind to fibrin. Homocysteinylation of the cysteine residues of metallothionein disrupts zinc binding by the protein and abrogates inherent superoxide dismutase activity. Thus, S-homocysteinylation of protein cysteine residues may explain mechanistically the cytotoxicity of elevated l-homocysteine. PMID:17760510

  7. Comparison of Protein N-Homocysteinylation in Rat Plasma under Elevated Homocysteine Using a Specific Chemical Labeling Method.

    PubMed

    Zang, Tianzhu; Pottenplackel, Ligi Paul; Handy, Diane E; Loscalzo, Joseph; Dai, Shujia; Deth, Richard C; Zhou, Zhaohui Sunny; Ma, Jisheng

    2016-01-01

    Elevated blood concentrations of homocysteine have been well established as a risk factor for cardiovascular diseases and neuropsychiatric diseases, yet the etiologic relationship of homocysteine to these disorders remains poorly understood. Protein N-homocysteinylation has been hypothesized as a contributing factor; however, it has not been examined globally owing to the lack of suitable detection methods. We recently developed a selective chemical method to label N-homocysteinylated proteins with a biotin-aldehyde tag followed by Western blotting analysis, which was further optimized in this study. We then investigated the variation of protein N-homocysteinylation in plasma from rats on a vitamin B12 deficient diet. Elevated "total homocysteine" concentrations were determined in rats with a vitamin B12 deficient diet. Correspondingly, overall levels of plasma protein N-homocysteinylation displayed an increased trend, and furthermore, more pronounced and statistically significant changes (e.g., 1.8-fold, p-value: 0.03) were observed for some individual protein bands. Our results suggest that, as expected, a general metabolic correlation exists between "total homocysteine" and N-homocysteinylation, although other factors are involved in homocysteine/homocysteine thiolactone metabolism, such as the transsulfuration of homocysteine by cystathionine β-synthase or the hydrolysis of homocysteine thiolactone by paraoxonase 1 (PON1), may play more significant or direct roles in determining the level of N-homocysteinylation. PMID:27617989

  8. Plasma B vitamins, homocysteine and their relation with bone loss and hip fracture in elderly men and women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Elevated homocysteine is a strong risk factor for osteoporotic fractures among elders, yet it may be a marker for low B vitamin status. Objective: To examine the associations of plasma concentrations of folate, vitamin B12, vitamin B6 and homocysteine with bone loss and hip fracture risk in elderly...

  9. The Effect of Serum 25-Hydroxyvitamin D on Elevated Homocysteine Concentrations in Participants of a Preventive Health Program

    PubMed Central

    Pham, Truong-Minh; Ekwaru, John Paul; Mastroeni, Silmara S.; Mastroeni, Marco F.; Loehr, Sarah A.; Veugelers, Paul J.

    2016-01-01

    Both lower serum 25-hydroxyvitamin D [25(OH)D] and elevated homocysteine concentrations are potential risk factors for cardiovascular disease (CVD). A recent analysis of the National Health and Nutrition Examination Survey reported an inverse association of serum 25(OH)D with homocysteine, however, the longitudinal relationship has yet to be investigated. We hypothesized and examined whether a temporal increase in 25(OH)D concentrations is paralleled by a reduction in the risk for elevated homocysteine. We analyzed data of 4475 participants with repeated assessments of serum 25(OH)D and homocysteine concentrations who enrolled in a preventive health program that encourages vitamin D supplementation and monitors serum 25(OH)D and homocysteine concentrations. We defined elevated homocysteine as concentrations greater than 13 micromoles per liter. Logistic regression was applied to assess the association of temporal changes in serum 25(OH)D with the risk of elevated homocysteine. We observed an inverse gradient whereby greater increases in 25(OH)D concentrations were associated with a lower prevalence of elevated homocysteine. Relative to those without temporal increases in 25(OH)D, participants who showed improvements in their serum 25(OH)D concentrations of “<25”, “25–50”, “50–75”, and “≥75” nanomoles per liter at follow up were 0.92 (95% confidence interval: 0.62–1.37), 0.52 (0.33–0.80), 0.34 (0.20–0.58), and 0.32 (0.19–0.54) times as likely to have elevated homocysteine, respectively. These observations suggest that temporal improvements in vitamin D status reduce serum homocysteine concentrations, and therefore may potentially contribute to the primary prevention of CVD. PMID:27548258

  10. Association between Homocysteine and Bone Mineral Density according to Age and Sex in Healthy Adults

    PubMed Central

    Kim, Joo Il; Moon, Ji Hyun; Chung, Hye Won; Kong, Mi Hee

    2016-01-01

    Background There are several studies about the relationship between serum homocysteine levels and bone mineral density (BMD), but the results are varied, and the studies are limited in Korea. In our study, the relationship between serum homocysteine levels and BMD by part according to age and sex is investigated. Methods From March 2012 to July 2015, the 3,337 healthy adults who took a medical examination were recruited. Subjects filled in the self-recording type questionnaire and physical examination, blood test, BMD of lumbar spine and femur were measured. After sorting by aging (≤49 year old, 50-59 year old, ≥60 year old) and sex, the results were adjusted with age and body mass index (BMI) and the relationship between serum homocysteine levels and BMD by lumbar spine and femur was analyzed by multiple regression analysis. Results As results of analysis, with the adjustment with age and BMI, all age groups of men had no significant relationship between log-converted serum homocysteine levels and BMD. In women aged under 50, there were significantly negative relationships at lumbar spine (β=-0.028, P=0.038), femur neck (β=-0.062, P=0.001), and total hip (β=-0.076, P<0.001), but there was no significant relationship in other age groups (50-59 year old and ≥60 year old). Conclusions As the serum homocysteine levels increased in women aged under 50, BMD of the lumbar spine and femur decreased, and correlations between homocysteine and BMD were different by sex and age. PMID:27622176

  11. A prospective study of maternal fatty acids, micronutrients and homocysteine and their association with birth outcome.

    PubMed

    Wadhwani, Nisha S; Pisal, Hemlata R; Mehendale, Savita S; Joshi, Sadhana R

    2015-10-01

    Our earlier studies both in animals and in humans have indicated that micronutrients (folic acid, vitamin B12) and long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are interlinked in the one-carbon cycle, which plays an important role in fetal 'programming' of adult diseases. The present study examines the levels of maternal and cord plasma fatty acids, maternal folate, vitamin B12 and homocysteine in healthy mothers at various time points during pregnancy and also examine an association between them. A longitudinal study of 106 normal pregnant women was carried out, and maternal blood was collected at three time points, viz., T1 = 16-20th week, T2 = 26-30th week and T3 = at delivery. Cord blood was collected at delivery. Fatty acids were estimated using a gas chromatograph. Levels of folate, vitamin B12 and homocysteine were estimated by the chemiluminescent microparticle immunoassay (CMIA) technology. Maternal plasma folate (P < 0.05), vitamin B12 (P < 0.01) and DHA (P < 0.05) levels were lowest, while maternal homocysteine levels were highest (P < 0.01) at T3. There was a negative association between maternal DHA and homocysteine at T2 (P < 0.05) and T3 (P < 0.01). There was a positive association between plasma DHA in maternal blood at T3 and cord blood. Furthermore, there was a positive association between maternal folate and vitamin B12 at T3 and baby weight, whereas maternal homocysteine at T1 were inversely associated with baby weight at delivery. Our study provides evidence for the associations of folic acid, vitamin B12, homocysteine with DHA and baby weight, suggesting that a balanced dietary supplementation of folate-vitamin B12-DHA during pregnancy may be beneficial.

  12. Poor nutrition and alcohol consumption are related to high serum homocysteine level at post-stroke

    PubMed Central

    Choi, Seung-Hye; Kim, Min-Sun; Kim, Jong-Sung

    2015-01-01

    BACKGROUND/OBJECTIVES Increased serum homocysteine (Hcy) levels have been reported to be related to the occurrence of cardio- and cerebrovascular diseases. High serum Hcy levels are also related to the development of secondary stroke and all-cause mortality. The purpose of this study was to investigate the prevalence of high serum homocysteine level and relating factors, and the change over the 10 month period post-stroke. SUBJECTS/METHODS Consecutive stroke patients who were admitted to the Asan Medical Center were enrolled. Ten months after the onset of stroke, an interview with a structured questionnaire was performed and blood samples were obtained for the biochemical parameters. Nutritional status was determined using the mini nutritional assessment (MNA) score and dietary nutrient intakes were also obtained using a 24 hour recall method. RESULTS Out of 203 patients, 84% were malnourished or at risk of malnutrition, and 26% had high homocysteine levels at 10 months post-stroke. Using logistic regression, the factors related with high homocysteine levels at 10 months post-stroke included heavy alcohol consumption (P = 0.020), low MNA scores (P = 0.026), low serum vitamin B12 (P = 0.021) and low serum folate levels (P = 0.003). Of the 156 patients who had normal homocysteine levels at admission, 36 patients developed hyperhomocysteinemia 10 months post-stroke, which was related to heavy alcohol consumption (P = 0.013). Persistent hyperhomocysteinemia, observed in 22 patients (11%), was related to male sex (P = 0.031), old age (P = 0.042), low vitamin B6 intake (P = 0.029), and heavy alcohol consumption (P = 0.013). CONCLUSION Hyperhomocysteinemia is common in post-stroke, and is related to malnutrition, heavy alcohol drinking and low serum level of folate and vitamin B12. Strategies to prevent or manage high homocysteine levels should consider these factors. PMID:26425280

  13. Association between Homocysteine and Bone Mineral Density according to Age and Sex in Healthy Adults

    PubMed Central

    Kim, Joo Il; Moon, Ji Hyun; Chung, Hye Won; Kong, Mi Hee

    2016-01-01

    Background There are several studies about the relationship between serum homocysteine levels and bone mineral density (BMD), but the results are varied, and the studies are limited in Korea. In our study, the relationship between serum homocysteine levels and BMD by part according to age and sex is investigated. Methods From March 2012 to July 2015, the 3,337 healthy adults who took a medical examination were recruited. Subjects filled in the self-recording type questionnaire and physical examination, blood test, BMD of lumbar spine and femur were measured. After sorting by aging (≤49 year old, 50-59 year old, ≥60 year old) and sex, the results were adjusted with age and body mass index (BMI) and the relationship between serum homocysteine levels and BMD by lumbar spine and femur was analyzed by multiple regression analysis. Results As results of analysis, with the adjustment with age and BMI, all age groups of men had no significant relationship between log-converted serum homocysteine levels and BMD. In women aged under 50, there were significantly negative relationships at lumbar spine (β=-0.028, P=0.038), femur neck (β=-0.062, P=0.001), and total hip (β=-0.076, P<0.001), but there was no significant relationship in other age groups (50-59 year old and ≥60 year old). Conclusions As the serum homocysteine levels increased in women aged under 50, BMD of the lumbar spine and femur decreased, and correlations between homocysteine and BMD were different by sex and age.

  14. Subacute methotrexate neurotoxicity and cerebral venous sinus thrombosis in a 12-year-old with acute lymphoblastic leukemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: homocysteine-mediated methotrexate neurotoxicity via direct endothelial injury.

    PubMed

    Mahadeo, Kris M; Dhall, Girish; Panigrahy, Ashok; Lastra, Carlos; Ettinger, Lawrence J

    2010-02-01

    From as early as the 1970s methotrexate has been associated with disseminated necrotizing leukoencephalopathy and other neurotoxic sequelae. Yet, a clear mechanism for methotrexate-induced neurotoxicity has not been established. The authors describe the case of a 12-year-old male with acute lymphoblastic leukemia and a homozygous methylenetetrahydrofolate reductase C677T mutation, who developed subacute methotrexate-induced toxicity and cerebral venous thrombosis after receiving intrathecal methotrexate. The role of homocysteine as a possible mediator in methotrexate-induced neurotoxicity via direct endothelial injury is discussed. PMID:20121554

  15. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves matrix metalloproteinase-2 modulation by homocysteine.

    PubMed

    Liu, Tingjiao; Lin, Jinghan; Ju, Ting; Chu, Lei; Zhang, Liming

    2015-08-01

    Arterial calcification is common in vascular diseases and involves conversion of vascular smooth muscle cells (VSMCs) to an osteoblast phenotype. Clinical studies suggest that the development of atherosclerosis can be promoted by homocysteine (HCY), but the mechanisms remain unclear. Here, we determined whether increases in HCY levels lead to an increase in VSMC calcification and differentiation, and examined the role of an extracellular matrix remodeler, matrix metalloproteinase-2 (MMP-2). Rat VSMCs were exposed to calcification medium in the absence or presence of HCY (10, 100 or 200 μmol/L) or an MMP-2 inhibitor (10(-6) or 10(-5) mol/L). MTT assays were performed to determine the cytotoxicity of the MMP-2 inhibitor in calcification medium containing 200 μmol/L HCY. Calcification was assessed by measurements of calcium deposition and alkaline phosphatase (ALP) activity as well as von Kossa staining. Expression of osteocalcin, bone morphogenetic protein (BMP)-2, and osteopontin, and MMP-2 was determined by immunoblotting. Calcification medium induced osteogenic differentiation of VSMCs. HCY promoted calcification, increased osteocalcin and BMP-2 expression, and decreased expression of osteopontin. MMP-2 expression was increased by HCY in a dose-dependent manner in VSMCs exposed to both control and calcification medium. The MMP-2 inhibitor decreased the calcium content and ALP activity, and attenuated the osteoblastic phenotype of VSMCs. Vascular calcification and osteogenic differentiation of VSMCs were positively regulated by HCY through increased/restored MMP-2 expression, increased expression of calcification proteins, and decreased anti-calcification protein levels. In summary, MMP-2 inhibition may be a protective strategy against VSMC calcification. PMID:25987498

  16. Oxidative markers, nitric oxide and homocysteine alteration in hypercholesterolimic rats: role of atorvastatine and cinnamon.

    PubMed

    Amin, Kamal A; Abd El-Twab, Thanaa M

    2009-01-01

    To investigate the effects of atorvastatin and cinnamon on serum lipid profile, oxidative stress, antioxidant capacity, hepatic enzymes activities, nitric oxide (NO) as well as homocysteine (Hcy) in hypercholesterolemic rats, 48 male albino rats, weighing 130-190 gm were divided into 2 groups, normal group fed on basal rat chow diet (n=12) and high cholesterol group (HCD) were fed on 1% cholesterol-enriched diet for 15 day (n=36). Hypercholesterolemic rats were divided into 3 subgroups (n=12 for each) fed the same diet and treated with atorvastatine (HCD+Atorvastatin) or cinnamon extract (HCD+cinnamon) or none treated (HCD) for 3&6 weeks. Serum triglycerides (TG), Total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), ALT, AST, NO, Hcy, hepatic reduced glutathione (GSH), Malondialdehyde (MDA) and antioxidant enzymes, Superoxide dismutase (SOD) and catalase activity were measured. Results showed that HCD increased significantly TG, TC, LDL-C, ALT, AST, Hcy and hepatic MDA, while lowered significantly antioxidant enzyme activities and NO levels. Atorvastatin therapy significantly increased HDL-C, NO and antioxidant activity while decreased LDL-C, MDA and Hcy concentrations. Serum TG, TC, LDL-C, ALT, AST and hepatic MDA levels were significantly lowered meanwhile, serum HDL, NO values and hepatic antioxidant activities were significantly, higher in cinnamon-treated than untreated group. These results indicate that lipid abnormalities, oxidative injury and hyperhomocystienemia were induced by HCD and this study recommend that administration of atorvastatine or cinnamon provided protection against the lipemic-oxidative disorder and act as hypocholesterolemic, hepatoprotective agent and improve cardiovascular function through modulation of oxidative stress, NO and Hcy. PMID:19918318

  17. Total plasma homocysteine and related amino acids in end-stage renal disease (ESRD) patients measured by gas chromatography-mass spectrometry--comparison with the Abbott IMx homocysteine assay and the HPLC method.

    PubMed

    Sigit, J I; Hages, M; Brensing, K A; Frotscher, U; Pietrzik, K; von Bergmann, K; Lütjohann, D

    2001-08-01

    Increased concentrations of homocysteine probably contribute to the high cardiovascular morbidity and mortality in hemodialysed end-stage renal disease (ESRD) patients and are determined by a variety of factors such as age, residual renal function, and vitamin status. Fasting plasma concentrations of total homocysteine, methionine, cysteine, and cystathionine were determined by gas chromatography-mass spectrometry (GC-MS) in 131 ESRD patients receiving daily oral folate (160-320 microg) and vitamin B6 (10-20 mg) supplements. Concentrations of homocysteine determined by GC-MS were compared with those measured by high-performance liquid chromatography (HPLC) and an immunofluorescence method (IMx analyzer) using Passing-Bablok regression analysis. Mean plasma concentration of total homocysteine determined by GC-MS (28.7+/-11.9 micromol/l [mean+/-SD]) was significantly lower than that determined by HPLC (34.0+/-14.5 micromol/l; p<0.001) or IMx (32.4+/-13.9 micromol/l; p<0.001). A close correlation existed between GC-MS and HPLC (r=0.931; y=1.203 x+0.279) and GC-MS and IMx (r=0.896; y=1.105 x+0.766). Linear regression analysis showed positive correlations between plasma concentrations of homocysteine and cysteine (r=0.434; p<0.001) and homocysteine and cystathionine (r=0.187; p=0.032). Plasma concentrations of homocysteine correlated negatively with folate (r=-0.281; p=0.001) and vitamin B12 (r=-0.229; p=0.009). GC-MS proved to be a sensitive and reliable method for the determination of total plasma homocysteine and related amino acids. Despite vitamin supplementation, ESRD patients requiring chronic maintenance hemodialysis, have high plasma concentrations of homocyst(e)ine which seems to be metabolized mainly within the transsulfuration pathway, while remethylation to methionine seems to be disturbed.

  18. [A correlation study on homocysteine metabolism in pregnant women and neural tube defects in urban and rural areas].

    PubMed

    Zhan, S; Hu, Y; Li, L

    1997-07-01

    Serum levels of homocysteine, folic acid and vitamin B12 in pregnant women in urban and rural areas were compared to study the relationship between homocysteine metabolism and neural tube defects. Four hundred and eleven serum specimens were sampled randomly from a serum bank for women with early pregnancy in Beijing area, 195 from urban and 216 from rural. Their levels of homocysteine were determined by high performance liquid chromatography combined with electrochemical methods, and those of folic acid and vitamin B12 by radioimmunoassay. Results showed that level of homocysteine was significantly higher in rural pregnant women than that in urban, with 9.31 mumol/L and 5.73 mumol/L, respectively, level of vitamin B12 was lower in rural than that in urban women, with 210.09 pmol/L and 233.35 pmol/L, respectively, and level of folic acid was higher in rural than that in urban women, but no significant difference in deficiency of folic acid between rural and urban was found. The average ratio of folic acid to homocysteine and that of vitamin B12 to homocysteine were higher in rural than those in urban women. It suggests that abnormal metabolism of homocysteine usually correlates with high incidence of neural tube defects in rural area. PMID:9812582

  19. Folate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry.

    PubMed

    Coşar, Alpaslan; Ipçioğlu, Osman Metin; Ozcan, Omer; Gültepe, Mustafa

    2014-01-01

    The term 'one-carbon metabolism' is commonly used to describe 3 separate metabolic processes: folate metabolism, the homocysteine remethylation cycle, and the transsulfuration pathway. Folate metabolism concerns the biochemical reactions in which endogenous and exogenous one-carbon units are transferred to tetrahydrofolates. The remethylation cycle is used for the synthesis of methionine from homocysteine with one-carbon units that come from folate. This methionine is thenfused for the synthesis of S-adenosyl methionine, which is a general donor of methyl groups for many biochemical reactions in the human body. In the transsulfuration pathway, some amino acids and polypeptides, such as cystathionine, cysteine, and glutathione, are synthesized from homocysteine. The kinetics of the enzymes in this pathway are regulated by the substrates of the remethylation cycle. The methylation process has been thought to have an important role in the biochemical basis of neuropsychiatry. An elevated homocysteine level is the most important marker of folate and vitamin B12 deficiencies, and also the most reliable biochemical sign of functional insufficiency. Some neurological and neuropsychiatric diseases, such as psychosis, Alzheimer's disease, and autism, have been found to be related to disorders of one-carbon metabolism. This review aims to summarize both one-carbon metabolism and its relationships with neuropsychiatric disorders.

  20. Total plasma homocysteine and arteriosclerotic outcomes in type 2 diabetes with nephropathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Total serum homocysteine (tHcy) has been shown to predict de novo and recurrent cardiovascular events in many studies. However, results in diabetic populations with minimal nephropathy are mixed. The independent relationship between tHcy and arteriosclerotic outcomes and congestive heart failure (CH...

  1. Trials That Matter: Should We Routinely Measure Homocysteine Levels and “Treat” Mild Hyperhomocysteinemia?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several observational studies involving healthy populations in the 1990s showed positive associations between elevated homocysteine level and increased risk for ischemic heart disease and stroke. Several small trials conducted in western populations in the early and mid-1990s suggested that “daily s...

  2. Quercetin Increases Hepatic Homocysteine Remethylation and Transsulfuration in Rats Fed a Methionine-Enriched Diet.

    PubMed

    Meng, Bin; Gao, Weina; Wei, Jingyu; Pu, Lingling; Tang, Zhenchuang; Guo, Changjiang

    2015-01-01

    This study was aimed at investigating the effects of quercetin on mRNA expression and activity of critical enzymes in homocysteine metabolism in rats fed a methionine-enriched diet. Rats were fed for 6 weeks the following diets, that is, control, 0.5% quercetin, 1.0% methionine, and 1.0% methionine plus 0.5% quercetin diets. Serum homocysteine was significantly increased after methionine treatment and decreased after the addition of quercetin. The mRNA expression of methionine synthase was significantly increased after methionine or methionine plus quercetin supplementation, while its enzymatic activity was significantly increased after methionine plus quercetin supplementation. The mRNA expression and enzymatic activity of cystathionine β-synthase and cystathionine γ-lyase were upregulated after quercetin, methionine, or quercetin plus methionine treatment and a more significant increase was observed for hepatic cystathionine β-synthase in the methionine plus quercetin treated rats, suggesting an interaction between methionine and quercetin. Meanwhile, hepatic ratio of S-adenosylmethionine to S-adenosylhomocysteine was significantly decreased in response to methionine supplementation and normalized after the addition of quercetin. It is concluded that quercetin reduces serum homocysteine by increasing remethylation and transsulfuration of homocysteine in rats exposed to a methionine-enriched diet.

  3. Boron deprivation increases plasma homocysteine, a factor negatively associated with bone composition and strength

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Boron (B) deprivation decreases trabecular bone in vertebrae of rats. Elevated plasma homocysteine (Hcy) has been associated with decreased trabecular bone. S-adenosylmethionine, an intermediate in the formation of Hcy, has the highest known affinity for B of all mammalian biocompounds examined. Thu...

  4. The Association of Homocysteine and Related Factors to Brachial Artery Diameter and Flow-Mediated Dilation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brachial artery flow-mediated dilation (BAFMD) has been proposed as a measurement of the degree and severity of cardiovascular disease. The purpose of this study was to (1) evaluate the associations between BAFMD and homocysteine, folate, vitamin B12, vitamin B6, (2) examine the influence of 5,10-me...

  5. Liquid chromatographic determination of total homocysteine in blood plasma with photometric detection.

    PubMed

    Zhloba, Alexander A; Blashko, Eduard L

    2004-02-01

    A rapid and sensitive method for quantification of homocysteine total forms and glutathione levels in blood plasma via HPLC was developed. Dithiotreitol as a water soluble agent has been used as a reductant for both protein and nonprotein disulphides. Dithiotreitol reacts with the mixed disulphides under 60 degrees C treatment within 10 min. Reduced aminothiols and homocystein were easily derivated with 5,5'-dithiobis-(2-nitrobenzoic acid) and the resultant ultraviolet absorbance within 330 nm was detected by the HPLC method. The concentration of total plasma homocysteine was significantly higher in groups of patients: with the end stage of renal disease: 45.5+/-40.9 micromol/l (n=79), with cerebral vascular disorders 12.3+/-7.0 micromol/l (n=65), and with coronary atherosclerosis 15.4+/-10.9 micromol/l (n=15) than that in healthy subjects (6.2+/-1.74 micromol/l, n=20). Some major advantages of the method include: simultaneous measurement of both total homocysteine and total glutathione, no loss of oxidized form during processing of blood plasma for aminothiols measurement, use of protein-bound aminothiols solution as a calibrator.

  6. Homocysteine lowering for stroke prevention: Unravelling the complexity of the evidence.

    PubMed

    Spence, J David

    2016-10-01

    Elevated levels of total homocysteine impair endothelial dysfunction and increase thrombosis. Homocysteine is causal in animal models, and in human studies, elevated total homocysteine is significantly associated with carotid atherosclerosis, lacunar infarction, and markedly increased risk of stroke in atrial fibrillation. Because two of the early large trials of B vitamin therapy (Vitamin Intervention for Stroke Prevention and the Norwegian Vitamin Study) did not show any reduction of stroke, and the Heart Outcomes Prevention Evaluation 2 trial was mistakenly interpreted as not showing a reduction of stroke (because the authors could not think of a biological difference between stroke and myocardial infarction), there has been widespread pessimism regarding treatment to lower total homocysteine for stroke prevention. However, the Heart Outcomes Prevention Evaluation 2 trial, the French trial of folic acid and omega three oils, the Vitamins to Prevent Stroke subgroup excluding antiplatelet therapy all showed a significant reduction of stroke. Reasons why the Vitamin Intervention for Stroke Prevention trial were negative included folate fortification in North America, provision of injections of B12 to patients with low baseline serum B12, and as it turns out, harm from cyanide in cyanocobalamin among participants with impaired renal function. In the Diabetic Intervention with Vitamins in Nephropathy trial, B vitamins including cyanocobalamin were harmful, and in a Vitamin Intervention for Stroke Prevention subgroup excluding participants who received B12 injections and those with impaired renal function, there was a statistically significant reduction of stroke/myocardial infarction/vascular death. In 2015, the China Stroke Primary Prevention Trial (CSPPT), in over 20,000 participants followed for 5 years, showed a significant reduction of stroke with folic acid in a setting where folate fortification has not been implemented. In the setting of folate fortification

  7. Inhibition of hydrogen sulfide on the proliferation of vascular smooth muscle cells involved in the modulation of calcium sensing receptor in high homocysteine.

    PubMed

    Wang, Yuwen; Wang, Xiyao; Liang, Xiaohui; Wu, Jichao; Dong, Shiyun; Li, Hongzhu; Jin, Meili; Sun, Dianjun; Zhang, Weihua; Zhong, Xin

    2016-09-10

    Hyperhomocysteinemia induces the proliferation of vascular smooth muscle cells (VSMCs). Hydrogen sulfide (H2S) inhibits the phenotype switch of VSMCs and calcium-sensing receptor (CaSR) regulated the production of endogenous H2S. However, whether CaSR inhibits the proliferation of VSMCs by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H2S) pathway in high homocysteine (HHcy) has not been previously investigated. The intracellular calcium concentration, the concentration of H2S, the cell viability, the proliferation and the expression of proteins of cultured VSMCs from rat thoracic aortas were measured, respectively. The results showed that the [Ca(2+)]i and the expression of p-CaMK and CSE increased upon treatment with CaSR agonist. In HHcy, the H2S concentration decrease, the proliferation and migration rate increased, the expression of Cyclin D1, PCNA, Osteopontin and p-Erk1/2 increased while the α-SM actin, P21(Cip/WAK-1) and Calponin decreased. The CaSR agonist or exogenous H2S significantly reversed the changes of VSMCs caused by HHcy. In conclusion, our results demonstrated that CaSR regulate the endogenous CSE/H2S is related to the PLC-IP3 receptor and CaM signal pathways which inhibit the proliferation of VSMCs, and the latter is involved in the Erk1/2 dependent signal pathway in high homocysteine. PMID:27502588

  8. Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter

    PubMed Central

    Li, Jiao-Jiao; Li, Qian; Du, Hua-Ping; Wang, Ya-Li; You, Shou-Jiang; Wang, Fen; Xu, Xing-Shun; Cheng, Jian; Cao, Yong-Jun; Liu, Chun-Feng; Hu, Li-Fang

    2015-01-01

    Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages. PMID:26047341

  9. Molecular characterization of betaine-homocysteine methyltransferase 1 from the liver, and effects of aestivation on its expressions and homocysteine concentrations in the liver, kidney and muscle, of the African lungfish, Protopterus annectens.

    PubMed

    Ong, Jasmine L Y; Woo, Jia M; Hiong, Kum C; Ching, Biyun; Wong, Wai P; Chew, Shit F; Ip, Yuen K

    2015-05-01

    Homocysteine accumulation has numerous deleterious effects, and betaine-homocysteine S-methyltransferase (BHMT) catalyses the synthesis of methionine from homocysteine and betaine. This study aimed to determine homocysteine concentrations, and mRNA expression levels and protein abundances of bhmt1/Bhmt1 in the liver, kidney and muscle of the African lungfish, Protopterus annectens, during the induction (6 days), maintenance (6 months) or arousal (3 days after arousal) phase of aestivation. The homocysteine concentration decreased significantly in the liver of P. annectens after 6 days or 6 months of aestivation, but it returned to the control level upon arousal. By contrast, homocysteine concentrations in the kidney and muscle remained unchanged during the three phases of aestivation. The complete coding cDNA sequence of bhmt1 from P. annectens consisted of 1236 bp, coding for 412 amino acids. The Bhmt1 from P. annectens had a close phylogenetic relationship with those from tetrapods and Callorhinchus milii. The expression of bhmt1 was detected in multiple organs/tissues of P. annectens, and this is the first report on the expression of bhmt1/Bhmt1 in animal skeletal muscle. The mRNA and protein expression levels of bhmt1/Bhmt1 were up-regulated in the liver of P. annectens during the induction and maintenance phases of aestivation, possibly to regulate the hepatic homocysteine concentration. The significant increase in hepatic Bhmt1 protein abundance during the arousal phase could be a response to increased cellular methylation for the purpose of tissue reconstruction. Unlike the liver, Bhmt1 expression in the kidney and muscle of P. annectens was regulated translationally, and its up-regulation could be crucial to prevent homocysteine accumulation.

  10. [Some aspects of homocysteine metabolism in hemodialysis patients].

    PubMed

    Bednarek-Skublewska, Anna; Buraczyńska, Monika; Wawrzycki, Sławomir; Baranowicz-Gaszczyk, Iwona; Ksiazek, Andrzej

    2002-11-01

    Homocysteine (Hcy) is a non-protein forming sulfur amino acid, synthesised from methionine (Met), whose metabolism is at the junction of two metabolic pathways: remethylation and transsulfuration. Increased Hcy serum concentration is a well established independent risk factor of cardiovascular diseases and a known feature of end stage renal disease. Hcy plasma level is influenced by folate, vitamin B6 and genetic factors. Mutation C677T in gene encoding methylenetetrahydrofolate reductase (MTHFR), an enzyme involved in Hcy remethylation has been associated with elevated Hcy in homozygous carriers (TT genotype). Several amino acids take part in metabolism of Hcy. There are abnormalities of concentration of the non essential and essential of amino acids in serum of patients treated with hemodialysis (HD). It is possible that these abnormalities of amino acids can change the Hcy metabolism. The aim of this study was the evaluation of some aspects of Hcy metabolism. We examined the MTHFR gene polymorphism and its relationship with plasma Hcy concentration. The plasma levels of total amino acids and amino acids connected with Hcy metabolism: methionine (Met), seryne (Ser), cysteine (Cyst) and tauryne (Tau) were evaluated in hemodialysis patients. The study was conducted in 71 (35 male, 36 female) patients, mean age 56.2 +/- 12.4 years. They were dialysed for a mean duration of 87.7 +/- 84.7 months (range 2-302). The control group (CG) in which Hcy and amino acids levels were examined consisted of 12 healthy subjects. Serum (EDTA) Hcy levels were measured by EIA-Hcy ELISA kit. The MTHFR gene polymorphism was evaluated by means of the polymerase chain reaction (PCR). The amino acids were measured by chromatography in amino acid analyser AAA 400. Mean concentration of Hcy was significantly higher in patients than in CG (31.1 +/- 9.1 vs 11.9 +/- 2.9 mumol/L; p < 0.01). Genotype frequencies in patients were: 42.8% for CC, 48.5% for CT and 8.7% for TT. Mean concentration of

  11. Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline.

    PubMed

    Wilson, Fiona A; van den Borne, Joost J G C; Calder, A Graham; O'Kennedy, Niamh; Holtrop, Grietje; Rees, William D; Lobley, Gerald E

    2009-04-01

    Impaired transfer of methyl groups via the methionine cycle leads to plasma hyperhomocysteinemia. The tissue sources of plasma homocysteine in vivo have not been quantified nor whether hyperhomocysteinemia is due to increased entry or decreased removal. These issues were addressed in female rats offered diets with either adequate or excess methionine (additional methyl groups) with or without folate and choline (impaired methyl group transfer) for 5 wk. Whole body and tissue metabolism was measured based on isotopomer analysis following infusion with either [1-(13)C,methyl-(2)H3]methionine or [U-(13)C]methionine plus [1-(13)C]homocysteine. Although the fraction of intracellular methionine derived from methylation of homocysteine was highest in liver (0.18-0.21), most was retained. In contrast, the pancreas exported to plasma more of methionine synthesized de novo. The pancreas also exported homocysteine to plasma, and this matched the contribution from liver. Synthesis of methionine from homocysteine was reduced in most tissues with excess methionine supply and was also lowered in liver (P<0.01) with diets devoid of folate and choline. Plasma homocysteine concentration (P<0.001) and flux (P=0.001) increased with folate plus choline deficiency, although the latter still represented <12% of estimated tissue production. Hyperhomocysteinemia also increased (P<0.01) the inflow of homocysteine into most tissues, including heart. These findings indicate that a full understanding of hyperhomocysteinemia needs to include metabolism in a variety of organs, rather than an exclusive focus on the liver. Furthermore, the high influx of homocysteine into cardiac tissue may relate to the known association between homocysteinemia and hypertension.

  12. Effects of pyridoxine on growth performance and plasma aminotransferases and homocysteine of white pekin ducks.

    PubMed

    Xie, Ming; Tang, Jing; Wen, Zhiguo; Huang, Wei; Hou, Shuisheng

    2014-12-01

    A dose-response experiment with seven supplemental pyridoxine levels (0, 0.66, 1.32, 1.98, 2.64, 3.30, and 3.96 mg/kg) was conducted to investigate the effects of pyridoxine on growth performance and plasma aminotransferases and homocysteine of White Pekin ducks and to estimate pyridoxine requirement for these birds. A total of 336 one-day-old male White Pekin ducks were divided to 7 experimental treatments and each treatment contained 8 replicate pens with 6 birds per pen. Ducks were reared in raised wire-floor pens from hatch to 28 d of age. At 28 d of age, the weight gain, feed intake, feed/gain, and the aspartate aminotransferase, alanine aminotransferase, and homocysteine in plasma of ducks from each pen were all measured. In our study, the pyridoxine deficiency of ducks was characterized by growth depression, decreasing plasma aspartate aminotransferase activity and increasing plasma homocysteine. The ducks fed vitamin B6-deficient basal diets had the worst weight gain and feed/gain among all birds and this growth depression was alleviated (p<0.05) when pyridoxine was supplemented to basal diets. On the other hand, plasma aspartate aminotransferase and homocysteine may be the sensitive indicators for vitamin B6 status of ducks. The ducks fed basal diets had much lower aspartate aminotransferase activity and higher homocysteine level in plasma compared with other birds fed pyridoxine-supplemented diets (p<0.05). According to quadratic regression, the supplemental pyridoxine requirements of Pekin ducks from hatch to 28 days of age was 2.44 mg/kg for feed/gain and 2.08 mg/kg for plasma aspartate aminotransferase and the corresponding total requirements of this vitamin for these two criteria were 4.37 and 4.01 mg/kg when the pyridoxine concentration of basal diets was included, respectively. All data suggested that pyridoxine deficiency could cause growth retardation in ducks and the deficiency of this vitamin could be indicated by decreasing plasma aspartate

  13. Effects of folic acid supplementation on serum folate and plasma homocysteine concentrations in older adults: a dose-response trial.

    PubMed

    Anderson, Cheryl A M; Jee, Sun Ha; Charleston, Jeanne; Narrett, Matthew; Appel, Lawrence J

    2010-10-15

    The authors' objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60-90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 μg/day of folic acid for 6 weeks. Data were collected in the United States between June and September 1996. At baseline, median serum folate and plasma homocysteine concentrations were 5.7 ng/mL (interquartile range (25th-75th percentiles), 4.1-7.8) and 8.3 μmol/L (interquartile range, 7.1-10.0), respectively. As the folic acid dose increased, serum folate levels increased (P-trend < 0.001). There was no dose-response relation with homocysteine level among all participants. In analyses restricted to persons with the lowest serum folate concentration (<4.5 ng/mL) at baseline, there was a trend (P = 0.06) toward decreased homocysteine levels with increasing folic acid dose. In healthy, older adults with adequate folate status, folic acid supplementation is not beneficial for homocysteine reduction. However, for older adults with low serum folate levels, supplementation will improve folate status and may be beneficial for lowering homocysteine concentrations.

  14. Cognitive impairment and its association with homocysteine plasma levels in females with eating disorders - findings from the HEaD-study.

    PubMed

    Frieling, H; Röschke, B; Kornhuber, J; Wilhelm, J; Römer, K D; Gruss, B; Bönsch, D; Hillemacher, T; de Zwaan, M; Jacoby, G E; Bleich, S

    2005-11-01

    Higher plasma homocysteine levels have been found in females with anorexia nervosa. Furthermore, elevated homocysteine levels are associated with cognitive decline in dementia and healthy elderly people. Aim of this prospective study was to investigate a possible association between homocysteine serum levels and Clinically well known cognitive deficits in females with eating disorders. We found that moderately elevated plasma homocysteine levels were associated with normal short- and long-term verbal memory while normal plasma homocysteine levels were associated with poorer memory performance in 14 females with anorexia nervosa and 12 females with bulimia nervosa (logistic forward regression Wald chi(2)=8.566, OR=24.75, CI 2.89 - 212.23, P=0.003). These results indicate that under the special circumstances of eating disorders elevated homocysteine levels improve memory signaling possibly by facilitating long-term potentiation.

  15. Biochemical and molecular characterization of the homocysteine S-methyltransferase from broccoli (Brassica oleracea var. italica).

    PubMed

    Lyi, Sangbom M; Zhou, Xin; Kochian, Leon V; Li, Li

    2007-04-01

    Plants are known for their unique ability to synthesize methionine from S-methylmethionine (SMM) and homocysteine using the enzyme SMM: homocysteine S-methyltransferase (HMT) in the SMM cycle. Two cDNAs exhibiting HMT activity were cloned from broccoli and functionally expressed in E. coli. One cDNA, that encodes an enzyme with high substrate specificity for homocysteine, was designated as BoHMT1. The other cDNA was the BoSMT gene that we previously characterized and encodes a selenocysteine methyltransferase (Lyi, S.M., Heller, L.I., Rutzke, M., Welch, R.M., Kochian, L.V., Li, L., 2005. Molecular and biochemical characterization of the selenocysteine Se-methyltransferase gene and Se-methylselenocysteine synthesis in broccoli. Plant Physiol. 138, 409-420). Both exist as single gene sequences in the broccoli genome. While BoSMT expression was extremely low or undetectable in broccoli plants unless the plants were exposed to selenium, the BoHMT1 mRNA accumulated in most tissues of the plant except older leaves. In contrast to BoSMT whose expression was dramatically upregulated by treating plants with selenate, the transcript levels of BoHMT1 were not markedly affected in plants exposed to selenium. BoHMT1 expression responded significantly to changes in plant sulfur status. However, its expression was not dramatically affected in plants treated with methionine, SMM, homocysteine, or the heavy metal, cadmium. The differences in the substrate specificity and gene expression in response to changes in plant sulfur and selenium status between BoHMT1 and BoSMT suggest that the enzymes encoded by these two genes play distinct roles in sulfur and selenium metabolism in broccoli.

  16. Study on relationships among deep vein thrombosis, homocysteine & related B group vitamins

    PubMed Central

    Ekim, Meral; Ekim, Hasan; Yilmaz, Yunus Keser; Kulah, Bahadir; Polat, M. Fevzi; Gocmen, A. Yesim

    2015-01-01

    Objectives: Hyperhomocysteinemia has been considered as a potential risk factor for deep venous thrombosis (DVT) but it is still controversy. We aimed to evaluate the prevalence of hyperhomocysteinemia in patients with DVT. Our second objective was to document the prevalence of folate, Vitamin B6, and Vitamin B12 level in this patient population. Methods: Sixty patients with DVT aged from 23 to 84 years, were assessed regarding demographic characteristics, serum levels of homocysteine, folate, vitamin B12, and vitamin B6. The diagnosis of DVT was based upon Wells scoring system and serum D-dimer level and confirmed by deep venous Doppler ultrasonography of the lower limbs. Results: Mean serum homocysteine levels were found significantly higher in patients over the age of 40 years (10.81±4.26 µmol/L vs 9.13±3.23 µmol/L). Of all the patients, 9 patients had homocysteine level above the 15µmol/L, 26 had folic acid level below 3 ng/ml, one had vitamin B12 level below 150 pmol/L, and two had vitamin B6 level below 30 nmol/L. In the hyperhomocysteinemic group, five patients had low folic acid level, one had low vitamin B12 level, and two had low vitamin B6 level. Conclusions: Hyperhomocysteinemia, in women older than 40 years, may be a risk factor for DVT. Folic acid deficiency may also influence serum homocysteine concentrations. Folate therapy may be offered to the patients with DVT. However further studies are required to clarify the underlying molecular mechanisms. PMID:26101499

  17. Serum folate, homocysteine and colorectal cancer risk in women: a nested case–control study

    PubMed Central

    Kato, I; Dnistrian, A M; Schwartz, M; Toniolo, P; Koenig, K; Shore, R E; Akhmedkhanov, A; Zeleniuch-Jacquotte, A; Riboli, E

    1999-01-01

    Accumulating evidence suggests that folate, which is plentiful in vegetables and fruits, may be protective against colorectal cancer. The authors have studied the relationship of baseline levels of serum folate and homocysteine to the subsequent risk of colorectal cancer in a nested case–control study including 105 cases and 523 matched controls from the New York University Women's Health Study cohort. In univariate analyses, the cases had lower serum folate and higher serum homocysteine levels than controls. The difference was more significant for folate (P < 0.001) than for homocysteine (P = 0.04). After ad'justing for potential confounders, the risk of colorectal cancer in the subjects in the highest quartile of serum folate was half that of those in the lowest quartile (odds ratio, OR = 0.52, 95% confidence interval, CI = 0.27–0.97, P-value for trend = 0.04). The OR for the highest quartile of homocysteine, relative to the lowest quartile, was 1.72 (95% CI = 0.83–3.65, P-value for trend = 0.09). In addition, the risk of colorectal cancer was almost twice as high in subjects with below-median serum folate and above-median total alcohol intake compared with those with above-median serum folate and below-median alcohol consumption (OR = 1.99, 95% CI = 0.92–4.29). The potentially protective effects of folate need to be confirmed in clinical trials. © 1999 Cancer Research Campaign PMID:10206314

  18. Homocysteine, folate, and vitamin B12 levels and vertebral fracture risk in postmenopausal women.

    PubMed

    El Maghraoui, Abdellah; Ghozlani, Imad; Mounach, Aziza; Rezqi, Asmaa; Oumghar, Khalid; Achemlal, Lahsen; Bezza, Ahmed; Ouzzif, Zhor

    2012-01-01

    The objective of this study was to examine the influence of homocysteine, vitamin B(12), and folate on the prevalence of asymptomatic osteoporotic vertebral fractures (VFs) using vertebral fracture assessment (VFA) in postmenopausal women. The study cohort consisted of 188 consecutive postmenopausal women (mean age, weight, and body mass index of 57.9 ± 8.5 [41-91]yr, 74.4 ± 13.5 [38-150]kg, and 30.4 ± 5.2 [17.1-50.7]kg/m(2), respectively). Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a Lunar Prodigy Vision densitometer (GE Healthcare Inc., Waukesha, WI). VFs were defined using a combination of Genant's semiquantitative approach and morphometry. Fifty-eight (30.9%) patients had densitometric osteoporosis. VFs were identified using VFA in 76 (40.4%) patients: 61 women had grade 1 VFs and 15 had grade 2 or 3 VFs. No statistical difference was shown between the 3 groups (absence of VFs, VFs grade 1, and VFs grade 2/3) concerning the biological parameters. Comparison of patients according to quartiles of homocysteine levels showed that women in the highest quartile were older and had a lower bone mineral density (BMD); however, the prevalence of VFs was not statistically different from that of women in the other quartile groups. Stepwise regression analysis showed that homocysteine was not independently associated with the presence of VFs, which was mainly related to the osteoporotic status. Although a weak association was observed between hyperhomocysteinemia and low BMD and a trend to higher prevalence of grade 2/3 VFs was observed, our study did not confirm that homocysteine, vitamin B(12), and folate status are important determinants of prevalent asymptomatic VFs in postmenopausal women.

  19. Human Valacyclovir Hydrolase/Biphenyl Hydrolase-Like Protein Is a Highly Efficient Homocysteine Thiolactonase

    PubMed Central

    McDonald, Matthew G.; Rademacher, Peter M.; MacCoss, Michael J.; Hsieh, Edward J.; Rettie, Allan E.; Furlong, Clement E.

    2014-01-01

    Homocysteinylation of lysine residues by homocysteine thiolactone (HCTL), a reactive homocysteine metabolite, results in protein aggregation and malfunction, and is a well-known risk factor for cardiovascular, autoimmune and neurological diseases. Human plasma paraoxonase-1 (PON1) and bleomycin hydrolase (Blmh) have been reported as the physiological HCTL detoxifying enzymes. However, the catalytic efficiency of HCTL hydrolysis by Blmh is low and not saturated at 20 mM HCTL. The catalytic efficiency of PON1 for HCTL hydrolysis is 100-fold lower than that of Blmh. A homocysteine thiolactonase (HCTLase) was purified from human liver and identified by mass spectrometry (MS) as the previously described human biphenyl hydrolase-like protein (BPHL). To further characterize this newly described HCTLase activity, BPHL was expressed in Escherichia coli and purified. The sequence of the recombinant BPHL (rBPHL) and hydrolytic products of the substrates HCTL and valacyclovir were verified by MS. We found that the catalytic efficiency (kcat/Km) of rBPHL for HCTL hydrolysis was 7.7 × 104 M−1s−1, orders of magnitude higher than that of PON1 or Blmh, indicating a more significant physiological role for BPHL in detoxifying HCTL. PMID:25333274

  20. Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality.

    PubMed

    McCaddon, Andrew; Miller, Joshua W

    2015-10-01

    Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill's criteria for assessing "causality," and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22,000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed.

  1. Vitamin B12, folate, homocysteine and urinary methylmalonic acid levels in infants.

    PubMed

    Karademir, F; Suleymanoglu, S; Ersen, A; Aydinoz, S; Gultepe, M; Meral, C; Ozkaya, H; Gocmen, I

    2007-01-01

    Serum vitamin B12 and folate, and their functional markers, plasma homocysteine and urinary methylmalonate (uMMA) were measured in 204 healthy, term infants at birth, and at 2 and 6 months. Compared with infants receiving formula food, those fed mother's milk had lower vitamin B12 and folate at 2 and 6 months. In infants receiving mother's milk, vitamin B12 levels were similar at birth (238 pg/ml) and 2 months (243 pg/ml), whereas with formula milk the level was significantly higher at 2 months (558 pg/ml) than at birth (257 pg/ml). Vitamin B12 was negatively correlated with homocysteine at birth and 6 months. The level of uMMA (mmol/mol creatinine) was higher at 2 (mother's milk, 25.5; formula, 23.97) and 6 months (19.77; 15) than at birth (11.97; 10.88), and was not correlated with vitamin B12 levels. Homocysteine may be a reliable marker of vitamin B12 status in neonates and infants; however, uMMA is not suitable as a marker of vitamin B12 status.

  2. Serum homocysteine, vitamin B12, folic acid levels and methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in vitiligo.

    PubMed

    Yasar, Ali; Gunduz, Kamer; Onur, Ece; Calkan, Mehmet

    2012-01-01

    The aim of this study was to determine serum vitamin B12, folic acid and homocysteine (Hcy) levels as well as MTHFR (C677, A1298C) gene polymorphisms in patients with vitiligo, and to compare the results with healthy controls. Forty patients with vitiligo and 40 age and sex matched healthy subjects were studied. Serum vitamin B12 and folate levels were determined by enzyme-linked immunosorbent assay. Plasma Hcy levels and MTHFR polymorphisms were determined by chemiluminescence and real time PCR methods, respectively. Mean serum vitamin B12 and Hcy levels were not significantly different while folic acid levels were significantly lower in the control group. There was no significant relationship between disease activity and vitamin B12, folic acid and homocystein levels. No significant difference in C677T gene polymorphism was detected. Heterozygote A1298C gene polymorphism in the patient group was statistically higher than the control group. There was no significant relationship between MTHFR gene polymorphisms and vitamin B12, folic acid and homocysteine levels. In conclusion, vitamin B12, folate and Hcy levels are not altered in vitiligo and MTHFR gene mutations (C677T and A1298C) do not seem to create susceptibility for vitiligo. PMID:22846211

  3. Structure—Activity Study of New Inhibitors of Human Betaine-Homocysteine S-Methyltransferase

    PubMed Central

    Vaněk, Václav; Buděšínský, Miloš; Kabeleová, Petra; Šanda, Miloslav; Kožíšek, Milan; Hančlová, Ivona; Mládková, Jana; Brynda, Jiří; Rosenberg, Ivan; Koutmos, Markos; Garrow, Timothy A.; Jiráček, Jiří

    2009-01-01

    Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to l-homocysteine, yielding dimethylglycine and l-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH3), or N(CH3)2 groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH3) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors. PMID:19534555

  4. Luciferase-based assay for adenosine: application to S-adenosyl-L-homocysteine hydrolase.

    PubMed

    Burgos, Emmanuel S; Gulab, Shivali A; Cassera, María B; Schramm, Vern L

    2012-04-17

    S-Adenosyl-L-homocysteine hydrolase (SAHH) catalyzes the reversible conversion of S-adenosyl-L-homocysteine (SAH) to adenosine (ADO) and L-homocysteine, promoting methyltransferase activity by relief of SAH inhibition. SAH catabolism is linked to S-adenosylmethionine metabolism, and the development of SAHH inhibitors is of interest for new therapeutics with anticancer or cholesterol-lowering effects. We have developed a continuous enzymatic assay for adenosine that facilitates high-throughput analysis of SAHH. This luciferase-based assay is 4000-fold more sensitive than former detection methods and is well suited for continuous monitoring of ADO formation in a 96-well-plate format. The high-affinity adenosine kinase from Anopheles gambiae efficiently converts adenosine to adenosine monophosphate (AMP) in the presence of guanosine triphosphate. AMP is converted to adenosine triphosphate and coupled to firefly luciferase. With this procedure, kinetic parameters (K(m), k(cat)) for SAHH were obtained, in good agreement with literature values. Assay characteristics include sustained light output combined with ultrasensitive detection (10(-7) unit of SAHH). The assay is documented with the characterization of slow-onset inhibition for inhibitors of the hydrolase. Application of this assay may facilitate the development of SAHH inhibitors and provide an ultrasensitive detection for the formation of adenosine from other biological reactions.

  5. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate.

    PubMed

    Klee, G G

    2000-08-01

    Vitamin B(12) and folate are two vitamins that have interdependent roles in nucleic acid synthesis. Deficiencies of either vitamin can cause megaloblastic anemia; however, inappropriate treatment of B(12) deficiency with folate can cause irreversible nerve degeneration. Inadequate folate nutrition during early pregnancy can cause neural tube defects in the developing fetus. In addition, folate and vitamin B(12) deficiency and the compensatory increase in homocysteine are a significant risk factor for cardiovascular disease. Laboratory support for the diagnosis and management of these multiple clinical entities is controversial and somewhat problematic. Automated ligand binding measurements of vitamin B(12) and folate are easiest to perform and widely used. Unfortunately, these tests are not the most sensitive indicators of disease. Measurement of red cell folate is less dependent on dietary fluctuations, but these measurements may not be reliable. Homocysteine and methylmalonic acid are better metabolic indicators of deficiencies at the tissue level. There are no "gold standards" for the diagnosis of these disorders, and controversy exists regarding the best diagnostic approach. Healthcare strategies that consider the impact of laboratory tests on the overall costs and quality of care should consider the advantages of including methylmalonic acid and homocysteine in the early evaluation of patients with suspected deficiencies of vitamin B(12) and folate.

  6. Effect of plasma homocysteine level and urinary monomethylarsonic acid on the risk of arsenic-associated carotid atherosclerosis

    SciTech Connect

    Wu, M.-M.; Chiou, H.-Y. . E-mail: hychiou@tmu.edu.tw; Hsueh, Y.-M.; Hong, C.-T.; Su, C.-L.; Chang, S.-F.; Huang, W.-L.; Wang, H.-T.; Wang, Y.-H.; Hsieh, Y.-C.; Chen, C.-J.

    2006-10-01

    Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMA{sup V}) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMA{sup V} (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMA{sup V}, and dimethylarsinic acid (DMA{sup V}). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0-15.0) for the study subjects with high MMA% ({>=}16.5%) and high homocysteine levels ({>=}12.7 {mu}mol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 {mu}mol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine.

  7. Evaluation of an Association of Blood Homocysteine Levels With Gastric Cancer Risk From 27 Case–Control Studies

    PubMed Central

    Xu, Wei; Cheng, Yuelei; Zhu, Huirong

    2016-01-01

    Abstract High blood homocysteine levels may risk gastric cancer. However, observational studies have been plagued by chance, bias, confounding, or reverse causality. In this study, we assessed the relationship between blood homocysteine levels and gastric cancer by using a Mendelian randomization method, which is independent of nongenetic confounding. We took 2 steps to perform Mendelian randomization analysis. First, we evaluated the methylenetetrahydrofolate reductase (MTHFR) C677T association with gastric cancer by a meta-analysis of case-control studies including 7566 patients with gastric cancer and 10 640 control subjects from 27 Case–Control studies. Second, MTHFR C677T polymorphism, which affects the blood homocysteine levels, was used as an instrumental variable to calculate the risk and estimate the association of gastric cancer with this single nucleotide polymorphism (SNP). We obtained an estimate to the association of blood total homocysteine levels with this SNP from a meta-analysis of Genome-Wide Association Studies (GWAS), which comprises a total of 44 147 individuals. In our Mendelian randomization analysis, we demonstrated a significant effect of the blood homocysteine levels on gastric cancer risk, representing an OR of 2.56 (95% CI = 2.41–2.72; P = 5.0×10−4) for gastric cancer per 1-SD increase in the natural log-transformed blood total homocysteine levels. We proved that there is a causal relationship between blood total homocysteine and risk of gastric cancer, and this study will add insight into the treatment and pathology research of gastric cancer. PMID:27196483

  8. Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD.

    PubMed

    Nakai, K; Itoh, C; Nakai, K; Habano, W; Gurwitz, D

    2001-01-01

    The lesions of coronary atherosclerosis represent the result of a complex, multicellular, inflammatory-healing response in the coronary arterial wall. In vivo and in vitro cellular and molecular studies have suggested a role for tissue homocysteine in endothelial cell injury and adverse extra-cellular matrix remodeling. Gene polymorphisms in relation with numerous risk factors might increase the incidence of coronary artery disease (CAD). In this review we have focused on the correlations between plasma homocysteine levels, the incidence of cardiovascular disease and the cytosine-to-thymidine substitution at nucleotide 677 (C677T) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, coding for a key enzyme in methionine-homocysteine metabolism. The role of the C677T MTHFR gene polymorphism in the causation of CAD is controversial. We reviewed 12 recent case-control studies comprising 5370 genotyped patients with CAD and 4961 genotyped participants without CAD. There was no significant difference between those with and without CAD in the frequency of the C677T polymorphism (34.9 vs 33.6%). The frequency of homozygous C677T polymorphism in these groups was 10.9 versus 12.8%, respectively, although there were some ethnic differences in the C677T MTHFR polymorphism. In the analysis of the 12 studies, the odds ratio of CAD associated with the TT genotype (homozygous C677T polymorphism) was 1.18. Only slightly higher plasma homocysteine levels were observed in participants with the val/val (TT) genotype (14.4+/-2.9 micro mol/L in TT genotype vs 11.1+/-1.9 and 11.9+/-2 micro mol/L in CC and CT genotype, respectively). In addition, the relation between homocysteine increase after methionine loading and MTHFR genotypes is also controversial. However, hyperhomocysteinemia because of the C677T MTHFR allele may be corrected with oral folic acid therapy. Further investigations on the relationships between MTHFR genotypes and the incidence of CAD should be based on

  9. Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases.

    PubMed

    Stanger, O; Herrmann, W; Pietrzik, K; Fowler, B; Geisel, J; Dierkes, J; Weger, M

    2004-06-01

    About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest. Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B(12), and vitamin B(6) deficiency and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma homocysteine levels (> 12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of

  10. Serum homocysteine as a risk factor for carotid intimal thickening in acute stroke: A cross sectional observational study

    PubMed Central

    Devasia, Anup J.; Joy, Binu; Tarey, Subhash D.

    2016-01-01

    Introduction: The present study aimed to analyse if there is a correlation between carotid intima medial thickening (CIMT) and Hcy in stroke patients. Methodology: We studied 100 consecutive cases of acute anterior circulation strokes at St. John's Medical College, Bangalore, India. Fasting serum samples for homocysteine were sent within 24 hours of admission and all patients underwent a carotid Doppler scan and carotid intima-medial thickness (CIMT) was estimated on both sides. Results: There was significant correlation between serum homocysteine levels and carotid intima-medial thickness (r = 0.409, p = 0.000). Also after controlling for other possible risk factors it was found that elevations in serum homocysteine levels would cause a variation of 60% in the carotid intima-medial thickening. Conclusion: Serum Hcy levels correlate well with CIMT and hence may predict atherothrombotic events. PMID:27011628

  11. Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

    PubMed Central

    Vučković, Biljana A.; Čabarkapa, Velibor S.; Ilić, Tatjana A.; Salatić, Iva R.; Lozanov-Crvenković, Zagorka S.; Mitić, Gorana P.

    2013-01-01

    Aim To determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and in controls, as well as between patients with thrombosis and controls with the same MTHFR 677 genotype. Methods This case-control study was conducted in Clinical Center of Vojvodina, Novi Sad, from June to December 2011. We included 65 patients with either arterial or venous thrombosis (mean age, 40.97 ± 11.38 years) and 65 controls with no history or clinical evidence of any thrombotic event (mean age, 41.23 ± 11.12 years). Patients and controls were age- and sex-matched. Results In comparison with controls, thrombotic patients had significantly higher homocysteine levels (12.81 ± 4.94 µmol/L vs 9.82 ± 3.68 µmol/L; P < 0.001) and significantly higher incidence of hyperhomocysteinemia (55% vs 22%; P < 0.001; odds ratio [OR] = 4.521). There were no significant differences in homocysteine levels between homozygous carriers, heterozygous carriers, and non-carriers of the MTHFR 677 mutation in either thrombotic patients (12.97 ± 5.40 µmol/L vs 12.55 ± 5.71 µmol/L vs 13.27 ± 1.71 µmol/L; P = 0.100) or controls (10.07 ± 2.50 µmol/L vs 10.25 ± 4.84 µmol/L vs 9.20 ± 2.44 µmol/L; P = 0.651). However, in comparison with controls, homozygous carriers in thrombotic patient group did not have significantly higher levels of homocysteine (12.97 ± 5.40 µmol/L vs 10.07 ± 2.50 µmol/L; P = 0.072), but heterozygous carriers (12.55 ± 5.71 µmol/L vs 10.25 ± 4.84 µmol/L; P = 0.020) and non-carriers (13.27 ± 1.71 µmol/L vs 9.20 ± 2.44 µmol/L; P < 0.001) did. There was no significant difference in homocysteine levels between patients with arterial and venous thrombosis (12.76 ± 3.60 µmol/L vs 12.86 ± 5.51 µmol/L; P = 0.990) and between patients with one thrombotic event and those with recurrent thrombotic events

  12. Association of homocysteine level with biopsy-proven non-alcoholic fatty liver disease: a meta-analysis

    PubMed Central

    Dai, Yining; Zhu, Jinzhou; Meng, Di; Yu, Chaohui; Li, Youming

    2016-01-01

    Previous studies have reported inconsistent findings regarding the association between plasmatic higher of homocysteine level and non-alcoholic fatty liver disease. We aimed to investigate this association by conducting a meta-analysis. Literature was searched on PubMed from inception to January 2015. Eight studies evaluating plasma level of homocysteine in biopsy-proven non-alcoholic fatty liver disease subjects compared to healthy controls were included. Compared with the controls, non-alcoholic fatty liver disease patients witnessed a higher level of homocysteine [standard mean difference (SMD): 0.66 µmol/L, 95% CI: 0.41, 0.92 µmol/L], and were associated with a significant increased risk for hyperhomocysteinemia [odds ratio (OR) 5.09, 95% CI: 1.69, 15.32]. In addition, patients with non-alcoholic fatty liver presented 0.45 µmol/L higher levels of homocysteine compared to healthy controls (95% CI: 0.09, 0.82 µmol/L), whereas non-alcoholic steatohepatitis patients had 1.02 µmol/L higher levels of homocysteine (95% CI: 0.28, 1.76 µmol/L). There was neither difference of folate level nor vitamin B12 level between non-alcoholic fatty liver disease subjects and healthy controls. This study revealed that non-alcoholic fatty liver disease patients presented an increased serum concentration of homocysteine, and were associated with an increased risk of hyperhomocysteinemia. Further studies are needed to demonstrate a causal role of hyperhomocysteinemia in non-alcoholic fatty liver disease. PMID:26798201

  13. Effect of Vitamin B12 supplementation on serum homocysteine in patients undergoing hemodialysis: A randomized controlled trial.

    PubMed

    Tayebi, Ali; Biniaz, Vajihe; Savari, Samira; Ebadi, Abbas; Shermeh, Mahdi Sadeghi; Einollahi, Behzad; Rahimi, Abolfazl

    2016-03-01

    Clinical studies have shown that hyper-homocysteinemia is a potent independent risk factor for cardiovascular diseases, and many different methods have been investigated for lowering it in hemodialysis (HD) patients. Our study investigated the effect of Vitamin B 12 supplementation on serum homocysteine levels in these patients. This randomized trial was conducted on 140 HD patients. They were randomly distributed by lottery method into two groups: intervention and control. In the intervention group, 100 μg/mL of Vitamin B 12 was intravenously injected two times a week, for eight weeks. No intervention was performed in the control group. Serum levels of homocysteine, hemoglobin (Hb), and hematocrit (Hct) were measured at the beginning and again after eight weeks (2 months) of treatment. About 91% of the patients had hyperhomocysteinemia (serum homocysteine >15 μmol/L). The median baseline levels of serum homocysteine in the intervention and control groups were 31.9 and 26.9 μmol/L, respectively (P = 0.1). After eight weeks, the median homocysteine level reduced significantly in the Vitamin B 12 group to 22.2 versus 28.4 μmol/L in control group (P = 0.006). The mean Hb and Hct also changed significantly during our study (12.3 vs. 11.4 g/dL; P = 0.003 and 37.9 vs. 35.3%; P = 0.02, respectively). Our results demonstrated the existence of a statistical negative relationship between Vitamin B 12 and serum levels of homocysteine. Detailed investigations with larger sample sizes and longer-term use of Vitamin B 12 are recommended. PMID:26997378

  14. Effect of body weight on serum homocysteine level in patients with polycystic ovarian syndrome: A case control study

    PubMed Central

    I. Al- Gareeb, Ali; Abd Al- Amieer, Wafaa Salah; M. Alkuraishy, Hayder; J. Al- Mayahi, Thabat

    2016-01-01

    Background: Polycystic ovarian syndrome (PCOS) represent one of the common endocrine disorders which influence around 8% of reproductive women whom usually suffering from obesity and increase cardiovascular risk. Serum homocysteine levels are associated with bad impact on endothelial functions and considered as an independent risk factor for cardiovascular disease. Objective: The aim was to study the level of plasma homocysteine in obese and non-obese Iraqi patients with PCOS. Materials and Methods: This study was carried out on 207 women. Of theme, 101 women with PCOS and 106 PCOS- free women served as controls. Blood sample was taken from each participant on the 2nd day of menstruation morning after an overnight fasting. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone and androstenedione were measured. Moreover, total lipid profile and plasma homocysteine levels were measured in both groups. Results: Sixty percent of PCOS women were overweight or obese and 56% of them had a waist circumference >88cm. Moreover plasma homocysteine concentrations were found to be higher in patients with PCOS (11.5±5.41μmol/L) as compared with control (8.10±1.89 μmol/L) (p<0.002). Furthermore the homocysteine concentrations were 13.19±5.97 μmol/L and 9.38±2.99 μmol/L in both obese and normal-weight PCOS women respectively which was significantly higher than obese (p<0.002) and normal-weight (p<0.004) control women. Conclusion: Increase in body weight is not an independent risk factor to increase plasma homocysteine levels in PCOS women. PMID:27200421

  15. Elevated Homocysteine Level Related to Poor Outcome After Thrombolysis in Acute Ischemic Stroke.

    PubMed

    Yao, En-Sheng; Tang, Yan; Xie, Min-Jie; Wang, Ming-Huan; Wang, Hong; Luo, Xiang

    2016-01-01

    BACKGROUND Hyperhomocysteinemia (HHcy) is a well-known risk factor for ischemic stroke. However, whether HHcy can influence the treatment outcome of acute ischemic stroke (AIS) patients has yet to be fully determined. In this study, we investigated the relationship between serum homocysteine (Hcy) level and prognosis in AIS patients who received tissue plasminogen activator (tPA) treatment. MATERIAL AND METHODS Patients were recruited according to the research criteria and grouped by their serum Hcy levels. Neurological outcome was evaluated by National Institute of Health Stroke Scale (NIHSS) score system before and 1 week after treatment, and functional outcome was evaluated by modified Rankin Scale (MRS) score system after 3 months. All patients took CT/MRI examination to detect cerebral hemorrhage in 24 hours after tPA treatment. Receiver operating characteristic curve (ROC) was employed to assess if serum homocysteine level can be used as an index to predict the outcome after tPA treatment. RESULTS The mean (±SD) serum Hcy level of 194 patients was 22.62±21.23 μmol/L. After 1-week tPA treatment, the NIHSS scores of high Hcy level group were significantly higher than those of low level group (p<0.05), meantime the high Hcy group showed obvious symptomatic intracerebral hemorrhage risk after 24 hours (p<0.05). Poor outcome was presented in mRS score results after 3 months in high Hcy level group, which compared with low Hcy level group (p<0.01). The ROC showed that Hcy level was a moderately sensitive and specific index to predict the prognosis with an optimal cut-off value at 19.95 µmol/L (sensitivity [58.2%], specificity [80.3%]). CONCLUSIONS High serum homocysteine level could potentially predict poor prognosis in acute ischemic stroke patients after tPA treatment. PMID:27629768

  16. Elevated Homocysteine Level Related to Poor Outcome After Thrombolysis in Acute Ischemic Stroke

    PubMed Central

    Yao, En-Sheng; Tang, Yan; Xie, Min-Jie; Wang, Ming-Huan; Wang, Hong; Luo, Xiang

    2016-01-01

    Background Hyperhomocysteinemia (HHcy) is a well-known risk factor for ischemic stroke. However, whether HHcy can influence the treatment outcome of acute ischemic stroke (AIS) patients has yet to be fully determined. In this study, we investigated the relationship between serum homocysteine (Hcy) level and prognosis in AIS patients who received tissue plasminogen activator (tPA) treatment. Material/Methods Patients were recruited according to the research criteria and grouped by their serum Hcy levels. Neurological outcome was evaluated by National Institute of Health Stroke Scale (NIHSS) score system before and 1 week after treatment, and functional outcome was evaluated by modified Rankin Scale (MRS) score system after 3 months. All patients took CT/MRI examination to detect cerebral hemorrhage in 24 hours after tPA treatment. Receiver operating characteristic curve (ROC) was employed to assess if serum homocysteine level can be used as an index to predict the outcome after tPA treatment. Results The mean (±SD) serum Hcy level of 194 patients was 22.62±21.23 μmol/L. After 1-week tPA treatment, the NIHSS scores of high Hcy level group were significantly higher than those of low level group (p<0.05), meantime the high Hcy group showed obvious symptomatic intracerebral hemorrhage risk after 24 hours (p<0.05). Poor outcome was presented in mRS score results after 3 months in high Hcy level group, which compared with low Hcy level group (p<0.01). The ROC showed that Hcy level was a moderately sensitive and specific index to predict the prognosis with an optimal cut-off value at 19.95 μmol/L (sensitivity [58.2%], specificity [80.3%]). Conclusions High serum homocysteine level could potentially predict poor prognosis in acute ischemic stroke patients after tPA treatment. PMID:27629768

  17. AB156. Homocysteine and vitamin B12: risk factors for erectile dysfunction

    PubMed Central

    Lu, Zheng; Mo, Zengnan

    2014-01-01

    Background Increasing levels of homocysteine (Hcy) is associated with cardiovascular disease, and erectile dysfunction (ED) has close relation with cardiovascular disease, therefore, high homocysteine may be one of the risk factors of ED. During the metabolism of homocysteine, vitamin B12 plays an important role and could be the main factor in causing erectile dysfunction as well. Purpose To investigate the relationship between Hcy, vitamin B12 and ED in sample. Methods The study included 1,457 men aged 20-69 who participated in a series of physical examination at the Medical Centre in Fangchenggang First People’s Hospital from September 2009 to December 2009. ED was identified by the five-item International Index of Erectile Function (IIEF-5) questionnaire. All participants were measured for plasma Hcy, vitamin B12, folic acid, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), fasting plasma glucose, triglyceride and high-density lipoprotein cholesterol (HDL). Smoking, alcoholic drinking and physical activity were collected by face to face communication. Results A total of 691 (47.4%) men were identified as ED in this study, participants with ED were older or more likely to drink alcohol than the non-ED. It was higher Hcy (P=0.032), vitamin B12 (P=0.008) and fasting plasma glucose (P=0.014) in the participants with ED. There were significant positive correlation between ED status (none, mile, moderate and severe) and Hcy (P=0.024), vitamin B12 (P=0.015) and fasting plasma glucose (P=0.002). Logistic regression analysis showed that age, Hcy and vitamin B12 were the main determinants in ED. Hcy was positively associated with ED in the men more than 45, but vitamin B12 was positively related with ED in the men less than 45. Conclusions Hcy was positively associated with ED in elder, however, vitamin B12 was positively related with ED in younger.

  18. Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis.

    PubMed

    Obersby, Derek; Chappell, David C; Dunnett, Andrew; Tsiami, Amalia A

    2013-03-14

    There is strong evidence indicating that elevated plasma total homocysteine (tHcy) levels are a major independent biomarker and/or a contributor to chronic conditions, such as CVD. A deficiency of vitamin B₁₂ can elevate homocysteine. Vegetarians are a group of the population who are potentially at greater risk of vitamin B₁₂ deficiency than omnivores. This is the first systematic review and meta-analysis to appraise a range of studies that compared the homocysteine and vitamin B₁₂ levels of vegetarians and omnivores. The search methods employed identified 443 entries, from which, by screening using set inclusion and exclusion criteria, six eligible cohort case studies and eleven cross-sectional studies from 1999 to 2010 were revealed, which compared concentrations of plasma tHcy and serum vitamin B₁₂ of omnivores, lactovegetarians or lacto-ovovegetarians and vegans. Of the identified seventeen studies (3230 participants), only two studies reported that vegan concentrations of plasma tHcy and serum vitamin B₁₂ did not differ from omnivores. The present study confirmed that an inverse relationship exists between plasma tHcy and serum vitamin B₁₂, from which it can be concluded that the usual dietary source of vitamin B₁₂ is animal products and those who choose to omit or restrict these products are destined to become vitamin B₁₂ deficient. At present, the available supplement, which is usually used for fortification of food, is the unreliable cyanocobalamin. A well-designed study is needed to investigate a reliable and suitable supplement to normalise the elevated plasma tHcy of a high majority of vegetarians. This would fill the gaps in the present nutritional scientific knowledge. PMID:23298782

  19. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh.

    PubMed

    Gamble, Mary V; Liu, Xinhua; Ahsan, Habibul; Pilsner, Richard; Ilievski, Vesna; Slavkovich, Vesna; Parvez, Faruque; Levy, Diane; Factor-Litvak, Pam; Graziano, Joseph H

    2005-12-01

    Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = -0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = -0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = -0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = -0.45 for males, p < 0.0001; -0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.

  20. Plasma total homocysteine status of vegetarians compared with omnivores: a systematic review and meta-analysis.

    PubMed

    Obersby, Derek; Chappell, David C; Dunnett, Andrew; Tsiami, Amalia A

    2013-03-14

    There is strong evidence indicating that elevated plasma total homocysteine (tHcy) levels are a major independent biomarker and/or a contributor to chronic conditions, such as CVD. A deficiency of vitamin B₁₂ can elevate homocysteine. Vegetarians are a group of the population who are potentially at greater risk of vitamin B₁₂ deficiency than omnivores. This is the first systematic review and meta-analysis to appraise a range of studies that compared the homocysteine and vitamin B₁₂ levels of vegetarians and omnivores. The search methods employed identified 443 entries, from which, by screening using set inclusion and exclusion criteria, six eligible cohort case studies and eleven cross-sectional studies from 1999 to 2010 were revealed, which compared concentrations of plasma tHcy and serum vitamin B₁₂ of omnivores, lactovegetarians or lacto-ovovegetarians and vegans. Of the identified seventeen studies (3230 participants), only two studies reported that vegan concentrations of plasma tHcy and serum vitamin B₁₂ did not differ from omnivores. The present study confirmed that an inverse relationship exists between plasma tHcy and serum vitamin B₁₂, from which it can be concluded that the usual dietary source of vitamin B₁₂ is animal products and those who choose to omit or restrict these products are destined to become vitamin B₁₂ deficient. At present, the available supplement, which is usually used for fortification of food, is the unreliable cyanocobalamin. A well-designed study is needed to investigate a reliable and suitable supplement to normalise the elevated plasma tHcy of a high majority of vegetarians. This would fill the gaps in the present nutritional scientific knowledge.

  1. A comparison of the effects of cheese and butter on serum lipids, haemostatic variables and homocysteine.

    PubMed

    Biong, Anne S; Müller, Hanne; Seljeflot, Ingebjørg; Veierød, Marit B; Pedersen, Jan I

    2004-11-01

    Milk fat contains considerable amounts of saturated fatty acids, known to increase serum cholesterol. Little is known, however, about the relative effect of different milk products on risk factors for CHD. The aim of the present study was to compare the effects of Jarlsberg cheese (a Norwegian variety of Swiss cheese) with butter on serum lipoproteins, haemostatic variables and homocysteine. A controlled dietary study was performed with twenty-two test individuals (nine men and thirteen women) aged 23-54 years. The subjects consumed three isoenergetic test diets, with equal amounts of fat and protein, and containing either cheese (CH diet), butter + calcium caseinate (BC diet) or butter + egg-white protein (BE diet). The study was a randomised cross-over study and the subjects consumed each diet for 3 weeks, with 1 week when they consumed their habitual diet in between. Fasting blood samples were drawn at baseline and at the end of each period. Serum was analysed for lipids and plasma for haemostatic variables and homocysteine. Total cholesterol was significantly lower after the CH diet than after the BC diet (-0.27 mmol/l; P=0.03), while the difference in LDL-cholesterol was found to be below significance level (-0.22 mmol/l; P=0.06). There were no significant differences in HDL-cholesterol, triacylglycerols, apo A-I, apo B or lipoprotein (a), haemostatic variables and homocysteine between the diets. The results indicate that, at equal fat content, cheese may be less cholesterol increasing than butter.

  2. Homocysteine enriched diet leads to prolonged QT interval and reduced left ventricular performance in telemetric monitored mice

    PubMed Central

    Rosenberger, D; Gargoum, R; Tyagi, N; Metreveli, N; Sen, U; Maldonado, C; Tyagi, S

    2009-01-01

    Background and Aims Homocysteine (Hcy) is a sulfur-containing, non-protein amino acid produced in the metabolic pathway of methionine. Hyperhomocysteinemia is associated with cerebro- and cardiovascular disease in industrialized countries mostly resulting from protein rich diet and sedentary life style. Matrix metalloproteinases are involved in cardiac remodeling, leading to degradation of intercellular junctions, cardiac connexins and basement membranes. The study was designed to investigate the relationship between Hcy, cardiac remodeling, cardiac performance, and rhythm disturbances in an animal model of hyperhomocysteinemia. We tested the hypothesis that induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 leads to connexin 40, connexin 43, connexin 45 expression changes contributing to decreased cardiac performance and disturbed atrioventricular conduction. Methods and Results Hcy was added to drinking water of male C57/BL6J mice to achieve moderate Hcy blood levels. ECG was monitored in conscious mice with a telemetric ECG device; echocardiography was used for assessment of left ventricular function. Immunoblotting was used to evaluate matrix metalloproteinase-2, matrix metalloproteinase-9, connexin 40, connexin 43, and connexin 45 expression in cardiac tissue. Animals fed Hcy showed significant prolongation of QRS, QTc, and PR intervals along with reduced left ventricular function. Western blotting showed increased expression of matrix metalloproteinase-2, matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45. Conclusion Hcy has been identified as a nutritional factor contributing to cardiovascular disease. Cardiac remodelling induced by matrix metalloproteinase-2 and matrix metalloproteinase-9 and decreased expression of connexin 40, 43, and 45 appears to play a role in the pathomechansim of atrioventricular conduction delay and ventricular dilatation in hyperhomocysteinemia. PMID:20227264

  3. Effects of folic acid and vitamin B12 supplements on folate and homocysteine metabolism in pigs during early pregnancy.

    PubMed

    Guay, Frédéric; Jacques Matte, J; Girard, Christiane L; Palin, Marie-France; Giguère, Alain; Laforest, Jean-Paul

    2002-09-01

    The present experiment aimed to determine the effects of supplements of folic acid (FA) alone or in combination with vitamin B12 on folate and homocysteine metabolism in gestating nulliparous Yorkshire-Landrace (YL) and multiparous Landrace (LD) occidental sows and multiparous Chinese Meishan-Landrace (ML) sows. LD sows were randomly assigned to two treatments: 0 or 15 mg FA/kg diet while YL and ML sows were assigned to three treatments: 0 mg FA/kg diet, 15 mg FA/kg or 15 mg vitamin B12/kg diet. Supplements were given from the oestrus preceding insemination up to slaughter on day 15 of gestation. At slaughter, a uterine flush was collected to determine uterine contents of homocysteine, methionine, tetrahydrofolate (THF), 5-methyl-THF, pyridoxal 5-phosphate (P5P) and vitamin B12. Blood samples were taken at first oestrus, at insemination and on days 5, 10 and 15 of gestation to determine plasma concentrations of homocysteine, methionine, THF, 5-methyl-THF, P5P, vitamin B12 and relative total folate-binding capacity. In occidental sows (YL and LD), the FA supplement tended to decrease uterine flush content of homocysteine (P=0.06) and concentrations of plasma homocysteine (P=0.09). Nulliparous YL sows had lower concentrations of plasma homocysteine, methionine, THF and 5-methyl-THF (P<0.05) than multiparous LD sows. Multiparous ML and LD sows had similar concentrations of plasma THF, 5-methyl-THF, methionine and vitamin B12, but ML sows had lower concentrations of plasma homocysteine (P<0.05). The vitamin B12 supplement increased concentrations of plasma vitamin B12 (P<0.05) both in multiparous ML and nulliparous YL sows, but had no effect on the composition of either uterine flush or plasma. The present results showed also that sows had a low vitamin B12 status (<200 pg/ml) and high circulating homocysteine levels (>15 microm) during the first 15 d of gestation. Furthermore, the vitamin B12 content in uterine secretions represented between 180 and 300 % of the total

  4. Alpha-methyl-homocysteine thiolactone protects lung of BALB/c mice irradiated with 6 Gy

    NASA Astrophysics Data System (ADS)

    Lubec, G.; Foltinova, J.; Leplawy, T.; Mallinger, R.; Tichatschek, E.; Getoff, N.

    1996-06-01

    The radiation protective activity of intraperitoneally administered alpha-methyl-homocysteine thiolactone (α-MHCTL; 100 mg/kg body weight) in female BALB/c mice and such treated with cysteine treated (100 mg/kg body weight), using unirradiated and placebo treated irradiated mice were tested as controls. 6 Gy whole body irradiated was applied and after a period of three weeks the animals were sacrificed and lungs were taken for morphometry and the determination of o-tyrosine. Septal areas were highest in the irradiated, placebo treated mice (68.67 + 9.82% septal area to total area)and lowest in the α-MHCTL treated irradiated mice (55.67 +11.29%), significant at the p < 0.05 level. Morphometric data were accompanied by highest levels of o-tyrosine, a reliable parameter for OH-attack, in the irradiated, placebo treated group with 1.87 + 0.40 μM/g lung tissue and 0.32 + 0.13 gmM/g lung tissue in the αMHCTL treated group; the statistical difference was significant. Significant radiation protection in the mammalian system at the morphological and biochemical level were found. The potent effect could be explained by the influence of alpha-alkylation in homocysteine thiolactone (HCTL) which renders amino acids unmetabolizeable, nontoxic, increases lipophilicity and therefore improving permeability through membranes. The present report confirms morphological data on the radiation protective activity of this interesting thiol compound.

  5. Increased plasma homocysteine levels in patients with multiple sclerosis and depression

    PubMed Central

    Triantafyllou, Nikolaos; Evangelopoulos, Maria-Eleftheria; Kimiskidis, Vasilios K; Kararizou, Evangelia; Boufidou, Fotini; Fountoulakis, Konstantinos N; Siamouli, Melina; Nikolaou, Chrysoula; Sfagos, Constantinos; Vlaikidis, Nikolaos; Vassilopoulos, Dimitrios

    2008-01-01

    Background The aim of the study was to assess the plasma levels of homocysteine in patients with multiple sclerosis (MS) and to investigate whether an association with depression exists. Methods Plasma homocysteine (Hcy), vitamin B12 and plasma folate were measured in 65 moderately disabled patients with relapsing/remitting MS (RR-MS) and 60 healthy controls. All subjects were assessed with the Beck Depression Inventory (BDI). Results Hcy levels were significantly increased in MS patients compared to controls (13.5 ± 4.7 μmol/l vs 8.5 ± 3.1, p < 0.001). A significant correlation was found between Hcy levels and BDI scores (Pearson r = 0.3025, p < 0.05). Plasma Hcy was not related to Extended Disability Status Scale (EDSS) score, age, disease duration or vitamin B12 and folate. Conclusion Moderately disabled MS patients with elevated Hcy levels are particularly prone to develop depressive symptomatology. Further study is warranted in order to elucidate the prognostic and therapeutic implications of this novel finding. PMID:18782433

  6. Genetic encoding of caged cysteine and caged homocysteine in bacterial and mammalian cells.

    PubMed

    Uprety, Rajendra; Luo, Ji; Liu, Jihe; Naro, Yuta; Samanta, Subhas; Deiters, Alexander

    2014-08-18

    We report the genetic incorporation of caged cysteine and caged homocysteine into proteins in bacterial and mammalian cells. The genetic code of these cells was expanded with an engineered pyrrolysine tRNA/tRNA synthetase pair that accepts both light-activatable amino acids as substrates. Incorporation was validated by reporter assays, western blots, and mass spectrometry, and differences in incorporation efficiency were explained by molecular modeling of synthetase-amino acid interactions. As a proof-of-principle application, the genetic replacement of an active-site cysteine residue with a caged cysteine residue in Renilla luciferase led to a complete loss of enzyme activity; however, upon brief exposure to UV light, a >150-fold increase in enzymatic activity was observed, thus showcasing the applicability of the caged cysteine in live human cells. A simultaneously conducted genetic replacement with homocysteine yielded an enzyme with greatly reduced activity, thereby demonstrating the precise probing of a protein active site. These discoveries provide a new tool for the optochemical control of protein function in mammalian cells and expand the set of genetically encoded unnatural amino acids.

  7. A molecular model for the active site of S-adenosyl-L-homocysteine hydrolase.

    PubMed

    Yeh, J C; Borchardt, R T; Vedani, A

    1991-06-01

    S-adenosyl-L-homocysteine hydrolase (AdoHcy hydrolase, EC 3.3.1.1), a specific target for antiviral drug design, catalyzes the hydrolysis of AdoHcy to adenosine (Ado) and homocysteine (Hcy) as well as the synthesis of AdoHcy from Ado and Hcy. The enzyme isolated from different sources has been shown to contain tightly bound NAD+. Based on the 2.0 A-resolution X-ray crystal structure of dogfish lactate dehydrogenase (LDH), which is functionally homologous to AdoHcy hydrolase, and the primary sequence of rat liver AdoHcy hydrolase, we have derived a molecular model of an extended active site for AdoHcy hydrolase. The computational mutation was performed using the software MUTAR (Yeh et al., University of Kansas, Lawrence), followed by molecular mechanics optimizations using the programs AMBER (Singh et al., University of California, San Francisco) and YETI (Vedani, University of Kansas). Solvation of the model structure was achieved by use of the program SOLVGEN (Jacober, University of Kansas); 56 water molecules were explicitly included in all refinements. Some of these may be involved in the catalytic reaction. We also studied a model of the complex of AdoHcy hydrolase with NAD+, as well as the ternary complexes of the enzyme, NAD+, and substrate or inhibitor molecules. Our refined model is capable of explaining part of the redox reaction catalyzed by AdoHcy hydrolase and has been used to differentiate the relative binding strength of inhibitors.

  8. Evaluation of Serum Homocysteine, High-Sensitivity CRP, and RBC Folate in Patients with Alopecia Areata

    PubMed Central

    Yousefi, Maryam; Namazi, Mohammad Reza; Rahimi, Hoda; Younespour, Shima; Ehsani, Amir Houshang; Shakoei, Safoura

    2014-01-01

    Introduction: Alopecia areata (AA) is a common type of hair loss with an autoimmune basis. As the role of homocysteine (Hcys), folate, and CRP has been considered in some autoimmune diseases. Objectives: To evaluate homocysteine, folate and CRP level in AA. Methods: This study was performed on 29 patients who had AA for at least 6 months affecting more than 20% of scalp, and 32 healthy controls. Levels of serum Hcys, blood high-sensitivity CRP, and RBC folate were measured in all subjects. Results: The mean level of RBC folate was significantly lower in the patient group than that in controls (P < 0.001). Also, the level of RBC folate was significantly lower in patients with extensive forms of disease (alopecia totalis/alopecia universalis) in comparison with more localized form (patchy hair loss) (P < 0.05). Patients with higher “Severity of Alopecia Total” (SALT) score had lower RBC folate, as well. Serum Hcys and blood high-sensitivity CRP levels did not show a significant difference in two groups. Conclusion: Patients with alopecia areata have lower level of RBC folate which is in negative correlation with both severity and extension of AA. PMID:25484412

  9. Crystal structure of the homocysteine methyltransferase MmuM from Escherichia coli.

    PubMed

    Li, Kunhua; Li, Gengnan; Bradbury, Louis M T; Hanson, Andrew D; Bruner, Steven D

    2016-02-01

    Homocysteine S-methyltransferases (HMTs, EC 2.1.1.0) catalyse the conversion of homocysteine to methionine using S-methylmethionine or S-adenosylmethionine as the methyl donor. HMTs play an important role in methionine biosynthesis and are widely distributed among micro-organisms, plants and animals. Additionally, HMTs play a role in metabolite repair of S-adenosylmethionine by removing an inactive diastereomer from the pool. The mmuM gene product from Escherichia coli is an archetypal HMT family protein and contains a predicted zinc-binding motif in the enzyme active site. In the present study, we demonstrate X-ray structures for MmuM in oxidized, apo and metallated forms, representing the first such structures for any member of the HMT family. The structures reveal a metal/substrate-binding pocket distinct from those in related enzymes. The presented structure analysis and modelling of co-substrate interactions provide valuable insight into the function of MmuM in both methionine biosynthesis and cofactor repair.

  10. Structural insights into the reaction mechanism of S-adenosyl-L-homocysteine hydrolase

    PubMed Central

    Kusakabe, Yoshio; Ishihara, Masaaki; Umeda, Tomonobu; Kuroda, Daisuke; Nakanishi, Masayuki; Kitade, Yukio; Gouda, Hiroaki; Nakamura, Kazuo T.; Tanaka, Nobutada

    2015-01-01

    S-adenosyl-L-homocysteine hydrolase (SAH hydrolase or SAHH) is a highly conserved enzyme that catalyses the reversible hydrolysis of SAH to L-homocysteine (HCY) and adenosine (ADO). High-resolution crystal structures have been reported for bacterial and plant SAHHs, but not mammalian SAHHs. Here, we report the first high-resolution crystal structure of mammalian SAHH (mouse SAHH) in complex with a reaction product (ADO) and with two reaction intermediate analogues—3’-keto-aristeromycin (3KA) and noraristeromycin (NRN)—at resolutions of 1.55, 1.55, and 1.65 Å. Each of the three structures constitutes a structural snapshot of one of the last three steps of the five-step process of SAH hydrolysis by SAHH. In the NRN complex, a water molecule, which is an essential substrate for ADO formation, is structurally identified for the first time as the candidate donor in a Michael addition by SAHH to the 3’-keto-4’,5’-didehydroadenosine reaction intermediate. The presence of the water molecule is consistent with the reaction mechanism proposed by Palmer & Abeles in 1979. These results provide insights into the reaction mechanism of the SAHH enzyme. PMID:26573329

  11. Defective remethylation of homocysteine is related to decreased synthesis of coenzymes B2 in thyroidectomized rats.

    PubMed

    Ayav, A; Alberto, J M; Barbe, F; Brunaud, L; Gerard, P; Merten, M; Gueant, J L

    2005-02-01

    We investigated the influence of hypothyroidism on homocysteine metabolism in rats, focusing on a hypothetical deficient synthesis of FAD by riboflavin kinases. Animals were allocated in control group (n = 7), thyroidectomized rats (n = 6), rats with diet deficient in vitamin B2, B9, B12, choline and methionine (n = 7), thyroidectomized rats with deficient diet (n = 9). Homocysteine was decreased in operated rats (2.6 +/- 1.01 vs. 4.05 +/- 1.0 mumol/L, P = 0.02) and increased in deficient diet rats (29.56 +/- 4.52 vs. 4.05 +/- 1.0 micromol/L, P = 0.001), when compared to control group. Erythrocyte-Glutathione-Reductase-Activation-Coefficient (index of FAD deficiency) was increased in thyroidectomized or deficient diet rats (P = 0.004 for both). Methylenetetrahydrofolate-reductase and methionine-synthase activities were decreased in thyroidectomized rats but not in those subjected to deficient diet. Cystathionine-beta-synthase was increased only in operated rats. Taken together, these results showed a defective re-methylation in surgical hypothyroidism, which was due in part to a defective synthesis of vitamin B2 coenzymes. This defective pathway was overcompensated by the increased Cystathionine-beta-synthase activity.

  12. The Use of Screen-Printed Electrodes in a Proof of Concept Electrochemical Estimation of Homocysteine and Glutathione in the Presence of Cysteine Using Catechol

    PubMed Central

    Lee, Patricia T.; Lowinsohn, Denise; Compton, Richard G.

    2014-01-01

    Screen printed electrodes were employed in a proof of concept determination of homocysteine and glutathione using electrochemically oxidized catechol via a 1,4-Michael addition reaction in the absence and presence of cysteine, and each other. Using cyclic voltammetry, the Michael reaction introduces a new adduct peak which is analytically useful in detecting thiols. The proposed procedure relies on the different rates of reaction of glutathione and homocysteine with oxidized catechol so that at fast voltage scan rates only homocysteine is detected in cyclic voltammetry. At slower scan rates, both glutathione and homocysteine are detected. The combination of the two sets of data provides quantification for homocysteine and glutathione. The presence of cysteine is shown not to interfere provided sufficient high concentrations of catechol are used. Calibration curves were determined for each homocysteine and glutathione detection; where the sensitivities are 0.019 μA·μM−1 and 0.0019 μA·μM−1 and limit of detections are ca. 1.2 μM and 0.11 μM for homocysteine and glutathione, respectively, within the linear range. This work presents results with potential and beneficial use in re-useable and/or disposable point-of-use sensors for biological and medical applications. PMID:24926695

  13. Effect of Folic Acid, Betaine, Vitamin B6, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine

    PubMed Central

    Rajdl, Daniel; Racek, Jaroslav; Trefil, Ladislav; Stehlik, Pavel; Dobra, Jana; Babuska, Vaclav

    2016-01-01

    Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. Methods: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B6). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B6 supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration. PMID:26771632

  14. Electrocardiogram Derived QRS Duration >120 ms is Associated With Elevated Plasma Homocysteine Levels in a Rural Australian Cross-Sectional Population

    PubMed Central

    Leng, Yvonne Lee Yin; Zhou, Yuling; Ke, Honghong; Jelinek, Herbert; McCabe, Joel; Assareh, Hassan; McLachlan, Craig S.

    2015-01-01

    Abstract Homocysteine levels in the low to moderate range for cardiovascular risk have been previously associated with left ventricular cardiac hypertrophy (LVH). Electrocardiogram (ECG) derived QRS duration has also been used as an epidemiological screening marker for cardiac hypertrophy risk. QRS duration cut offs have not been previously modeled to assess homocysteine levels in community populations. Our aims are to determine if QRS duration is associated with an elevated homocysteine level in a cross-sectional Australian aging rural population. A retrospective study design utilizing a rural health diabetic screening clinic database containing observational data from the period January 9, 2002 till September 25, 2012. One hundred seventy-eight individuals (>21 years of age) from the database were included in the study. Inclusion criteria included being nondiabetic and having both a QRS duration measure and a matching homocysteine level within the same subject. All participants were from the Albury-Wodonga area, with a mean age of >64 years for both sexes. Mean population homocysteine plasma levels were 10.4 μmol/L (SD = 3.6). The mean QRS duration was 101.8 ms (SD = 17.4). Groups were stratified on the basis of QRS duration (≤120 ms [n = 157] and >120 ms [n = 21]). QRS duration subgroup (≤120 ms vs >120 ms) mean differences across homocysteine levels were 10.1 μmol/L (SD = 3.3) and 12.2 μmol/L (SD = 4.7), respectively (P = 0.016). Other ECG parameters (PQ interval, QTc interval, and QT dispersion) measurements were not significantly associated with differences in plasma homocysteine (P = not significant). We conclude that in community populations homocysteine may be moderately elevated when QRS durations are >120 ms. Small additional increases in homocysteine levels may suggest a risk factor for ECG diagnosis of LVH. PMID:26166085

  15. Impaired Homocysteine Transmethylation and Protein-Methyltransferase Activity Reduce Expression of Selenoprotein P: Implications for Obesity and Metabolic Syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity causes Metabolic Syndrome and Type-II Diabetes, disrupting hepatic function, methionine (Met)/homocysteine (Hcy) transmethylation and methyltransferase (PRMT) activities. Selenoprotein P (SEPP1), exported from the liver, is the predominate form of plasma selenium (Se) and the physiological S...

  16. Choline supplementation alters some amino acid concentrations with no change in homocysteine in children with cystic fibrosis and pancreatic insufficiency.

    PubMed

    Alshaikh, Belal; Schall, Joan I; Maqbool, Asim; Mascarenhas, Maria; Bennett, Michael J; Stallings, Virginia A

    2016-05-01

    The present study determined the plasma amino acid status in children with cystic fibrosis (CF) and pancreatic insufficiency (PI) in the modern medical and nutritional care setting and investigated the effect of choline supplementation on amino acid status. A total of 110 children aged 5 to 18 years with CF and PI were randomized to receive choline-enriched structured lipid (LYM-X-SORB) or placebo with similar energy and fat content. Plasma amino acids were measured at baseline and 3 and 12 months. We hypothesized that choline supplementation would result in lower plasma homocysteine concentrations in children with CF. At baseline, dietary protein intake was high and the amino acid profile was within laboratory reference ranges in most participants. Alanine and cysteine were elevated in 24% and 36% of participants, respectively. Children with baseline alanine above reference range had improved weight, body mass index, and fat-free mass. Low homocysteine was found in 62% of children 11 years and older. After 3 and 12 months, there was no effect of choline supplementation on methionine or homocysteine status. Compared with placebo, choline supplementation resulted in increased glycine and decreased threonine, histidine, valine, and total branch chained amino acids at 12 months. In conclusion, daily choline supplementation with LYM-X-SORB did not alter methionine-homocysteine metabolism but did result in alterations in other amino acids in children with CF and PI.

  17. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely believed to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate ...

  18. Regular Exercise Training Increases the Number of Endothelial Progenitor Cells and Decreases Homocysteine Levels in Healthy Peripheral Blood

    PubMed Central

    Choi, Jeong Kyu; Moon, Ki Myung; Jung, Seok Yun; Kim, Ji Yong; Choi, Sung Hyun; Kim, Da Yeon; Kang, Songhwa; Chu, Chong Woo

    2014-01-01

    Endothelial progenitor cells (EPCs) are known to play an important role in the repair of damaged blood vessels. We used an endothelial progenitor cell colony-forming assay (EPC-CFA) to determine whether EPC numbers could be increased in healthy individuals through regular exercise training. The number of functional EPCs obtained from human peripheral blood-derived AC133 stem cells was measured after a 28-day regular exercise training program. The number of total endothelial progenitor cell colony-forming units (EPC-CFU) was significantly increased compared to that in the control group (p=0.02, n=5). In addition, we observed a significant decrease in homocysteine levels followed by an increase in the number of EPC-CFUs (p=0.04, n=5), indicating that the 28-day regular exercise training could increase the number of EPC colonies and decrease homocysteine levels. Moreover, an inverse correlation was observed between small-endothelial progenitor cell colony-forming units (small-EPC-CFUs) and plasma homocysteine levels in healthy men (r=-0.8125, p=0.047). We found that regular exercise training could increase the number of EPC-CFUs and decrease homocysteine levels, thus decreasing the cardiovascular disease risk in men. PMID:24757379

  19. Interactions between genetic variants of folate metabolism genes and lifestyle affect plasma homocysteine concentrations in the Boston Puerto Rican Population

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Results of studies investigating relationships between lifestyle factors and elevated plasma homocysteine (Hcy), an independent risk factor for cardiovascular disease, are conflicting. The objective of this study was to investigate genetic and lifestyle factors and their interactions on plasma Hcy c...

  20. Reduction of plasma lipid and homocysteine levels by pyridoxine, folate, cobalamin, choline, riboflavin, and troxerutin in atherosclerosis.

    PubMed

    Olszewski, A J; Szostak, W B; Bialkowska, M; Rudnicki, S; McCully, K S

    1989-01-01

    Elevated plasma homocysteine and lipid levels are risk factors for atherosclerosis. The plasma levels of homocysteine, determined in acid hydrolyzates of plasma, were found to be correlated with total cholesterol (r = 0.47, P less than 0.001), triglycerides (r = 0.40, P less than 0.01), and body mass index (r = 0.42, P less than 0.01) in 52 males, aged 30-60. A group of 12 male survivors of acute myocardial infarction was given pyridoxine, folate, cobalamin, choline, riboflavin, and troxerutin for 21 days. The plasma concentrations of homocysteine and alpha-amino adipic acid declined to 68% (P less than 0.001) and 57% (P less than 0.001) of the pretreatment values, and the cholesterol, triglycerides, and LDL apo B declined to 79% (P less than 0.001), 68% (P less than 0.01), and 63% (P less than 0.001) of the pretreatment values, respectively. The results suggest a new strategy for control of the metabolic abnormalities in atherosclerosis through the use of naturally occurring, non-toxic nutrients which minimize homocysteine accumulation.

  1. Phorbol esters induce death in MCF-7 breast cancer cells with altered expression of protein kinase C isoforms. Role for p53-independent induction of gadd-45 in initiating death.

    PubMed Central

    de Vente, J E; Kukoly, C A; Bryant, W O; Posekany, K J; Chen, J; Fletcher, D J; Parker, P J; Pettit, G J; Lozano, G; Cook, P P

    1995-01-01

    Protein kinase C (PKC) modulates growth, differentiation and apoptosis in a cell-specific fashion. Overexpression of PKC-alpha in MCF-7 breast cancer cells (MCF-7-PKC-alpha cell) leads to expression of a more transformed phenotype. The response of MCF-7 and MCF-7-PKC-alpha cells to phorbol esters (TPA) was examined. TPA-treated MCF-7 cells demonstrated a modest cytostatic response associated with a G1 arrest that was accompanied by Cip1 expression and retinoblastoma hypophosphorylation. While p53 was detected in MCF-7 cells, evidence for TPA-induced stimulation of p53 transcriptional activity was not evident. In contrast, TPA treatment induced death of MCF-7-PKC-alpha cells. Bryostatin 1, another PKC activator, exerted modest cytostatic effects on MCF-7 cells while producing a cytotoxic response at low doses in MCF-7-PKC-alpha cells that waned at higher concentrations. TPA-treated MCF-7-PKC-alpha cells accumulated in G2/M, did not express p53, displayed decreased Cip1 expression, and demonstrated a reduction in retinoblastoma hypophosphorylation. TPA-treated MCF-7-PKC-alpha cells expressed gadd-45 which occurred before the onset of apoptosis. Thus, alterations in the PKC pathway can modulate the decision of a breast cancer cell to undergo death or differentiation. In addition, these data show that PKC activation can induce expression of gadd45 in a p53-independent fashion. Images PMID:7560079

  2. Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia.

    PubMed

    Satyanarayana, Alleboena; Balakrishna, Nagalla; Pitla, Sujatha; Reddy, Paduru Yadagiri; Mudili, Sivaprasad; Lopamudra, Pratti; Suryanarayana, Palla; Viswanath, Kalluru; Ayyagari, Radha; Reddy, Geereddy Bhanuprakash

    2011-01-01

    Diabetic retinopathy (DR) is a common cause of blindness. Although many studies have indicated an association between homocysteine and DR, the results so far have been equivocal. Amongst the many determinants of homocysteine, B-vitamin status was shown to be a major confounding factor, yet very little is known about its relationship to DR. In the present study, we, therefore, investigated the status of B-vitamins and homocysteine in DR. A cross-sectional case-control study was conducted with 100 normal control (CN) subjects and 300 subjects with type-2 diabetes (T2D). Of the 300 subjects with T2D, 200 had retinopathy (DR) and 100 did not (DNR). After a complete ophthalmic examination including fundus fluorescein angiography, the clinical profile and the blood levels of all B-vitamins and homocysteine were analyzed. While mean plasma homocysteine levels were found to be higher in T2D patients compared with CN subjects, homocysteine levels were particularly high in the DR group. There were no group differences in the blood levels of vitamins B1 and B2. Although the plasma vitamin-B6 and folic acid levels were significantly lower in the DNR and DR groups compared with the CN group, there were no significant differences between the diabetes groups. Interestingly, plasma vitamin-B12 levels were found to be significantly lower in the diabetes groups compared with the CN group; further, the levels were significantly lower in the DR group compared with the DNR group. Higher homocysteine levels were significantly associated with lower vitamin-B12 and folic acid but not with other B-vitamins. Additionally, hyperhomocysteinemia and vitamin-B12 deficiency did not seem to be related to subjects' age, body mass index, or duration of diabetes. These results thus suggest a possible association between vitamin-B12 deficiency and hyperhomocysteinemia in DR. Further, the data indicate that vitamin-B12 deficiency could be an independent risk factor for DR.

  3. Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine–homocysteine S-methyltransferase

    PubMed Central

    Sparks, Janet D.; Collins, Heidi L.; Chirieac, Doru V.; Cianci, Joanne; Jokinen, Jenny; Sowden, Mark P.; Galloway, Chad A.; Sparks, Charles E.

    2006-01-01

    We have previously reported a positive correlation between the expression of BHMT (betaine–homocysteine S-methyltransferase) and ApoB (apolipoprotein B) in rat hepatoma McA (McArdle RH-7777) cells [Sowden, Collins, Smith, Garrow, Sparks and Sparks (1999) Biochem. J. 341, 639–645]. To examine whether a similar relationship occurs in vivo, hepatic BHMT expression was induced by feeding rats a Met (L-methionine)-restricted betaine-containing diet, and parameters of ApoB metabolism were evaluated. There were no generalized metabolic abnormalities associated with Met restriction for 7 days, as evidenced by control levels of serum glucose, ketones, alanine aminotransferase and L-homocysteine levels. Betaine plus the Met restriction resulted in lower serum insulin and non-esterified fatty acid levels. Betaine plus Met restriction induced hepatic BHMT 4-fold and ApoB mRNA 3-fold compared with Met restriction alone. No changes in percentage of edited ApoB mRNA were observed on the test diets. An increase in liver ApoB mRNA correlated with an 82% and 46% increase in ApoB and triacylglycerol production respectively using in vivo Triton WR 1339. Increased secretion of VLDL (very-low-density lipoprotein) with Met restriction plus betaine was associated with a 45% reduction in liver triacylglycerol compared with control. Nuclear run-off assays established that transcription of both bhmt and apob genes was also increased in Met-restricted plus betaine diets. No change in ApoB mRNA stability was detected in BHMT-transfected McA cells. Hepatic ApoB and BHMT mRNA levels were also increased by 1.8- and 3-fold respectively by betaine supplementation of Met-replete diets. Since dietary betaine increased ApoB mRNA, VLDL ApoB and triacylglycerol production and decreased hepatic triacylglycerol, results suggest that induction of apob transcription may provide a potential mechanism for mobilizing hepatic triacylglycerol by increasing ApoB available for VLDL assembly and secretion

  4. Homocysteine in renovascular complications: hydrogen sulfide is a modulator and plausible anaerobic ATP generator

    PubMed Central

    Sen, Utpal; Pushpakumar, Sathnur B.; Amin, Matthew A.; Tyagi, Suresh C.

    2014-01-01

    Homocysteine (Hcy) is a non-protein amino acid derived from dietary methionine. High levels of Hcy, known as hyperhomocysteinemia (HHcy) is known to cause vascular complications. In the mammalian tissue, Hcy is metabolized by transsulfuration enzymes to produce hydrogen sulfide (H2S). H2S, a pungent smelling gas was previously known for its toxic effects in the central nervous system, recent studies however has revealed protective effects in a variety of diseases including hypertension, diabetes, inflammation, atherosclerosis, and renal disease progression and failure. Interestingly, under stress conditions including hypoxia, H2S can reduce metabolic demand and also act as a substrate for ATP production. This review highlights some of the recent advances in H2S research as a potential therapeutic agent targeting renovascular diseases associated with HHcy. PMID:24963795

  5. Critical levels of brain atrophy associated with homocysteine and cognitive decline.

    PubMed

    de Jager, Celeste A

    2014-09-01

    Few B-vitamin trials to lower homocysteine (Hcy) have reported evidence of beneficial effects on cognition in older adults with cognitive impairment or Alzheimer's disease. This article reviews the role of Hcy in cognitive decline. It also considers some reasons why meta-analyses have failed to find effects of B-vitamin treatment. Findings from the successful VITACOG trial are examined from a new perspective of critical levels of Hcy and brain atrophy that may impact on the efficacy of B-vitamin treatment. It appears that there is a critical level of brain shrinkage, possibly mediated by elevated Hcy, which when reached, results in cognitive decline, especially in episodic memory performance. Supplements, food sources, and effects of folic acid fortification are discussed in relation to B12 deficiency.

  6. Reintroduction of a Homocysteine Level-Associated Allele into East Asians by Neanderthal Introgression.

    PubMed

    Hu, Ya; Ding, Qiliang; He, Yungang; Xu, Shuhua; Jin, Li

    2015-12-01

    In this study, we present an analysis of Neanderthal introgression at the dipeptidase 1 gene, DPEP1. A Neanderthal origin for the putative introgressive haplotypes was demonstrated using an established three-step approach. This introgression was under positive natural selection, reached a frequency of >50%, and introduced a homocysteine level- and pigmentation-associated allele (rs460879-T) into East Asians. However, the same allele was also found in non-East Asians, but not from Neanderthal introgression. It is likely that rs460879-T was lost in East Asians and was reintroduced subsequently through Neanderthal introgression. Our findings suggest that Neanderthal introgression could reintroduce an important previously existing allele into populations where the allele had been lost. This study sheds new light on understanding the contribution of Neanderthal introgression to the adaptation of non-Africans. PMID:26392408

  7. Homocysteine in renovascular complications: hydrogen sulfide is a modulator and plausible anaerobic ATP generator.

    PubMed

    Sen, Utpal; Pushpakumar, Sathnur B; Amin, Matthew A; Tyagi, Suresh C

    2014-09-15

    Homocysteine (Hcy) is a non-protein amino acid derived from dietary methionine. High levels of Hcy, known as hyperhomocysteinemia (HHcy) is known to cause vascular complications. In the mammalian tissue, Hcy is metabolized by transsulfuration enzymes to produce hydrogen sulfide (H2S). H2S, a pungent smelling gas was previously known for its toxic effects in the central nervous system, recent studies however has revealed protective effects in a variety of diseases including hypertension, diabetes, inflammation, atherosclerosis, and renal disease progression and failure. Interestingly, under stress conditions including hypoxia, H2S can reduce metabolic demand and also act as a substrate for ATP production. This review highlights some of the recent advances in H2S research as a potential therapeutic agent targeting renovascular diseases associated with HHcy.

  8. Studies on N5-methyltetrahydrofolate-homocystein methyltransferase in normal and leukemia leukocytes.

    PubMed

    Peytremann, R; Thorndike, J; Beck, W S

    1975-11-01

    A cobalamin-dependent N5-methyltetra-hydrofolate-homocysteine methyltransferase (methyl-transferase) was demonstrated in unfractioned extracts of human normal and leukemia leukocytes. Activity was substantially reduced in the absence of an added cobalamin derivative. Presumably, this residual activity reflects the endogeneous level of holoenzyme. Enzyme activity was notably higher in lymphoid cells than in myeloid cells. Thus, mean specific activities (+/-SD) were: chronic lymphocytic leukemia lymphocytes, 2.15+/-1.16; normal lymphocytes, 0.91+/-0.59; normal mature granulocytes, 0.15+/-0.10; chronic myelocytic leukemia granulocytes, barely detectable activity. Properties of leukocytes enzymes resembled those of methyltransferases previously studied in bacteria and other animal cells. Granulocytes and chronic myelocytic leukemia cells contain a factor or factors that inhibits Escherichia coli enzyme. The data suggest that the prominence of this cobalamin-dependent enzyme in lymphocytes and other mononuclear cell types may be related to their potential for cell division.

  9. Studies on N5-methyltetrahydrofolate-homocystein methyltransferase in normal and leukemia leukocytes.

    PubMed Central

    Peytremann, R; Thorndike, J; Beck, W S

    1975-01-01

    A cobalamin-dependent N5-methyltetra-hydrofolate-homocysteine methyltransferase (methyl-transferase) was demonstrated in unfractioned extracts of human normal and leukemia leukocytes. Activity was substantially reduced in the absence of an added cobalamin derivative. Presumably, this residual activity reflects the endogeneous level of holoenzyme. Enzyme activity was notably higher in lymphoid cells than in myeloid cells. Thus, mean specific activities (+/-SD) were: chronic lymphocytic leukemia lymphocytes, 2.15+/-1.16; normal lymphocytes, 0.91+/-0.59; normal mature granulocytes, 0.15+/-0.10; chronic myelocytic leukemia granulocytes, barely detectable activity. Properties of leukocytes enzymes resembled those of methyltransferases previously studied in bacteria and other animal cells. Granulocytes and chronic myelocytic leukemia cells contain a factor or factors that inhibits Escherichia coli enzyme. The data suggest that the prominence of this cobalamin-dependent enzyme in lymphocytes and other mononuclear cell types may be related to their potential for cell division. PMID:1184750

  10. Association between High Serum Homocysteine Levels and Biochemical Characteristics in Women with Polycystic Ovarian Syndrome: A Systematic Review and Meta-Analysis

    PubMed Central

    Peng, Zheng; Liu, Xuexiang; Sun, Yifan; Dai, Shengming

    2016-01-01

    Background Elevated homocysteine levels have been observed in previous studies of PCOS; however, the nature of the associations between high homocysteine levels and the biochemical characteristics of polycystic ovarian syndrome (PCOS)—such as obesity, insulin resistance (IR), and androgen levels—is still uncertain. Methods A systematic search was conducted electronically up to December 28, 2015 using specific eligibility criteria. Standardized mean difference (SMD) and the corresponding 95% confidence intervals (95% CIs) were used as a measure of effect size. Results A total of 34 studies (with 1,718 cases and 1,399 controls) of homocysteine levels in PCOS were pooled in this meta-analysis. Significantly lower homocysteine levels were found in controls than in PCOS patients (SMD = 0.895, 95% CI = 0.643–1.146, P<0.001; I2 = 90.4% and P<0.001 for heterogeneity), regardless of the degree of obesity, IR, or androgen levels. Homocysteine levels in non-IR PCOS patients were significantly lower than those of PCOS patients with IR (SMD = 0.69, 95% CI = 0.37–1.01, P<0.01; I2 = 0% and P = 0.50 for heterogeneity). However, metformin treatment did not appear to cause any significant change in the homocysteine levels of PCOS patients (SMD = –0.17, 95% CI = –1.10–0.75, P = 0.71; I2 = 92% and P<0.01 for heterogeneity). Conclusions High homocysteine levels in women with PCOS are not related to degree of obesity, IR, or androgen levels. Metformin treatment cannot decrease the homocysteine levels in PCOS patients. PMID:27281026

  11. Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID).

    PubMed

    Hainsworth, Atticus H; Yeo, Natalie E; Weekman, Erica M; Wilcock, Donna M

    2016-05-01

    Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID). Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26689889

  12. Traditional and alternative nutrition--levels of homocysteine and lipid parameters in adults.

    PubMed

    Krajcovicová-Kudlácková, M; Blazícek, P; Babinská, K; Kopcová, J; Klvanová, J; Béderová, A; Magálová, T

    2000-12-01

    Values of homocysteine and lipid parameters were measured in groups of adults consuming alternative nutrition (vegetarians/lactoovo/, vegans) and compared with a group consuming traditional diet (omnivores, general population). Frequency of hyperhomocysteinemia was 53% in the vegans group, 28% in vegetarians vs. 5% in omnivores. In conditions of lower methionine intake (reduced content in plant proteins), the remethylation pathway of homocysteine metabolism prevails and it is vitamin B12 and folate-dependent. The intake of vitamin B12 is equal to zero in vegans; vegetarians consume 124% of the RDA vs. 383% in omnivores. Serum vitamin levels are significantly lower in subjects consuming alternative nutrition with deficiency observed in 24% of vegetarians, 78% of vegans vs. 0% in omnivores. Serum folate levels are within the reference range in all groups. Mild hyperhomocysteinemia in the groups consuming alternative diet is a consequence of vitamin B12 deficiency. Vegetarians and vegans meet the RDA for energy and fat, and have a favourable proportion of saturated, mono- and polyunsaturated fatty acids on total energy intake; the ratio of linoleic/alpha-linolenic acid in their diet corresponds with the recommendations. They have low cholesterol consumption and higher vitamin E and C intake. Optimal fat intake of correct composition is reflected in lower values of atherosclerosis risk factors (cholesterol, LDL-cholesterol, atherogenic index, saturated fatty acids, triacylglycerols), and significantly higher levels of protective substances (linoleic acid, alpha-linolenic acid, HDL-cholesterol, vitamin E, vitamin E/cholesterol, vitamin C). Low lipid risk factors but higher findings of mild hyperhomocysteinemia in vegetarians mean a diminished protective effect of alternative nutrition in cardiovascular disease prevention.

  13. Traditional and alternative nutrition--levels of homocysteine and lipid parameters in adults.

    PubMed

    Krajcovicová-Kudlácková, M; Blazícek, P; Babinská, K; Kopcová, J; Klvanová, J; Béderová, A; Magálová, T

    2000-12-01

    Values of homocysteine and lipid parameters were measured in groups of adults consuming alternative nutrition (vegetarians/lactoovo/, vegans) and compared with a group consuming traditional diet (omnivores, general population). Frequency of hyperhomocysteinemia was 53% in the vegans group, 28% in vegetarians vs. 5% in omnivores. In conditions of lower methionine intake (reduced content in plant proteins), the remethylation pathway of homocysteine metabolism prevails and it is vitamin B12 and folate-dependent. The intake of vitamin B12 is equal to zero in vegans; vegetarians consume 124% of the RDA vs. 383% in omnivores. Serum vitamin levels are significantly lower in subjects consuming alternative nutrition with deficiency observed in 24% of vegetarians, 78% of vegans vs. 0% in omnivores. Serum folate levels are within the reference range in all groups. Mild hyperhomocysteinemia in the groups consuming alternative diet is a consequence of vitamin B12 deficiency. Vegetarians and vegans meet the RDA for energy and fat, and have a favourable proportion of saturated, mono- and polyunsaturated fatty acids on total energy intake; the ratio of linoleic/alpha-linolenic acid in their diet corresponds with the recommendations. They have low cholesterol consumption and higher vitamin E and C intake. Optimal fat intake of correct composition is reflected in lower values of atherosclerosis risk factors (cholesterol, LDL-cholesterol, atherogenic index, saturated fatty acids, triacylglycerols), and significantly higher levels of protective substances (linoleic acid, alpha-linolenic acid, HDL-cholesterol, vitamin E, vitamin E/cholesterol, vitamin C). Low lipid risk factors but higher findings of mild hyperhomocysteinemia in vegetarians mean a diminished protective effect of alternative nutrition in cardiovascular disease prevention. PMID:11218148

  14. Plasma lipoprotein (a), homocysteine, and other cardiovascular disease (CVD) risk factors in Nigerians with CVD.

    PubMed

    Ebesunun, M O; Agbedana, E O; Taylor, G O L; Oladapo, O O

    2008-04-01

    Elevated plasma lipoprotein (a) (Lp(a)) and total homocysteine (tHcy) concentrations, as well as fat distributions, are associated with cardiovascular disease (CVD) risk. The purpose of this study was to evaluate plasma Lp(a), tHcy, percentage body fat, anthropometric indices, and blood pressure (BP) and their relationships with each other in well-defined, hospital-based, CVD patients in a Nigerian African community. One hundred seventy patients suffering from hypertensive heart disease, hypertension, ischaemic heart disease, and myocardial infraction with the mean age of 45.3 +/- 1.3 years and 58 apparently healthy volunteers with the mean age of 44.8 +/-1.2 years were selected. Anthropometric indices and BP were measured. Percentage body fat, body mass index, and waist-to-hip ratio (WHR) were calculated. Plasma Lp(a) and tHcy concentrations were determined. The results showed significant increases in BP, skinfold thickness (SFT) variables, and WHR in all of the CVD patients. Plasma Lp(a) was also significantly increased (p < 0.001), whereas the slight increase in the mean tHcy was not statistically significant. Positive significant correlations were found between systolic BP, triceps, SFT, and percentage body fat (p < 0.01), whereas significant correlations were found between some body composition variables, tHcy, and systolic BP (p < 0.05). Our findings provide supportive evidence for altered plasma Lp(a) concentration in addition to some other traditional CVD risk factors in Nigerians. The role of homocysteine is not well defined.

  15. Association Between Serum B12 and Serum Homocysteine Levels in Diabetic Patients on Metformin

    PubMed Central

    Kothari, Nitin; Shah, Hitesh

    2016-01-01

    Introduction Type-2 Diabetes Mellitus (T2DM) and metformin both can lower serum B12 (s.B12). Raised serum Homocysteine (s.Hcy) is considered as an early marker of B12 deficiency. Aim The study aimed to check whether homocysteine levels are more sensitive indicator of s. B12 deficiency or not among diabetics using metformin. Materials and Methods Mean s.B12 and s.Hcy levels of 30 cases (diabetics on metformin <5years) were compared with 30 diabetic controls not on metformin and 31 nondiabetic controls and statistically analysed by ANOVA and post-hoc tests. Results No significant differences in either s.B12 mean or s.Hcy mean were found between cases and diabetic controls. s.B12 mean did not differ significantly but s.Hcy mean was significantly higher among nondiabetics as compared to diabetic control. s. B12 level of Nondiabetic group was in borderline category while mean s. B12 levels of cases and diabetic control groups was in normal category but nearer to the lower cut off. Mean s.Hcy values in all the groups were high. Pearson correlation showed strong association between s.B12 and s.Hcy in all the groups. Additionally equation based on linear regression was derived to calculate either of the s.B12 or s.Hcy. On Receiver Operative Characteristic (ROC) curve, area under curve value was 0.842 for the value of s.Hcy. Conclusion In this study neither metformin nor T2DM could be identified as a cause for s.B12 lowering and raised s.Hcy in the scenario of low normal levels of s.B12 (<300pmol/L). If B12 deficiency recognized early using s. Hcy, consequences due to B12 deficiency can be prevented or delayed among nondiabetics as well as among diabetics and metformin users. PMID:27190787

  16. Homocysteine Test

    MedlinePlus

    ... elevated. If an individual does not get enough B vitamins and/or folate through diet or supplements, then ... given that several trials investigating folic acid and B vitamin supplementation indicate no benefit or lowering of CVD ...

  17. Meta-analysis of plasma homocysteine content and cognitive function in elderly patients with Alzheimer’s disease and vascular dementia

    PubMed Central

    Wang, Beiyun; Zhong, Yuan; Yan, Hong; Cui, Liang

    2014-01-01

    Objective: To evaluate the relationship between homocysteine and cognitive function of Alzheimer’s disease (AD) patients and vascular dementia (VD) patients. Methods: By Cochrane system evaluation we retrieved relevant publications from MEDLINE, Embase, OVID, controlled clinical trial database of the Cochrane library and others. Two evaluators jointly assessed the research quality of the retrieved publications and carried out meta-analysis on the homogeneous study. Results: MMSE score in the AD group was lower than that in normal control group (MD = -11.98, 95% CI (-13.30, -10.65)), and the homocysteine content was higher than that in the normal control group (MD = 2.72, 95% CI (1.79, 3.64)), with a statistical difference between the two groups (P < 0.05). The homocysteine content in the AD group was higher than that in the VD group (MD = -4.76, 95% CI (-7.59, -1.93), P < 0.05). Conclusions: MSE score and homocysteine content can be used as useful indicators to distinguish AD and normal subjects; homocysteine content can be used as an indicator to differentiate AD from VD. Clinically, more randomized controlled trials are needed to test and verify the relationship in cognitive function between homocysteine and AD and VD. PMID:25664013

  18. [HOMOCYSTEINE AS A PROGNOSTIC MARKER OF ATRIAL REMODELING AND CLINICAL PICTURE IN PATIENTS WITH PAROXYSMAL AND PERSISTENT FORMS OF ATRIAL FIBRILLATION].

    PubMed

    Snezhitsky, V A; Yatskevich, E S; Doroshenko, E M; Smirnov, V Yu; Dolgoshey, T S; Rubinsky, A Yu

    2016-01-01

    The aim of this work was to study prognostic significance of the relationship between the homocysteine level, structural/functional atrial remodeling, and clinical picture of paroxysmal and persistent forms of atrial fibrillation (AF). The study included 75 patients with AF concomitant with coronary heart disease and hypertensive disease without apparent structural changes in myocardium. Group 1 was comprised of 48 patients with paroxysmal AF, group 2 of 27 patients with persistent AF. 19 patients with coronary heart disease and hypertensive disease without AF served as controls. The structural and functional state of the heart was evaluated based on two-dimensional trans-thoracal echocardiography with the use of the formulas for calculating left ventricular characteristics. Blood homocysteine levels were measured The frequency of AF relapses was determined after an 1 year follow-up. The homocysteine level over 11.2 mcmol/l was related to left ventricle enlargement (over 40 mm), high frequency and relapse rate of AF. It is concluded that the relationship between homocysteine levels, left ventricle size, frequency and relapse rate of AF suggests the influence of homocysteine on atrial remodeling. A rise in the homocysteine level above 11 mcmol/l should be regarded as a prognostic factor of increased AF relapse rate. PMID:27172716

  19. Effect of Short-Term Maximal Exercise on Biochemical Markers of Muscle Damage, Total Antioxidant Status, and Homocysteine Levels in Football Players

    PubMed Central

    Hammouda, Omar; Chtourou, Hamdi; Chaouachi, Anis; Chahed, Henda; Ferchichi, Salyma; Kallel, Choumous; Chamari, Karim; Souissi, Nizar

    2012-01-01

    Purpose Prolonged physical exercise results in transient elevations of biochemical markers of muscular damage. This study examined the effect of short-term maximal exercise on these markers, homocysteine levels (Hcy), and total antioxidant status (TAS) in trained subjects. Methods Eighteen male football players participated in this study. Blood samples were collected 5-min before and 3-min after a 30-s Wingate test. Results The results indicated that plasma biochemical markers of muscle injury increased significantly after the Wingate test (P<0.05). Moreover, significant increase of white blood Cells and their main subpopulations (i.e. monocytes, neutrophiles, and lymphocytes) (P<0.001) has been observed. Likewise, uric acid, total bilirubin, and TAS increased significantly after exercise (P<0.05). However, Hcy levels were unaffected by the Wingate test (for 3-min post-exercise measurement). Conclusions Short-term maximal exercise (e.g. 30-s Wingate test) is of sufficient intensity and duration to increase markers of muscle damage, and TAS; but not Hcy levels. Increases in the selected enzymes probably come primarily from muscle damage, rather than liver damage. Moreover, increase of TAS confirms the Wingate test induced oxidative stress. PMID:23342222

  20. Long‐term effect of Helicobacter pylori eradication on plasma homocysteine in elderly patients with cobalamin deficiency

    PubMed Central

    Marino, Marília Campos Abreu; de Oliveira, Celso Affonso; Rocha, Andreia Maria Camargos; Rocha, Gifone Aguiar; Clementino, Nelma Cristina Diogo; Antunes, Leonardo França; Oliveira, Ricardo Araújo; Martins, Almir Sousa; Del Puerto, Helen Lima; D'Almeida, Vânia; Galdieri, Luciano; Pedroso, Ênio Roberto Pietra; Cabral, Mônica Maria Demas Álvares; Nogueira, Ana Margarida Miguel Ferreira; Queiroz, Dulciene Maria Magalhães

    2007-01-01

    Background Helicobacter pylori gastritis may lead to impairment of the production of pepsinogen and acid, which are essential to cobalamin absorption. In turn, cobalamin deficiency leads to hyperhomocysteinaemia, a risk factor for cardio and cerebrovascular diseases. Aim To evaluate the effect of H pylori eradication on plasma homocysteine levels in elderly patients. Patients Sixty‐two H pylori‐positive elderly patients with cobalamin deficiency were prospectively studied. Methods Homocysteine and cobalamin concentrations were determined before, 6 and 12 months after H pylori eradication. Results Corpus atrophy was observed in a few patients; otherwise, in most of them, the degree of corpus gastritis was moderate to severe. The initial homocysteine mean (SD) levels decreased from 41.0 (27.1) to 21.6 (10.1) μmol/l at the 6 month follow‐up (p<0.001) and to 13.1 (3.8) μmol/l 12 months after H pylori eradication (p<0.001). Conversely, initial cobalamin mean levels increased from 145.5 (48.7) pmol/l to 209.8 (87.1) pmol/l and to 271.2 (140.8) pmol/l, 6 and 12 months after treatment, respectively (p<0.001 for both). Although the erythrocyte mean corpuscular volume was within reference intervals, it decreased significantly 6 (p = 0.002) and 12 (p<0.001) months after treatment. Conclusions The results of the current study demonstrated that the eradication of H pylori in elderly patients with cobalamin deficiency is followed by increasing of cobalamin and decreasing of homocysteine blood levels. PMID:17005765

  1. Consumption of soy isoflavones does not affect plasma total homocysteine or asymmetric dimethylarginine concentrations in healthy postmenopausal women.

    PubMed

    Reimann, Manja; Dierkes, Jutta; Carlsohn, Anja; Talbot, Duncan; Ferrari, Marika; Hallund, Jesper; Hall, Wendy L; Vafeiadou, Katerina; Huebner, Ulrich; Branca, Francesco; Bugel, Susanne; Williams, Christine M; Zunft, H-J Franz; Koebnick, Corinna

    2006-01-01

    Postmenopausal women are at increased risk for cardiovascular disease because many risk factors are aggravated by menopause. Phytoestrogens may modulate risk factors favorably, involving mechanisms similar to estrogen. The effect of phytoestrogens on the atherogenic amino acids homocysteine and asymmetric dimethylarginine (ADMA) was investigated in a controlled intervention study in healthy postmenopausal women. A multicenter, double-blind, crossover intervention trial in 89 postmenopausal women from Denmark, Germany, and the UK was performed. Subjects consumed fruit cereal bars with or without soy isoflavones (50 mg/d) for 8 wk each with an 8-wk washout period in between. Urinary phytoestrogens increased significantly after isoflavone intervention (P < 0.001). Isoflavone supplementation did not affect plasma total homocysteine or ADMA. For homocysteine, changes from baseline were 0.32 micromol/L (range: -0.31-0.92; 95% CI 0.13-0.72), and 0.29 micromol/L (range: -0.45-1.09; 95% CI 0.01-0.63, P = 0.286) for isoflavone treatment and placebo, respectively. For ADMA concentrations, changes from baseline were -0.02 micromol/L (range: -0.08-0.03; 95% CI -0.04-0.01, and 0.00 micromol/L (range: -0.05-0.03; 95% CI -0.03-0.01, P = 0.397) for isoflavone treatment and placebo, respectively. There was no association between plasma total homocysteine and ADMA. Changes from baseline in plasma ADMA and folate were negatively correlated (r = -0.18, P = 0.017). These results challenge the overall health effect of isoflavone supplementation in healthy postmenopausal women. PMID:16365066

  2. Gestational Vitamin B Deficiency Leads to Homocysteine-Associated Brain Apoptosis and Alters Neurobehavioral Development in Rats

    PubMed Central

    Blaise, Sébastien A.; Nédélec, Emmanuelle; Schroeder, Henri; Alberto, Jean-Marc; Bossenmeyer-Pourié, Carine; Guéant, Jean-Louis; Daval, Jean-Luc

    2007-01-01

    Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3 ± 3.7 μmol/L versus 6.8 ± 0.3 μmol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine. PMID:17255334

  3. Gestational vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats.

    PubMed

    Blaise, Sébastien A; Nédélec, Emmanuelle; Schroeder, Henri; Alberto, Jean-Marc; Bossenmeyer-Pourié, Carine; Guéant, Jean-Louis; Daval, Jean-Luc

    2007-02-01

    Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3+/-3.7 micromol/L versus 6.8+/-0.3 micromol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine.

  4. High-resolution structures of complexes of plant S-­adenosyl-l-homocysteine hydrolase (Lupinus luteus)

    PubMed Central

    Brzezinski, Krzysztof; Dauter, Zbigniew; Jaskolski, Mariusz

    2012-01-01

    S-Adenosyl-l-homocysteine hydrolase (SAHase) catalyzes the reversible breakdown of S-adenosyl-l-homocysteine (SAH) to adenosine and homocysteine. SAH is formed in methylation reactions that utilize S-adenosyl-l-methionine (SAM) as a methyl donor. By removing the SAH byproduct, SAHase serves as a major regulator of SAM-dependent biological methylation reactions. Here, the first crystal structure of SAHase of plant origin, that from the legume yellow lupin (LlSAHase), is presented. Structures have been determined at high resolution for three complexes of the enzyme: those with a reaction byproduct/substrate (adenosine), with its nonoxidizable analog (cordycepin) and with a product of inhibitor cleavage (adenine). In all three cases the enzyme has a closed conformation. A sodium cation is found near the active site, coordinated by residues from a conserved loop that hinges domain movement upon reactant binding. An insertion segment that is present in all plant SAHases is located near a substrate-pocket access channel and participates in its formation. In contrast to mammalian and bacterial SAHases, the channel is open when adenosine or cordycepin is bound and is closed in the adenine complex. In contrast to SAHases from other organisms, which are active as tetramers, the plant enzyme functions as a homodimer in solution. PMID:22349223

  5. Plasmatic higher levels of homocysteine in Non-alcoholic fatty liver disease (NAFLD)

    PubMed Central

    2013-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD. Methods Thirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies. Results The plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005). Conclusion Our results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17

  6. High Homocysteine and Blood Pressure Related to Poor Outcome of Acute Ischemia Stroke in Chinese Population

    PubMed Central

    Liu, Changjiang; Zhao, Liang; Zhou, Mo; Sun, Wenjie; Xu, Tan; Tong, Weijun

    2014-01-01

    Objectives To assess the association between plasma homocysteine (Hcy), blood pressure (BP) and poor outcome at hospital discharge among acute ischemic stroke patients, and if high Hcy increases the risk of poor outcome based on high BP status in a northern Chinese population. Methods Between June 1, 2009 and May 31, 2013, a total of 3695 acute ischemic stroke patients were recruited from three hospitals in northern Chinese cities. Demographic characteristics, lifestyle risk factors, medical history, and other clinical characteristics were recorded for all subjects. Poor outcome was defined as a discharge modified Rankin Scale (mRS) score ≥3 or death. The association between homocysteine concentration, admission blood pressure, and risk of poor outcome following acute ischemic stroke was analyzed by using multivariate non-conditional logistic regression models. Results Compared with those in the lowest quartile of Hcy concentration in a multivariate-adjusted model, those in the highest quartile of Hcy concentration had increased risk of poor outcome after acute ischemic stroke, (OR = 1.33, P<0.05). The dose-response relationship between Hcy concentration and risk of poor outcome was statistically significant (p-value for trend  = 0.027). High BP was significantly associated with poor outcome following acute ischemic stroke (adjusted OR = 1.44, 95%CI, 1.19–1.74). Compared with non-high BP with nhHcy, in a multivariate-adjusted model, the ORs (95% CI) of non-high BP with hHcy, high BP with nhHcy, and high BP with hHcy to poor outcome were 1.14 (0.85–1.53), 1.37 (1.03–1.84) and 1.70 (1.29–2.34), respectively. Conclusion The present study suggested that high plasma Hcy and blood pressure were independent risk factors for prognosis of acute ischemic stroke, and hHcy may further increase the risk of poor outcome among patients with high blood pressure. Additionally, the results indicate that high Hcy with high BP may cause increased susceptibility

  7. Homocysteine homeostasis in the rat is maintained by compensatory changes in cystathionine β-synthase, betaine-homocysteine methyltransferase, and phosphatidylethanolamine N-methyltransferase gene transcription occurring in response to maternal protein and folic acid intake during pregnancy and fat intake after weaning.

    PubMed

    Chmurzynska, Agata; Malinowska, Anna M

    2011-07-01

    The reactions of the methionine/homocysteine pathway are mediated by several enzymes, including phosphatidylethanolamine N-methyltransferase, cystathionine β-synthase, and betaine-homocysteine methyltransferase. Homocysteine homeostasis is regulated by these enzymes. We hypothesized here that the protein and folic acid content in the maternal diet affects methionine/homocysteine metabolism in the progeny. To test this hypothesis, pregnant rats were fed a diet with normal protein and normal folic acid levels (a modified casein-based AIN-93G diet), a protein-restricted and normal folic acid diet, a protein-restricted and folic acid-supplemented diet, or a normal protein and folic acid-supplemented diet. The progeny were fed either the modified AIN-93G diet or a high-fat lard-based diet. Progeny were analyzed for expression of the phosphatidylethanolamine N-methyltransferase, cystathionine β-synthase, and betaine-homocysteine methyltransferase genes in the liver and for serum homocysteine concentration. Interactions between prenatal and postnatal nutrition were also determined. The progeny of the dams fed the diets supplemented with folic acid showed decreased expression of all 3 genes (P < .001). An interaction effect between the protein and folic acid content in the maternal diet contributed to this down-regulation (P < .001), and the postweaning diet modified these effects. Serum homocysteine concentrations were approximately 15% higher in the male rats (P < .01), but neither prenatal nutrition nor the postweaning diet affected it significantly. We conclude that maternal diet during gestation has an important effect on the transcription level of these 3 genes, but changes in gene expression were not associated with significant changes in progeny homocysteine concentrations.

  8. Osmotic regulation of betaine homocysteine-S-methyltransferase expression in H4IIE rat hepatoma cells.

    PubMed

    Schäfer, Christine; Hoffmann, Lars; Heldt, Katrin; Lornejad-Schäfer, Mohammad Reza; Brauers, Gernot; Gehrmann, Thor; Garrow, Timothy A; Häussinger, Dieter; Mayatepek, Ertan; Schwahn, Bernd C; Schliess, Freimut

    2007-04-01

    Cell hydration changes critically affect liver metabolism and gene expression. In the course of gene expression studies using nylon cDNA-arrays we found that hyperosmolarity (405 mosmol/l) suppressed the betaine-homocysteine methyltransferase (Bhmt) mRNA expression in H4IIE rat hepatoma cells. This was confirmed by Northern blot and real-time quantitative RT-PCR analysis, which in addition unraveled a pronounced induction of Bhmt mRNA expression by hypoosmotic (205 mosmol/l) swelling. Osmotic regulation of Bhmt mRNA expression was largely paralleled at the levels of Bhmt protein and enzymatic activity. Like hyperosmotic NaCl, hyperosmotic raffinose but not hyperosmotic urea suppressed Bhmt mRNA expression, suggesting that cell shrinkage rather than increased ionic strength or hyperosmolarity per se is the trigger. Hypoosmolarity increased the expression of a reporter gene driven by the entire human BHMT promoter, whereas destabilization of BHMT mRNA was observed under hyperosmotic conditions. Osmosensitivity of Bhmt mRNA expression was impaired by inhibitors of tyrosine kinases and cyclic nucleotide-dependent kinases. The osmotic regulation of BHMT may be part of a cell volume-regulatory response and additionally lead to metabolic alterations that depend on the availability of betaine-derived methyl groups. PMID:17218476

  9. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway.

    PubMed

    Obeid, Rima

    2013-09-09

    Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available.

  10. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females.

    PubMed

    Green, T J; Houghton, L A; Donovan, U; Gibson, R S; O'Connor, D L

    1998-01-01

    The impact of oral contraceptive (OC) use, smoking, and alcohol drinking on biochemical indexes of folate and vitamin B-12 was investigated in 229 adolescents 14-20 years old recruited from advertisements in Ontario, Canada. Subjects completed a life-style questionnaire and a 3-day, weighed food record, followed by overnight fasting and the collection of blood samples. Of the 48 participants (21%) who were OC users, 30 had used the pill for more than 12 months. Only 37 adolescents (16%) smoked, but 94 (60%) had consumed alcohol in the month preceding the study. Median daily intake of folate and vitamin B-12 (including intake from supplements) was 215 mcg and 1.9 mcg, respectively. OC use, smoking, and alcohol consumption were not significantly associated with lower serum or red blood cell folate levels, after controlling for folate intake. Serum homocysteine levels were not correlated with smoking or OC use, but were 13% higher among alcohol drinkers than nondrinkers. Finally, although smoking and alcohol use were not associated with serum B-12 levels, OC use was linked with an estimated 33% lower serum B-12 level than was nonuse. These findings fail to validate concerns that OC use has a negative impact on the folate status of adolescent females, but suggest a need to improve the dietary folate intake of young women who smoke.

  11. Variability and determinants of total homocysteine concentrations in plasma in an elderly population.

    PubMed

    Clarke, R; Woodhouse, P; Ulvik, A; Frost, C; Sherliker, P; Refsum, H; Ueland, P M; Khaw, K T

    1998-01-01

    The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the within-person SD was 0.93 micromol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentrations were inversely related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35) concentrations. Median tHcy concentrations were approximately 1 micromol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetrahydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on single tHcy measurements may underestimate the magnitude of any risk associations with disease by 10-15%. PMID:9550566

  12. The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

    PubMed Central

    Škovierová, Henrieta; Vidomanová, Eva; Mahmood, Silvia; Sopková, Janka; Drgová, Anna; Červeňová, Tatiana; Halašová, Erika; Lehotský, Ján

    2016-01-01

    Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid derived in methionine metabolism. The increased level of Hcy in plasma, hyperhomocysteinemia, is considered to be an independent risk factor for cardio and cerebrovascular diseases. However, it is still not clear if Hcy is a marker or a causative agent of diseases. More and more research data suggest that Hcy is an important indicator for overall health status. This review represents the current understanding of molecular mechanism of Hcy metabolism and its link to hyperhomocysteinemia-related pathologies in humans. The aberrant Hcy metabolism could lead to the redox imbalance and oxidative stress resulting in elevated protein, nucleic acid and carbohydrate oxidation and lipoperoxidation, products known to be involved in cytotoxicity. Additionally, we examine the role of Hcy in thiolation of proteins, which results in their molecular and functional modifications. We also highlight the relationship between the imbalance in Hcy metabolism and pathogenesis of diseases, such as cardiovascular diseases, neurological and psychiatric disorders, chronic kidney disease, bone tissue damages, gastrointestinal disorders, cancer, and congenital defects. PMID:27775595

  13. Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer's Disease: Insights from Meta-Analyses.

    PubMed

    Shen, Liang; Ji, Hong-Fang

    2015-01-01

    The associations between homocysteine (Hcy), folic acid, and vitamin B12 and Alzheimer's disease (AD) have gained much interest, while remaining controversial. We aim to perform meta-analyses to evaluate comprehensively: i) Hcy, folic acid, and vitamin B12 levels in AD patients in comparison with controls; and ii) the association between Hcy, folic acid, and vitamin B12 levels and risk of AD. A literature search was performed using Medline and Scopus databases. A total of 68 studies were identified and included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analyses. First, AD patients may have higher level of Hcy, and lower levels of folate and vitamin B12 in plasma than controls. Further age-subgroup analysis showed no age effect for Hcy levels in plasma between AD patients and matched controls, while the differences in folate and vitamin B12 levels further enlarged with increased age. Second, data suggests that high Hcy and low folate levels may correlate with increased risk of AD occurrence. The comprehensive meta-analyses not only confirmed higher Hcy, lower folic acid, and vitamin B12 levels in AD patients than controls, but also implicated that high Hcy and low folic acid levels may be risk factors of AD. Further studies are encouraged to elucidate mechanisms linking these conditions.

  14. Total serum homocysteine as an indicator of vitamin B12 and folate status

    SciTech Connect

    Chu, R.C.; Hall, C.A.

    1988-10-01

    Presented is a modification of an assay for total serum homocysteine (Hcy) in which the Hcy plus radioactive adenosine is converted enzymatically to labeled S-adenosylhomocysteine (AdoHcy). The modifications included a commerical source for the AdoHcy hydrolase, adenosine labeled with either /sup 14/C or /sup 3/H, and separation of the AdoHcy by thin layer chromatography. The assay was sensitive to 25 pmol. Hcy levels in sera from 18 controls ranged from 6.9 to 12.1 mumol/L with a mean of 9.1 and a SD of 1.5 mumol/L. The total serum Hcy was increased in vitamin B12 and folate deficiency. The level was high in congenital defects of vitamin B12 metabolism, blocking the methylation of Hcy regardless of the serum vitamin B12 levels, but was normal in the absence of tissue deficiency even if the serum vitamin B12 levels were low. The procedure has been found practical in two years of use and requires only 0.1 mL of serum.

  15. Metal active site elasticity linked to activation of homocysteine in methionine synthases

    SciTech Connect

    Koutmos, Markos; Pejchal, Robert; Bomer, Theresa M.; Matthews, Rowena G.; Smith, Janet L.; Ludwig, Martha L.

    2008-04-02

    Enzymes possessing catalytic zinc centers perform a variety of fundamental processes in nature, including methyl transfer to thiols. Cobalamin-independent (MetE) and cobalamin-dependent (MetH) methionine synthases are two such enzyme families. Although they perform the same net reaction, transfer of a methyl group from methyltetrahydrofolate to homocysteine (Hcy) to form methionine, they display markedly different catalytic strategies, modular organization, and active site zinc centers. Here we report crystal structures of zinc-replete MetE and MetH, both in the presence and absence of Hcy. Structural investigation of the catalytic zinc sites of these two methyltransferases reveals an unexpected inversion of zinc geometry upon binding of Hcy and displacement of an endogenous ligand in both enzymes. In both cases a significant movement of the zinc relative to the protein scaffold accompanies inversion. These structures provide new information on the activation of thiols by zinc-containing enzymes and have led us to propose a paradigm for the mechanism of action of the catalytic zinc sites in these and related methyltransferases. Specifically, zinc is mobile in the active sites of MetE and MetH, and its dynamic nature helps facilitate the active site conformational changes necessary for thiol activation and methyl transfer.

  16. Homocysteine in embryo culture media as a predictor of pregnancy outcome in assisted reproductive technology.

    PubMed

    Boyama, Burcu Aydin; Cepni, Ismail; Imamoglu, Metehan; Oncul, Mahmut; Tuten, Abdullah; Yuksel, Mehmet Aytac; Kervancioglu, Mehmet Ertan; Kaleli, Semih; Ocal, Pelin

    2016-01-01

    The aim of this study was to determine whether homocysteine (hcy) concentrations in embryo culture media correlate with pregnancy outcome in assisted reproductive technology (ART) cycles. Forty patients who underwent single embryo transfer at the infertility clinic of a tertiary care center were recruited for this case-control study. Spent embryo culture media from all patients were collected after single embryo transfer on day 3 (n = 40). Hcy concentrations in embryo culture media were analyzed by enzyme cycling method. Patients were grouped according to the diagnosis of a clinical pregnancy. Sixteen patients were pregnant while 24 patients failed to achieve conception. Mean Hcy levels in the culture media were significantly different between the groups (p < 0.003), as 4.58 ± 1.31 μmol/l in the non-pregnant group and 3.37 ± 0.92 μmol/l in the pregnant group. Receiver operator curve analysis for determining the diagnostic potential of Hcy for pregnancy revealed an area under the curve of 0.792 (confidence interval: 0.65-0.94; p < 0.05). A cut-off value of 3.53 μmol/l was determined with a sensitivity of 83.3%, and a specificity of 68.8%. Lower hcy levels were associated with a better chance of pregnancy and better embryo grades. Hcy may be introduced as an individual metabolomic profiling marker for embryos.

  17. Variability and determinants of total homocysteine concentrations in plasma in an elderly population.

    PubMed

    Clarke, R; Woodhouse, P; Ulvik, A; Frost, C; Sherliker, P; Refsum, H; Ueland, P M; Khaw, K T

    1998-01-01

    The variability of plasma total homocysteine (tHcy) was examined in 96 individuals over a 1-yr period. Blood tHcy concentrations varied from 7.1 micromol/L in the bottom quintile to 14.5 micromol/L in the top quintile. The mean tHcy was 10.4 micromol/L, the between-person SD was 2.5 micromol/L, and the within-person SD was 0.93 micromol/L. There was little seasonal variation, and the reliability coefficient was 0.88. Mean tHcy concentrations were inversely related to mean plasma folate (r = -0.36) and vitamin B12 (r = -0.35) concentrations. Median tHcy concentrations were approximately 1 micromol/L higher in men than in women and in older (70 to 74 years) than in younger (65 to 69 years) individuals and higher in those with the TT and CT genotypes for the methylenetetrahydrofolate reductase polymorphism than in those with the CC genotype (10.7 and 10.6 vs 9.6 micromol/L). Epidemiological studies based on single tHcy measurements may underestimate the magnitude of any risk associations with disease by 10-15%.

  18. Zinc and homocysteine levels in polycystic ovarian syndrome patients with insulin resistance.

    PubMed

    Guler, Ismail; Himmetoglu, Ozdemir; Turp, Ahmet; Erdem, Ahmet; Erdem, Mehmet; Onan, M Anıl; Taskiran, Cagatay; Taslipinar, Mine Yavuz; Guner, Haldun

    2014-06-01

    In this study, our objective was to evaluating the value of serum zinc levels as an etiologic and prognostic marker in patients with polycystic ovarian syndrome. We conducted a prospective study, including 53 women with polycystic ovarian syndrome and 33 healthy controls. We compared serum zinc levels, as well as clinical and metabolic features, of the cases. We also compared serum zinc levels between patients with polycystic ovarian syndrome with insulin resistance. Mean zinc levels were found to be significantly lower in patients with polycystic ovarian syndrome than healthy controls. Multiple logistic regression analysis of significant metabolic variables between polycystic ovarian syndrome and control groups (serum zinc level, body mass index, the ratio of triglyceride/high-density lipoprotein cholesterol, and homocysteine) revealed that zinc level was the most significant variable to predict polycystic ovarian syndrome. Mean serum zinc levels tended to be lower in patients with polycystic ovarian syndrome with impaired glucose tolerance than patients with normal glucose tolerance, but the difference was not statistically significant. In conclusion, zinc deficiency may play a role in the pathogenesis of polycystic ovarian syndrome and may be related with its long-term metabolic complications.

  19. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level

    PubMed Central

    Eskandari, Zahra; Sadrkhanlou, Rajab-Ali; Nejati, Vahid; Tizro, Gholamreza

    2016-01-01

    Background: It is reasonable to think that some biochemical characteristics of follicular fluid (FF) surrounding the oocyte may play a critical role in determining the quality of oocyte and the subsequent potential needed to achieve fertilization and embryo development. Objective: This study was carried out to evaluate the levels of FF homocysteine (Hcy) in IVF candidate polycystic ovary syndrome (PCOS) women and any relationships with FF glucose and estradiol (E2) levels. Materials and Methods: In this case control study which was performed in Dr. Tizro Day Care and IVF Center 70 infertile patients were enrolled in two groups: comprising 35 PCOS and 35 non PCOS women. Long protocol was performed for all patients. FF Hcy, glucose and E2 levels were analyzed at the time of oocyte retrieval. Results: It was observed that FF Hcy level was significantly higher in PCOS patients compared with non PCOSs (p<0.01). Observations demonstrated that in PCOS group, the Hcy level increased independent to E2, glucose levels, BMI and age, while the PCOS group showed significantly higher BMI compared with non-PCOS group (p=0.03). However, no significant differences were revealed between groups for FF glucose and E2 levels. Conclusion: Present data showed that although FF glucose and E2 levels were constant in PCOS and non PCOS patients, but the FF Hcy levels in PCOS were significantly increased (p=0.01). PMID:27679823

  20. Evaluation of homocysteine levels in individuals having nonsyndromic cleft lip with or without palate

    PubMed Central

    Abdulla, Riaz; Tellis, Rouchelle Charmaine; Athikari, Roshan; Kudkuli, Jagadish

    2016-01-01

    Context: Nonsyndromic cleft lip with or without palate (NSCL ± P) is a genetic predisposition involving defects in shape and makeup of the lip and palate. Elevation of homocysteine (Hcy) levels is seen in medical complications such as developmental anomalies causing neural tube defects, congenital vascular diseases, neurodegenerative and psychiatric conditions. Evaluation of serum Hcy levels forms an important feature to look further into molecular aspects. Aims: The aim of this study was to evaluate the Hcy levels in NSCL ± P cases by comparing with control cases having no orofacial deformities. Settings and Design: This study was performed with a biochemical assay in a research laboratory. Materials and Methods: A cross-sectional prevalence study was done to compare the concentrations of Hcy between 25 NSCL ± P patients and 15 healthy controls. Blood samples were collected from both the patients and controls and assessed for serum Hcy level using competent chemiluminescent immunoassay technique. Statistical Analysis Used: Student's t-test was used for statistical analysis. Results: The average Hcy concentration was 9.5 μmol/L in control group. There was an increase in Hcy concentration among the NSCL ± P cases with an average value of 18.4 μmol/L. The results were found to be statistically significant using Student's t-test. Conclusions: The results of this study indicate that Hcy concentration has a significant elevation in NSCL ± P patients when compared with that of control cases. PMID:27721602

  1. Homocysteine, circulating vascular cell adhesion molecule and carotid atherosclerosis in postmenopausal vegetarian women and omnivores.

    PubMed

    Su, Ta-Chen; Jeng, Jiann-Shing; Wang, Jung-Der; Torng, Pao-Ling; Chang, Sue-Joan; Chen, Chen-Fang; Liau, Chiau-Suong

    2006-02-01

    Since the adoption of vegetarian diets as a healthy lifestyle has become popular, the cardiovascular effects of long-term vegetarianism need to be explored. The present study aimed to compare the presence and severity of carotid atherosclerosis (CA), and the blood levels of Vitamin B12, homocysteine (Hcy) and soluble vascular cell adhesion molecule-1 (sVCAM-1) between 57 healthy postmenopausal vegetarians and 61 age-matched omnivores. Carotid atherosclerosis, as measured by ultrasound, was found to be of no significant difference between the two groups. Yet, fasting blood glucose, low-density lipoprotein cholesterol, and Vitamin B12 were significantly lower, while Hcy and sVCAM-1 were higher in the vegetarians as comparing with the omnivores. Multivariate regression analysis showed that the level of Vitamin B12 was negatively associated with the level of Hcy. Vegetarianism itself and Hcy level were significantly associated with sVCAM-1 level in univariate analysis; however, after adjustment for covariates, we identified age but not vegetarianism as the determinant of sVCAM-1 level. Multiple linear regression analysis identified age and systolic blood pressure, but not vegetarianism, as determinants of common carotid artery IMT. In conclusion, there was no significant difference in CA between apparently healthy postmenopausal vegetarians and omnivores. The findings of elevated Hcy in vegetarians indicate the importance of prevention of Vitamin B12 deficiency.

  2. Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

    PubMed Central

    Zhao, Yaqian; Huang, Guowei; Chen, Shuang; Gou, Yun; Dong, Zhiping; Zhang, Xumei

    2016-01-01

    Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level. PMID:27455253

  3. The relationship between copper, homocysteine and early vascular disease in lean women with polycystic ovary syndrome.

    PubMed

    Celik, Cem; Bastu, Ercan; Abali, Remzi; Alpsoy, Seref; Guzel, Eda Celik; Aydemir, Birsen; Yeh, John

    2013-05-01

    This study investigates copper (Cu) levels and vascular dysfunction in lean women with polycystic ovary syndrome (PCOS). 44 subjects with PCOS, diagnosed according to Rotterdam criteria, and 42 healthy subjects matched for body mass index and age. Comparison of serum Cu, homocysteine, carotid intima-media thickness (CIMT), brachial artery flow mediated dilation (FMD) was carried out between PCOS patients and the control group. Clinical study was done in Namik Kemal University School of Medicine. The CIMT and concentration of Cu in PCOS patients was significantly higher than the healthy controls. FMD levels in PCOS patients were significantly lower than those in controls. In PCOS patients, CIMT was correlated with estrogen and Cu levels. However, FMD was correlated with age and Cu levels. Among these contributing factors, Cu levels were correlated with a change in CIMT and FMD. CIMT and FMD in PCOS patients were related to Cu levels as well as several cardiovascular risk factors. Thus, increased Cu levels may be responsible for the increased risk of early vascular disease in women with PCOS.

  4. Chiral effects in amino acid adsorption on Au(111): A comparison of cysteine, homocysteine and methionine

    NASA Astrophysics Data System (ADS)

    Popa, Tatiana; Ting, Elvis C. M.; Paci, Irina

    2014-11-01

    A combined classical/quantum methodology is used to examine chiral effects upon adsorption of three sulfur-containing amino acids on the Au(111) surface: cysteine, homocysteine and methionine. Parallel tempering Monte Carlo simulations were employed to broadly examine the configurational space of monomers, dimers and trimers of the molecules on the gold surface. Density functional theory was applied to promising structural targets in order to incorporate higher order electronic structure effects in a study of relative stabilities of the various molecular states upon adsorption. As the precursors of chiral structure formation, like and unlike dimers were investigated at some length, with consideration given to the mode of sorption (chemisorption of physisorption) and the existence of zwitterionic states. We found that neutral (non-zwitterionic) molecules adsorbed weakly on the highly-coordinated Au(111) surfaces. As a consequence, pair configurations in dimers were insufficiently constrained to lead to differential stabilities of homochiral and heterochiral dimers. Whereas neutral molecule interactions were non-discriminating, strong chiral discrimination was found in zwitterionic amino acids. The zwitterionic forms of the larger molecules equilibrated closer to the surface, and the stronger molecule-molecule and molecule-surface interactions were such that homochiral dimers were stable whereas heterochiral dimers were not.

  5. Whey protein supplementation increases methionine intake but not homocysteine plasma concentration in rats.

    PubMed

    Deminice, Rafael; Comparotto, Hugo; Jordao, Alceu Afonso

    2015-01-01

    The purpose of this study was to examine the effects of whey protein supplementation on homocysteine (Hcy) metabolism and liver oxidative stress in rats. Twenty-four rats were divided into 3 groups (n = 8) to receive one of the following diets for 4 weeks: control diet (C), whey protein-composed diet (WP), and whey protein-supplemented diet (WPS). The C and WP diets consisted of AIN-93 with 20% casein and 20% whey protein as protein source, respectively. WPS was AIN-93 (20% casein) supplemented by the addition of 20% (w/w) whey protein. Four weeks of ingesting a WPS diet resulted in a significantly higher (P < 0.05) total protein and methionine intakes. Although a significant increase (P < 0.05) in the hepatic S-adenosylmethionine and S-adenosylhomocysteine levels occurred in WPS group compared with C and WP, no significant change was observed in plasma Hcy concentration between groups. Furthermore, the levels of lipid hydroperoxides and advanced oxidation protein products, known liver oxidative stress markers, were increased in the WPS group compared with the C group. In addition, no change in glutathione liver concentration was observed in any of the groups studied. In conclusion, whey protein supplementation increases methionine intake substantially; however, it does not change plasma Hcy concentrations. On the other hand, increased hepatic oxidative stress markers were observed in whey protein supplemented rats were probably due to high protein intake.

  6. PCOS women show significantly higher homocysteine level, independent to glucose and E2 level

    PubMed Central

    Eskandari, Zahra; Sadrkhanlou, Rajab-Ali; Nejati, Vahid; Tizro, Gholamreza

    2016-01-01

    Background: It is reasonable to think that some biochemical characteristics of follicular fluid (FF) surrounding the oocyte may play a critical role in determining the quality of oocyte and the subsequent potential needed to achieve fertilization and embryo development. Objective: This study was carried out to evaluate the levels of FF homocysteine (Hcy) in IVF candidate polycystic ovary syndrome (PCOS) women and any relationships with FF glucose and estradiol (E2) levels. Materials and Methods: In this case control study which was performed in Dr. Tizro Day Care and IVF Center 70 infertile patients were enrolled in two groups: comprising 35 PCOS and 35 non PCOS women. Long protocol was performed for all patients. FF Hcy, glucose and E2 levels were analyzed at the time of oocyte retrieval. Results: It was observed that FF Hcy level was significantly higher in PCOS patients compared with non PCOSs (p<0.01). Observations demonstrated that in PCOS group, the Hcy level increased independent to E2, glucose levels, BMI and age, while the PCOS group showed significantly higher BMI compared with non-PCOS group (p=0.03). However, no significant differences were revealed between groups for FF glucose and E2 levels. Conclusion: Present data showed that although FF glucose and E2 levels were constant in PCOS and non PCOS patients, but the FF Hcy levels in PCOS were significantly increased (p=0.01).

  7. Homocysteine levels in patients with primary and secondary Raynaud's phenomenon. Its association with microangiopathy severity.

    PubMed

    Vayá, Amparo; Sánchez, Fernando; Todolí, Jose; Calvo, Javier; Alis, Rafael; Collado, Susana; Ricart, Jose M

    2014-01-01

    The association between hyperhomocysteinemia (HHcy) and Raynaud's phenomenon (RP) remains a matter of debate. In 18 primary RP, 23 secondary RP and 41 controls, we investigated homocysteine (Hcy) levels along with biochemical and inflammatory parameters. The Hcy levels in both primary and secondary RP were elevated when compared with controls (p < 0.05 and p < 0.01, respectively). As age was higher in secondary RP as compared with controls (p < 0.01), both primary and secondary RP were age-matched with a corresponding control group, and with Hcy maintaining its statistical significance (p < 0.05). No differences in creatinine, B12 vitamin or folic acid were observed between groups (p > 0.05), or in the prevalence of cardiovascular risk factors (p > 0.05). When patients were classified according to presence or absence of digital ulcers, as a sign of microangiopathy severity, the former showed higher Hcy levels than the latter (p = 0.035). Our results indicate that both primary and secondary RP patients show a mild increase in Hcy levels, which is not related to age, vitamin deficiencies or impaired renal function, but is related to microangiopathy severity. Therefore the association of HHcy and RP suggest that Hcy may contribute to endothelial dysregulation, which characterizes this disease. Specific studies should be designed to elucidate the pathogenesis of HHcy in these patients.

  8. Distribution and determinants of plasma homocysteine levels in rural Chinese twins across the lifespan.

    PubMed

    Ji, Yuelong; Kong, Xiangyi; Wang, Guoying; Hong, Xiumei; Xu, Xin; Chen, Zhu; Bartell, Tami; Xu, Xiping; Tang, Genfu; Hou, Fanfan; Huo, Yong; Wang, Xiaobin; Wang, Binyan

    2014-12-01

    Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10-66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome. PMID:25529062

  9. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease.

    PubMed

    Debreceni, Balazs; Debreceni, Laszlo

    2014-06-01

    Cardiovascular disease (CVD) is the leading cause of mortality in the Western world. The effort of research should aim at the primary prevention of CVD. Alongside statin therapy, which is maintained to be an effective method of CVD prevention, there are alternative methods such as vitamin B substitution therapy with folic acid (FA), and vitamins B12 and B6 . B-vitamins may inhibit atherogenesis by decreasing the plasma level of homocysteine (Hcy)-a suspected etiological factor for atherosclerosis-and by other mechanisms, primarily through their antioxidant properties. Although Hcy-lowering vitamin trials have failed to demonstrate beneficial effects of B-vitamins in the prevention of CVD, a meta-analysis and stratification of a number of large vitamin trials have suggested their effectiveness in cardiovascular prevention (CVP) in some aspects. Furthermore, interpretation of the results from these large vitamin trials has been troubled by statin/aspirin therapy, which was applied along with the vitamin substitution, and FA fortification, both of which obscured the separate effects of vitamins in CVP. Recent research results have accentuated a new approach to vitamin therapy for CVP. Studies undertaken with the aim of primary prevention have shown that vitamin B substitution may be effective in the primary prevention of CVD and may also be an option in the secondary prevention of disease if statin therapy is accompanied by serious adverse effects. Further investigations are needed to determine the validity of vitamin substitution therapy before its introduction in the protocol of CVD prevention.

  10. Vitamin B-6 Supplementation Could Mediate Antioxidant Capacity by Reducing Plasma Homocysteine Concentration in Patients with Hepatocellular Carcinoma after Tumor Resection.

    PubMed

    Cheng, Shao-Bin; Lin, Ping-Ting; Liu, Hsiao-Tien; Peng, Yi-Shan; Huang, Shih-Chien; Huang, Yi-Chia

    2016-01-01

    Vitamin B-6 has a strong antioxidative effect. It would be useful to determine whether vitamin B-6 supplementation had effects on antioxidant capacities in patients with hepatocellular carcinoma (HCC) who had recently undergone tumor resection. Thirty-three HCC patients were randomly assigned to either the placebo (n = 16) group or the vitamin B-6 50 mg/d (n = 17) group for 12 weeks. Plasma pyridoxal 5'-phosphate, homocysteine, indicators of oxidative stress, and antioxidant capacities were measured. Plasma homocysteine in the vitamin B-6 group was significantly decreased at week 12, while the level of trolox equivalent antioxidant capacity (TEAC) was significantly increased at the end of the intervention period. Vitamin B-6 supplementation had a significant reducing effect on the change of plasma homocysteine (β = -2.4, p = 0.02) but not on the change of TEAC level after adjusting for potential confounders. The change of plasma homocysteine was significantly associated with the change of TEAC after adjusting for potential confounders (β = -162.0, p = 0.03). Vitamin B-6 supplementation seemed to mediate antioxidant capacity via reducing plasma homocysteine rather than having a direct antioxidative effect in HCC patients who had recently undergone tumor resection. The clinical trial number is NCT01964001, ClinicalTrials.gov. PMID:27051670

  11. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2R, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell...

  12. High intake of folic acid or complex of B vitamins provides anti-Parkinsonism effect: no role for serum level of homocysteine.

    PubMed

    Haghdoost-Yazdi, Hashem; Fraidouni, Negin; Faraji, Ayda; Jahanihashemi, Hassan; Sarookhani, Mohammad

    2012-08-01

    Several lines of evidence show that homocysteine (Hcy) levels are increased in blood and CSF of patients with Parkinson's disease. B vitamins are necessary for Hcy metabolism and their deficiencies cause hyperhomocysteinemia and neurodegeneration. In present study, effect of B vitamin supplementation on the severity of 6-hydroxydopamine (6-OHDA)-induced Parkinsonism was investigated. Rats were nourished with B vitamin supplements from 1 month before of stereotaxic injection of 6-OHDA to the end of experiments. Total serum Hcy was measured at the end of experiments to identify its association with Parkinsonism. Both rotational and rotarod tests revealed that supplementation of folic acid, in a dose dependent manner, attenuates severity of Parkinsonism. Supplement of B complex also had beneficial effect and improved motor performance in rotarod test and decreased biased swings in elevated body swing test but had no effect on the apomorphine-induced rotational behavior. Supplement of B(6) attenuated rotational behavior but had no effect on the rotarod performance and swinging behavior. Supplement of B(12) or combination of folic acid with B(6) and B(12) had no effect on the behavioral symptoms of Parkinsonism. Except one group, the levels of Hcy in other vitamin B treated groups were near to that in control group. Surprisingly, Hcy in group of rats that received high intake of folic acid was significantly higher than that in control group. Our results indicate that high intake of folic acid or B complex provides anti-Parkinsonism effect but it is not mediated by lowering plasma Hcy.

  13. A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: A meta-analysis.

    PubMed

    Dawson, Samantha Loren; Bowe, Steven John; Crowe, Timothy Charles

    2016-06-01

    The aim of the study was to assess whether omega-3 polyunsaturated fatty acid supplementation alone or in combination with folic acid and B-group vitamins is effective in lowering homocysteine. The Medline Ovid, Embase and Cochrane databases were searched for randomized-controlled trial studies that intervened with omega-3 supplementation (with or without folic acid) and measured changes in homocysteine concentration. Studies were pooled using a random effects model for meta-analysis. Three different models were analyzed: all trials combined, omega-3 polyunsaturated fatty acid trials, and omega-3 polyunsaturated fatty acids with folic acid and B-group vitamin trials. Nineteen studies were included, consisting of 3267 participants completing 21 trials. Studies were heterogeneous; varying by dose, duration and participant health conditions. Across all trials, omega-3 supplementation was effective in lowering homocysteine by an average of 1.18μmol/L (95%CI: (-1.89, -0.48), P=.001). The average homocysteine-lowering effect was greater when omega-3 supplementation was combined with folic acid and B-group vitamins (-1.37μmol/L, 95%CI: (-2.38, -0.36), P<.01) compared to omega-3 supplementation alone (-1.09μmol/L 95%CI: (-2.04, -0.13), P=.03). Omega-3 polyunsaturated fatty acid supplementation was associated with a modest reduction in homocysteine. For the purposes of reducing homocysteine, a combination of omega-3s (0.2-6g/day), folic acid (150 - 2500μg/day) and vitamins B6 and B12 may be more effective than omega-3 supplementation alone.

  14. A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: A meta-analysis.

    PubMed

    Dawson, Samantha Loren; Bowe, Steven John; Crowe, Timothy Charles

    2016-06-01

    The aim of the study was to assess whether omega-3 polyunsaturated fatty acid supplementation alone or in combination with folic acid and B-group vitamins is effective in lowering homocysteine. The Medline Ovid, Embase and Cochrane databases were searched for randomized-controlled trial studies that intervened with omega-3 supplementation (with or without folic acid) and measured changes in homocysteine concentration. Studies were pooled using a random effects model for meta-analysis. Three different models were analyzed: all trials combined, omega-3 polyunsaturated fatty acid trials, and omega-3 polyunsaturated fatty acids with folic acid and B-group vitamin trials. Nineteen studies were included, consisting of 3267 participants completing 21 trials. Studies were heterogeneous; varying by dose, duration and participant health conditions. Across all trials, omega-3 supplementation was effective in lowering homocysteine by an average of 1.18μmol/L (95%CI: (-1.89, -0.48), P=.001). The average homocysteine-lowering effect was greater when omega-3 supplementation was combined with folic acid and B-group vitamins (-1.37μmol/L, 95%CI: (-2.38, -0.36), P<.01) compared to omega-3 supplementation alone (-1.09μmol/L 95%CI: (-2.04, -0.13), P=.03). Omega-3 polyunsaturated fatty acid supplementation was associated with a modest reduction in homocysteine. For the purposes of reducing homocysteine, a combination of omega-3s (0.2-6g/day), folic acid (150 - 2500μg/day) and vitamins B6 and B12 may be more effective than omega-3 supplementation alone. PMID:27188895

  15. Highly enhanced electrochemiluminescent strategy for tumor biomarkers detection with in situ generation of L-homocysteine for signal amplification.

    PubMed

    Wang, Haijun; Chai, Yaqin; Yuan, Ruo; Cao, Yaling; Bai, Lijuan

    2014-03-01

    In this work, an ultrasensitive peroxydisulfate electrochemiluminescence (ECL) immunosensor using in situ generation of L-homocysteine (L-Hcys) for signal amplification was successfully constructed for detection of carcinoembryonic antigen (CEA). In the reaction of biological methylation, S-adenosyl-L-homocysteine hydrolase (SAHH) catalyzed the reversible hydrolysis of S-adenosyl-L-homocysteine (SAH) to produce L-Hcys, which was inducted into ECL system to construct the immunosensor for signal amplification in this work. Simultaneously, Gold and palladium nanoparticles functionalized multi-walled carbon nanotubes (Au-PdNPs@MWCNTs) were prepared, which were introduced to immobilize the secondary antibody (Ab2) and SAHH with high loading amount and good biological activity due to their improved surface area and excellent biocompatibility. Then the proposed ECL immunosensor was developed by a sandwich-type format using Au-PdNPs@MWCNTs-SAHH-Ab2 as tracer and graphene together with AuNPs as substrate. Besides the enhancement of Au-PdNPs, the enzymatic catalysis reaction also amplified the ECL signal dramatically, which was achieved by efficient catalysis of the SAHH towards the hydrolysis of SAH to generate improved amount of L-Hcys in situ. Furthermore, due to the special interaction between Au-PdNPs and -SH or -NH2 in L-Hcys, L-Hcys would gradually accumulate on the surface of the immunosensor, which greatly enhanced the concentration of L-Hcys on the immunosensor surface and further improved the ECL intensity. With the amplification factors above, a wide linear ranged from 0.1 pg mL(-1) to 80 ng mL(-1) was acquired with a relatively low detection limit of 33 fg mL(-1) for CEA.

  16. Evolutionary Analyses and Natural Selection of Betaine-Homocysteine S-Methyltransferase (BHMT) and BHMT2 Genes

    PubMed Central

    Ganu, Radhika S.; Ishida, Yasuko; Koutmos, Markos; Kolokotronis, Sergios-Orestis; Roca, Alfred L.; Garrow, Timothy A.; Schook, Lawrence B.

    2015-01-01

    Betaine-homocysteine S-methyltransferase (BHMT) and BHMT2 convert homocysteine to methionine using betaine and S-methylmethionine, respectively, as methyl donor substrates. Increased levels of homocysteine in blood are associated with cardiovascular disease. Given their role in human health and nutrition, we identified BHMT and BHMT2 genes and proteins from 38 species of deuterostomes including human and non-human primates. We aligned the genes to look for signatures of selection, to infer evolutionary rates and events across lineages, and to identify the evolutionary timing of a gene duplication event that gave rise to two genes, BHMT and BHMT2. We found that BHMT was present in the genomes of the sea urchin, amphibians, reptiles, birds and mammals; BHMT2 was present only across mammals. BHMT and BHMT2 were present in tandem in the genomes of all monotreme, marsupial and placental species examined. Evolutionary rates were accelerated for BHMT2 relative to BHMT. Selective pressure varied across lineages, with the highest dN/dS ratios for BHMT and BHMT2 occurring immediately following the gene duplication event, as determined using GA Branch analysis. Nine codons were found to display signatures suggestive of positive selection; these contribute to the enzymatic or oligomerization domains, suggesting involvement in enzyme function. Gene duplication likely occurred after the divergence of mammals from other vertebrates but prior to the divergence of extant mammalian subclasses, followed by two deletions in BHMT2 that affect oligomerization and methyl donor specificity. The faster evolutionary rate of BHMT2 overall suggests that selective constraints were reduced relative to BHMT. The dN/dS ratios in both BHMT and BHMT2 was highest following the gene duplication, suggesting that purifying selection played a lesser role as the two paralogs diverged in function. PMID:26213999

  17. Effect of excess methionine and methionine hydroxy analogue on growth performance and plasma homocysteine of growing Pekin ducks.

    PubMed

    Xie, M; Hou, S S; Huang, W; Fan, H P

    2007-09-01

    One experiment was conducted to study the effect of excess dl-methionine (DLM) and dl-2-hydroxy-4-methylthiobutanoic acid free acid (dl-HMB-FA) on duck growth. One-day-old male white Pekin ducklings were fed common starter diets from hatch to 21 d of age and then fed the experimental diets from 21 to 42 d of age. Three hundred twenty 21-d-old birds were allotted to 40 raised wire-floor pens with 8 birds per pen according to similar pen weight. There were 5 dietary treatments that included a methionine-adequate control diet and control diets supplemented with 2 levels of dry DLM (1 or 2%) or 2 equimolar levels of liquid dl-HMB-FA (1.13 or 2.26%). Each dietary treatment was replicated 8 times. At 42 d of age, weight gain, feed intake, and gain/feed were measured and plasma was collected to analyze homocysteine. Compared with ducks fed control diets, excess DLM or dl-HMB-FA supplementation reduced weight gain and feed intake of birds significantly. However, on the equimolar basis, at 1 or 2% supplemental methionine activity, dl-HMB-FA was less growth-depressing than DLM. According to the growth response to excess methionine, the tolerable upper limit of dietary methionine for growing ducks may be less than 1.38% when the methionine level of the control diet (0.38%) was considered. On the other hand, plasma homocysteine was elevated markedly when 2% DLM or 2.26% dl-HMB-FA was added to control diets, but plasma homocysteine of ducks fed 2.26% dl-HMB-FA supplemented diets was lower significantly than birds fed equimolar DLM-supplemented diets, which indicated the toxicity of excess methionine sources and less toxicity of dl-HMB-FA relative to DLM.

  18. A flavone-based turn-on fluorescent probe for intracellular cysteine/homocysteine sensing with high selectivity.

    PubMed

    Zhang, Jian; Lv, Yanlin; Zhang, Wei; Ding, Hui; Liu, Rongji; Zhao, Yongsheng; Zhang, Guangjin; Tian, Zhiyuan

    2016-01-01

    A new type of flavone-based fluorescent probe (DMAF) capable of cysteine (Cys)/homocysteine (Hcy) sensing with high selectivity over other amino acids was developed. Such type of probe undergoes Cys/Hcy-mediated cyclization reaction with the involvement of its aldehyde group, which suppresses of the photoinduced electron transfer (PET) process of the probe molecule and consequently leads to the enhancement of fluorescence emission upon excitation using visible light. The formation of product of the Cys/Hcy-mediated cyclization reaction was confirmed and the preliminary fluorescence imaging experiments revealed the biocompatibility of the as-prepared probe and validated its practicability for intracellular Cys/Hcy sensing.

  19. A flavone-based turn-on fluorescent probe for intracellular cysteine/homocysteine sensing with high selectivity.

    PubMed

    Zhang, Jian; Lv, Yanlin; Zhang, Wei; Ding, Hui; Liu, Rongji; Zhao, Yongsheng; Zhang, Guangjin; Tian, Zhiyuan

    2016-01-01

    A new type of flavone-based fluorescent probe (DMAF) capable of cysteine (Cys)/homocysteine (Hcy) sensing with high selectivity over other amino acids was developed. Such type of probe undergoes Cys/Hcy-mediated cyclization reaction with the involvement of its aldehyde group, which suppresses of the photoinduced electron transfer (PET) process of the probe molecule and consequently leads to the enhancement of fluorescence emission upon excitation using visible light. The formation of product of the Cys/Hcy-mediated cyclization reaction was confirmed and the preliminary fluorescence imaging experiments revealed the biocompatibility of the as-prepared probe and validated its practicability for intracellular Cys/Hcy sensing. PMID:26695232

  20. Secondary palatal closure in rats in association with relative maternofetal levels of folic acid, vitamin B12, and homocysteine.

    PubMed

    Weingärtner, Jens; Maile, Sergei; Proff, Peter; Reicheneder, Claudia; Bienengräber, Volker; Fanghänel, Jochen; Gedrange, Tomas

    2007-01-01

    Animal experiments are used in embryological and teratological studies of matters relevant to humans. In gravid rats, a decrease in the levels of folic acid and vitamin B12 was observed in maternal blood and in amniotic fluid. At the time of secondary palatal closure (14th day of pregnancy), the folic acid level of the amniotic fluid was 73% lower than that of the maternal blood. A drop in vitamin B12 in conjunction with an increase in amniotic homocysteine levels is seen as a risk factor for malformation of the palate. The understanding of causes of cleft generation could lead to a prophylactic treatment approach.

  1. Effects of folic acid supplementation on serum homocysteine and lipoprotein (a) levels during pregnancy

    PubMed Central

    Hekmati Azar Mehrabani, Zohreh; Ghorbanihaghjo, Amir; Sayyah Melli, Manizheh; Hamzeh-Mivehroud, Maryam; Fathi Maroufi, Nazila; Bargahi, Nasrin; Bannazadeh Amirkhiz, Maryam; Rashtchizadeh, Nadereh

    2015-01-01

    Introduction:There are many ideas concerning the etiology and pathogenesis of preeclampsia including endothelial dysfunction, inflammation and angiogenesis. Elevated levels of total homocysteine (Hcy) and lipoprotein (a) [Lp(a)] are risk factors for endothelial dysfunction. This study aimed to evaluate the effect of high dose folic acid (FA) on serum Hcy and Lp(a) concentrations with respect to methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677C→T during pregnancy. Methods: In a prospective uncontrolled intervention, 90 pregnant women received 5 mg FA supplementation before pregnancy till 36th week of pregnancy. The MTHFR polymorphisms 677C→T, serum lactate dehydrogenase activity, urine protein and creatinine concentrations were measured before starting folic acid administration. Serum levels of Hcy and Lp(a) were determined before and after completion of folic acid supplementation period. Results: Supplementation of the patients with FA for 36 week decreased the median (minimum– maximum) levels of serum Hcy from 11.40 μmol/L (4.40-28.70) to 9.70 (1.60-20.80) μmol/L (p=0.001). There was no significant change in serum Lp(a) after FA supplementation (p=0.17). The overall prevalence of genotypes in pregnant women that were under study for MTHFR C677T polymorphism was 53.3% CC, 26.7% CT and 20.0% TT. There was no correlation between decreasing level of serum Hcy in the patients receiving FA and MTHFR polymorphisms. Conclusion:Although FA supplementation decreased serum levels of Hcy in different MTHFR genotypes, serum Lp(a) was not changed by FA supplements. Our data suggests that FA supplementation effects on serum Hcy is MTHFR genotype independent in pregnant women. PMID:26929921

  2. Evaluation of Serum Homocysteine and Leptin Levels in Patients with Uveitis

    PubMed Central

    Elbay, Arif Emre; Topalkara, Ayşen; Elbay, Ahmet; Erdoğan, Haydar; Vural, Ayşe; Bahadır Çetin, Abdi

    2015-01-01

    Objectives: To evaluate the serum homocysteine (Hcy) and leptin levels in patients with uveitis. Ma­te­ri­als and Met­hods: The 70 cases included in the study comprised 3 groups: patients with Behçet’s uveitis (BU), patients with non-Behçet’s uveitis (NBU) and healthy controls. Body mass index was calculated for each subject. Serum Hcy and leptin levels were measured. Furthermore, acute-phase reactants including erythrocyte sedimentation rate (ESR), C-reactive protein and neutrophil count were measured. Re­sults: Serum Hcy levels were 15.04±4.59 µmol/L in the BU group, 15.4±6.87 µmol/L in the NBU group and 13.64±4.72 µmol/L in the control group (p>0.05). The serum leptin levels of male patients in the BU group, NBU group and control group were 4.76±3.54 ng/ml, 6.33±3.74 ng/ml and 5.47±6.33 ng/ml, respectively (p>0.05). When we compared serum leptin levels in female patients and controls, the mean serum leptin concentrations were significantly higher in female BU and NBU patients (24.83±17.62 ng/ml and 28.46±13.90 ng/ml, respectively) than in healthy control volunteers (9.62±6.36 ng/ml, p<0.05). In addition, the ESR value differences between groups were statistically significant (p<0.05). Conclusion: A larger case series is necessary to investigate serum Hcy and leptin concentrations in uveitis patients. PMID:27800222

  3. Total Homocysteine, Diet, and Lipid Profiles in Type 1 and Type 2 Diabetic and Nondiabetic Adolescents

    PubMed Central

    Faulkner, Melissa Spezia; Chao, Wei-Hsun; Kamath, Savitri K.; Quinn, Laurie; Fritschi, Cynthia; Maggiore, Jack A.; Williams, Robert H.; Reynolds, Robert D.

    2008-01-01

    Background and Research Objective Limited research is available on the possible differences in the cardiovascular risk factors of total homocysteine (tHcy), dietary energy, and lipids among adolescents with type 1 diabetes mellitus (DM), type 2 DM, or healthy controls. This study’s primary aim was to compare the dietary energy and the intake of macronutrients and micronutrients of folate, and vitamins B6 and B12, as well as lipids and tHcy for adolescents with type 1 DM, type 2 DM, and healthy non-DM controls. Subjects and Methods This secondary analysis of the merging of 2 datasets included the following adolescents: 50 with type 1 DM, 14 with type 2 DM, and 53 controls. Mean ages for those with type 1 versus type 2 DM were 15.2 ± 1.9 versus 16.1 ± 1.9 years, respectively. Mean age for the controls was 16.5 ± 1.0 years. Variables included fasting tHcy and lipids, and 24-hour dietary recalls for macronutrients and micronutrients. Hemoglobin A1c was obtained for those with DM. Statistical analyses included one-way analyses of variance, Pearson correlations, and stepwise regression. Results and Conclusions Adolescents with type 1 DM had the lowest tHcy values (P < .05), which were reflective of the limited extant research with this population. Lipid profiles and dietary energy did not differ significantly among the 3 groups. Hemoglobin A1c was related to total cholesterol and triglycerides in those with type 1 DM, confirming the importance of promoting better metabolic control in lipid management for these youth. Future research should continue to explore the validity of tHcy and lipids as predictors of CV risks for youth with type 1 and type 2 DM. PMID:16407737

  4. C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores.

    PubMed

    Kajanachumpol, Saowanee; Atamasirikul, Kalayanee; Tantibhedhyangkul, Phieuvit

    2013-01-01

    Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) µmol/L vs. 8.53 (8.12 - 8.95) µmol/L, p < 0.001. A C-to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 µmol/L, 20.4 µmol/L, and 30.0 µmol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia.

  5. Physiologically relevant plasma d,l-homocysteine concentrations mobilize Cd from human serum albumin.

    PubMed

    Sagmeister, Peter; Gibson, Matthew A; McDade, Kyle H; Gailer, Jürgen

    2016-08-01

    Although low-level chronic exposure of humans to cadmium (Cd(2+)) can result in a variety of adverse health effects, little is known about the role that its interactions with plasma proteins and small molecular weight (SMW) ligands in the bloodstream may play in delivering this metal to its target organs. To gain insight, a Cd-human serum albumin (HSA) 1:1 (molar ratio) complex was analyzed by size exclusion chromatography (SEC) coupled on-line to a flame atomic absorption spectrometer (FAAS). Using a phosphate buffered saline (PBS)-buffer mobile phase, the stability of the Cd-HSA complex was investigated in the presence of 2.0mM of SMW ligands, including taurine, acetaminophen, l-methionine, l-cysteine (Cys), d,l-homocysteine (hCys) or l-cysteine methyl-ester (Cys-Me). While taurine, acetaminophen and l-methionine did not affect its integrity, Cys, hCys and Cys-Me completely abstracted Cd from HSA. Subsequent investigations into the effect of 1.5, 1.0 and 0.5mM Cys and hCys on the integrity of the Cd-HSA complex revealed clear differences with regard to the nature of the eluting SMW-Cd species between these structurally related endogenous thiols. Interestingly, the Cd-specific chromatograms that were obtained for 0.5mM hCys revealed the elution of an apparent mixture of the parent Cd-HSA complex with a significant contribution of a structurally uncharacterized CdxhCysy species. Since this hCys concentration is encountered in blood plasma of hyperhomocysteinemia patients and since previous studies by others have revealed that a SH-containing carrier mediates the uptake of Cd into hepatocytes, our results suggest that plasma hCys may play a role in the toxicologically relevant translocation of Cd from the bloodstream to mammalian target organs. PMID:27294530

  6. Effects of traditional Chinese medicines on serum lipid profiles and homocysteine in the ovariectomized rats.

    PubMed

    Lee, Su-Chen; Chang, Shun-Jen; Tsai, Li-Yu

    2004-01-01

    To investigate the effects of the traditional Chinese medicines, kuei-lu-erh-hsien-chiao and chia-wei-hsiao-yao-san, on the cardiovascular systems of mimic menopausal rats, five groups were formed: group 1 (the control group) was given a sham operation and received distilled water, while groups 2, 3, 4 and 5 were ovariectomized and received distilled water, kuei-lu-erh-hsien-chiao, chia-wei-hsiao-yao-san and 17-beta-estradiol, respectively, for4 months. Our results demonstrated that the mean differences of the estrogen levels in groups 3 or 5 were significantly higher than those of group 2. These data suggest that there might be some estrogen-like substances in kuei-lu-erh-hsien-chiao. However, the function of these estrogen-like substances was unknown. The mean differences of the triglyceride (TG) levels, high-density lipoprotein cholesterol (HDL-C) levels, low-density lipoprotein cholesterol (LDL-C) levels, and the ratios of TC/HDL-C and LDL-C/HDL-C in groups 1, 3, 4 and 5 were not significantly different from those in group 2. The mean differences of the total cholesterol (TC) levels in group 5 were significantly higher than those in group 2 (p < 0.05), but no obvious difference of the TC levels was found between groups 2 and 4. Nevertheless, the mean differences of the homocysteine (Hcy) levels in groups 4 and 5 were statistically lower than those of group 2. Therefore, administration of chia-wei-hsiao-yao-san declines the Hcy levels in OVX rats and does not affect the TC levels in these animals. In conclusion, our results indicate that chia-wei-hsiao-yao-san shows a more profound effect than 17-beta-estradiol in the prevention of atherosclerosis in these OVX rats. PMID:15481644

  7. Physiologically relevant plasma d,l-homocysteine concentrations mobilize Cd from human serum albumin.

    PubMed

    Sagmeister, Peter; Gibson, Matthew A; McDade, Kyle H; Gailer, Jürgen

    2016-08-01

    Although low-level chronic exposure of humans to cadmium (Cd(2+)) can result in a variety of adverse health effects, little is known about the role that its interactions with plasma proteins and small molecular weight (SMW) ligands in the bloodstream may play in delivering this metal to its target organs. To gain insight, a Cd-human serum albumin (HSA) 1:1 (molar ratio) complex was analyzed by size exclusion chromatography (SEC) coupled on-line to a flame atomic absorption spectrometer (FAAS). Using a phosphate buffered saline (PBS)-buffer mobile phase, the stability of the Cd-HSA complex was investigated in the presence of 2.0mM of SMW ligands, including taurine, acetaminophen, l-methionine, l-cysteine (Cys), d,l-homocysteine (hCys) or l-cysteine methyl-ester (Cys-Me). While taurine, acetaminophen and l-methionine did not affect its integrity, Cys, hCys and Cys-Me completely abstracted Cd from HSA. Subsequent investigations into the effect of 1.5, 1.0 and 0.5mM Cys and hCys on the integrity of the Cd-HSA complex revealed clear differences with regard to the nature of the eluting SMW-Cd species between these structurally related endogenous thiols. Interestingly, the Cd-specific chromatograms that were obtained for 0.5mM hCys revealed the elution of an apparent mixture of the parent Cd-HSA complex with a significant contribution of a structurally uncharacterized CdxhCysy species. Since this hCys concentration is encountered in blood plasma of hyperhomocysteinemia patients and since previous studies by others have revealed that a SH-containing carrier mediates the uptake of Cd into hepatocytes, our results suggest that plasma hCys may play a role in the toxicologically relevant translocation of Cd from the bloodstream to mammalian target organs.

  8. Association Between Leukocyte Telomere Length and Plasma Homocysteine in a Singapore Chinese Population

    PubMed Central

    Rane, Grishma; Koh, Woon-Puay; Kanchi, Madhu Mathi; Wang, Renwei; Yuan, Jian-Min

    2015-01-01

    Abstract Rationale: Leukocyte telomere length (LTL) and plasma homocysteine (HCY) have been independently associated with cardiovascular disease (CVD) morbidity and mortality. However, few studies have investigated the association between LTL and HCY levels. Objective: This study investigated the association of LTL with CVD risk factors, including HCY, in an overt CVD-free Singapore Chinese population comprised of middle aged and elderly, the age group at risk of developing CVD. Approach: The association of plasma HCY and other CVD biomarkers with LTL were assessed in 100 samples drawn from the Singapore Chinese Health Study (SCHS). SCHS, a population-based cohort, recruited Chinese individuals, aged 45–74 years, between 1993 and 1998. Questionnaire data were collected via face-to-face interviews. Known CVD biomarkers were measured from the blood collected at the time of recruitment, and LTL was measured using the conventional Southern blot method. Results: After adjustment for age, gender, smoking status, education, and dialect, LTL was found to be inversely associated with plasma HCY levels (p for trend=0.014). Serum urate showed a weak association (p for trend=0.056). Other CVD risk factors and nutrients, namely total cholesterol, low-density lipoprotein (LDL), triglycerides and creatinine, high-density lipoprotein (HDL), folate, and vitamin B6 showed the expected trend with LTL, but did not reach statistical significance. Conclusion: LTL displayed an inverse association with plasma HCY. This LTL–HCY inverse association in subjects lacking obvious cardiovascular events suggests that telomere length may be an intermediary in the biological mechanism by which elevated HCY leads to CVD. PMID:25546508

  9. Fatty acid status and its relationship to cognitive decline and homocysteine levels in the elderly.

    PubMed

    Baierle, Marília; Vencato, Patrícia H; Oldenburg, Luiza; Bordignon, Suelen; Zibetti, Murilo; Trentini, Clarissa M; Duarte, Marta M M F; Veit, Juliana C; Somacal, Sabrina; Emanuelli, Tatiana; Grune, Tilman; Breusing, Nicolle; Garcia, Solange C

    2014-09-01

    Polyunsaturated fatty acids (PUFAs), especially the n-3 series, are known for their protective effects. Considering that cardiovascular diseases are risk factors for dementia, which is common at aging, the aim of this study was to evaluate whether fatty acid status in the elderly was associated with cognitive function and cardiovascular risk. Forty-five elderly persons (age ≥ 60 years) were included and divided into two groups based on their Mini-Mental Status Examination score adjusted for educational level: the case group (n = 12) and the control group (n = 33). Serum fatty acid composition, homocysteine (Hcy), hs-CRP, lipid profile and different cognitive domains were evaluated. The case group, characterized by reduced cognitive performance, showed higher levels of 14:0, 16:0, 16:1n-7 fatty acids and lower levels of 22:0, 24:1n-9, 22:6n-3 (DHA) and total PUFAs compared to the control group (p < 0.05). The n-6/n-3 ratio was elevated in both study groups, whereas alterations in Hcy, hs-CRP and lipid profile were observed in the case group. Cognitive function was positively associated with the 24:1n-9, DHA and total n-3 PUFAs, while 14:0, 16:0 and 16:1n-7 fatty acids, the n-6/n-3 ratio and Hcy were inversely associated. In addition, n-3 PUFAs, particularly DHA, were inversely associated with cardiovascular risk, assessed by Hcy levels in the elderly. PMID:25221976

  10. Quantification of urinary S- and N-homocysteinylated protein and homocysteine-thiolactone in mice.

    PubMed

    Jakubowski, Hieronim

    2016-09-01

    Homocysteine (Hcy) and its metabolites Hcy-thiolactone, N-Hcy-protein, and S-Hcy-protein are implicated in vascular and neurological diseases. However, quantification of these metabolites remains challenging. Here I describe streamlined assays for these metabolites based on their conversion to Hcy-thiolactone. Free Hcy-thiolactone is extracted from the urine with chloroform/methanol. Total Hcy is converted to Hcy-thiolactone in the presence of 1 N HCl. Major urinary protein (MUP)-bound S-linked Hcy is liberated from the protein by reduction with dithiothreitol and converted to Hcy-thiolactone. Acid hydrolysis of MUP with 6 N HCl liberates N-linked Hcy as Hcy-thiolactone, which is then extracted with chloroform/methanol. Ferritin is used as an N-Hcy-protein standard and an authentic Hcy-thiolactone is used to monitor the efficiency of extraction. Hcy-thiolactone (free, derived from total Hcy, or from MUP-bound N-linked or S-linked Hcy) is separated by a cation exchange high-performance liquid chromatography, post-column derivatized with o-phthaldialdehyde, and quantified by fluorescence. Using these assays with as little as 2-20 μL of urine I show that MUP carry N-linked and S-linked Hcy and that N-Hcy-MUP and S-Hcy-MUP and Hcy-thiolactone are severely elevated in cystathionine β-synthase-deficient mice. These assays will facilitate examination of the role of protein-related Hcy metabolites in health and disease.

  11. Plasma Homocysteine and Carotid Intima-Media Thickness in Type 1 Diabetes: A Prospective Study

    PubMed Central

    Stoner, Julie A.; Thorpe, Suzanne R.; Klein, Richard L.; Lopes-Virella, Maria F.; Garvey, W. Timothy; Lyons, Timothy J.

    2014-01-01

    OBJECTIVE Plasma homocysteine (tHcy) has been positively associated with carotid intima-media thickness (IMT) in non-diabetic populations and in a few cross-sectional studies of diabetic patients. We investigated cross-sectional and prospective associations of a single measure of tHcy with common and internal carotid IMT over a 6-year period in type 1 diabetes. RESEARCH DESIGN AND METHODS tHcy levels were measured once, in plasma obtained in 1997-1999 from patients (n=599) in the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the observational follow-up of the Diabetes Control and Complications Trial (DCCT). Common and internal carotid IMT were determined twice, in EDIC “Year 6” (1998-2000) and “Year 12” (2004-2006), using B-mode ultra-sonography. RESULTS After adjustment, plasma tHcy [median (interquartile range): 6.2 (5.1, 7.5) μmol/L] was significantly correlated with age, diastolic blood pressure, renal dysfunction, and smoking (all p<0.05). In an unadjusted model only, increasing quartiles of tHcy correlated with common and internal carotid IMT, again at both EDIC time-points (p<0.01). However, multivariate logistic regression revealed no significant associations between increasing quartiles of tHcy and the 6-year change in common and internal carotid IMT (highest vs. lowest quintile) when adjusted for conventional risk factors. CONCLUSIONS In a type 1 diabetes cohort from the EDIC study, plasma tHcy measured in samples drawn in 1997-1999 was associated with measures of common and internal carotid IMT measured both one and seven years later, but not with IMT progression between the two time-points. The data do not support routine measurement of tHcy in people with Type 1 diabetes. PMID:25063949

  12. Effect of folic acid on homocysteine and insulin resistance of overweight and obese children and adolescents

    PubMed Central

    Dehkordi, Elham Hashemi; Sedehi, Morteza; Shahraki, Zohre Gholipour; Najafi, Reza

    2016-01-01

    Background: Considering the increasing trend of childhood obesity and subsequent burden of the disease in Iran and other countries and importance of early life intervention for achieving sustained effect on health of children and adolescents, this study aimed to investigate the effect of two different dose of folic acid on homocysteine (Hcy) level and insulin resistance of obese children. Materials and Methods: In this randomized, double-blind controlled clinical trial study, 60 obese and overweight children aged 5–12 years were enrolled. Selected obese children randomly allocated in two interventional (1 mg/day folic acid and 5 mg/day folic acid, for 8 weeks) and one control groups. Biochemical measurements including folic acid, Hcy, insulin and insulin resistance were measured between and within groups before and after trial. Results: In each group, 20 obese children were studied. The three groups were age and sex matched. After folic acid administration, mean of Hcy, insulin resistance and insulin decreased significantly in two groups which folic acid administrated with two different doses (P < 0.05). The reduction in studied biochemical variables was similar in two interventional groups (1 and 5 mg folic acid daily) (P > 0.05). Mean differences for Hcy, insulin resistance and insulin, in two intervention groups were significantly higher than the control group (P < 0.0001). Mean differences of Hcy, insulin resistance and insulin, in two intervention groups were not different significantly (P > 0.05). Conclusion: The findings of current trial showed that folic acid in two studied doses could be a safe and effective supplement for obese children to reduce Hcy level and insulin resistance, which consequently could prevent obesity-related complications including cardiovascular and metabolic disorders. PMID:27274503

  13. Associations of plasma phospholipid fatty acids with plasma homocysteine in Chinese vegetarians.

    PubMed

    Huang, Tao; Yu, Xiaomei; Shou, Tianxing; Wahlqvist, Mark L; Li, Duo

    2013-05-01

    The association of plasma phospholipid (PL) fatty acid composition with plasma homocysteine (Hcy) in Chinese vegetarians is not understood. The main aim of the present study was to investigate the plasma PL fatty acid status, and its association with plasma Hcy in Chinese vegetarians and omnivores. A total of 103 male vegetarians and 128 male omnivores were recruited in Linyin Temple, Hangzhou. Plasma Hcy and PL fatty acid concentrations were determined by standard methods. Compared with omnivores, plasma PL n-3 PUFA (P< 0·001), 22 : 6n-3 (P< 0·001), 22 : 5n-6 (P= 0·021), 22 : 2n-6 (P< 0·001) and SFA (P= 0·017) were significantly lower, while plasma PL n-6 PUFA (P= 0·007) and total PUFA (P< 0·001) were significantly higher in vegetarians. The prevalence of hyperhomocysteinaemia (HHcy) in vegetarians (26·47 %) was significantly higher than that in omnivores (13·28 %). In vegetarians, plasma PL 22 : 6n-3 (r − 0·257, P= 0·046) was significantly negatively associated with plasma Hcy. In omnivores, plasma PL 18 : 1n-7 (r 0·237, P= 0·030) was significantly positively associated with plasma Hcy. Plasma PL 22 : 6n-3 (r − 0·217, P= 0·048) was negatively associated with plasma Hcy in omnivores. Plasma PL SFA were positively associated with the prevalence of HHcy. It would seem appropriate for vegetarians to increase their dietary n-3 PUFA and decrease dietary SFA, and thus reduce the risk of HHcy.

  14. Association of homocysteine with type 2 diabetes: a meta-analysis implementing Mendelian randomization approach

    PubMed Central

    2013-01-01

    Background We tested the hypothesis that elevated homocysteine (Hcy) level is causally associated with increased risk of type 2 diabetes mellitus (T2DM). Results The meta-analysis and Mendelian randomization analysis were performed among 4011 cases and 4303 controls. The absolute pooled mean Hcy concentration in subjects with MTHFR 677TT was 5.55 μmol/L (95% CI, 1.33 to 9.77) greater than that in subjects with MTHFR 677CC in T2DM. Overall, the T allele of the MTHFR 677 C > T conferred a greater risk for T2DM [Random effect (RE) OR = 1.31(1.17-1.64), I2 = 41.0%, p = 0.055]. The random effect (RE) pooled OR associated with T2DM for MTHFR 677TT relative to the 677CC was [RE OR = 1.38(1.18-1.62)]. The fixed-effect pooled OR of the association for the MTHFR 677 TT vs CT was 1.29 (95% CI, 1.09-1.51). MTHFR 677 TT showed a significantly higher risk for T2DM compared with MTHFR 677 CC + CT [Fixed effect (FE) OR = 1.32(1.14-1.54), I2 = 0.0%, p = 0.686]. The absolute pooled mean Hcy concentration in individuals with T2DM was 0.94 μmol/L (95% CI, 0.40-1.48) greater than that in control subjects. The estimated causal OR associated with T2DM was 1.29 for 5 μmol/L increment in Hcy. Conclusions Our findings provided strong evidence on the causal association of Hcy level with the development of T2DM. PMID:24320691

  15. Effect of folic acid supplementation on homocysteine concentration and association with training in handball players

    PubMed Central

    2013-01-01

    Background Strenuous physical activity can alter the status of folic acid, a vitamin directly associated with homocysteine (Hcy); alterations in this nutrient are a risk factor for cardiovascular disease. Handball players are a population at risk for nutrient deficiency because of poor dietary habits. Objective The aims of this study were to evaluate nutritional status for macronutrients and folic acid in members of a high-performance handball team, and determine the effect of a nutritional intervention with folic acid supplementation and education. Design A total of 14 high-performance handball players were monitored by recording training time, training intensity (according to three levels of residual heart rate (RHR): <60%, 60%–80% and >80%), and subjective perceived exertion (RPE) during a 4-month training period. Nutritional, laboratory and physical activity variables were recorded at baseline (Week 0), after 2 months of dietary supplementation with 200 μg folic acid (50% of the recommended daily allowance) (Week 8) and after 2 months without supplementation (Week 16). We compared training load and analyzed changes in plasma concentrations of Hcy before and after the intervention. Results Bivariate analysis showed a significant negative correlation (P < 0.01) between Hcy and folic acid concentrations (r = −0.84) at Week 8, reflecting a significant change in Hcy concentration (P < 0.05) as a result of hyperhomocysteinemia following the accumulation of high training loads. At Week 16 we observed a significant negative correlation (P < 0.01) between Hcy concentration and training time with an RHR <60%, indicating that aerobic exercise avoided abrupt changes in Hcy and may thus reduce the risk of cardiovascular accidents in high-performance athletes. Conclusion Integral monitoring and education are needed for practitioners of handball sports to record their folic acid status, a factor that directly affects Hcy metabolism. Folic acid

  16. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia

    PubMed Central

    Zappacosta, Bruno; Mastroiacovo, Pierpaolo; Persichilli, Silvia; Pounis, George; Ruggeri, Stefania; Minucci, Angelo; Carnovale, Emilia; Andria, Generoso; Ricci, Roberta; Scala, Iris; Genovese, Orazio; Turrini, Aida; Mistura, Lorenza; Giardina, Bruno; Iacoviello, Licia

    2013-01-01

    Background/Objectives: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF), 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations. PMID:23698160

  17. Transient Increase in Homocysteine but Not Hyperhomocysteinemia during Acute Exercise at Different Intensities in Sedentary Individuals

    PubMed Central

    Iglesias-Gutiérrez, Eduardo; Egan, Brendan; Díaz-Martínez, Ángel Enrique; Peñalvo, José Luis; González-Medina, Antonio; Martínez-Camblor, Pablo; O’Gorman, Donal J.; Úbeda, Natalia

    2012-01-01

    Considering that hyperhomocysteinemia is an independent risk factor for cardiovascular disease, the purpose of this study was to determine the kinetics of serum homocysteine (tHcy) and the vitamins involved in its metabolism (folates, B12, and B6) in response to acute exercise at different intensities. Eight sedentary males (18–27 yr) took part in the study. Subjects were required to complete two isocaloric (400 kcal) acute exercise trials on separate occasions at 40% (low intensity, LI) and 80% VO2peak (high intensity, HI). Blood samples were drawn at different points before (pre4 and pre0 h), during (exer10, exer20, exer30, exer45, and exer60 min), and after exercise (post0, post3, and post19 h). Dietary, genetic, and lifestyle factors were controlled. Maximum tHcy occurred during exercise, both at LI (8.6 (8.0–10.1) µmol/L, 9.3% increase from pre0) and HI (9.4 (8.2–10.6) µmol/L, 25.7% increase from pre0), coinciding with an accumulated energy expenditure independent of the exercise intensity. From this point onwards tHcy declined until the cessation of exercise and continued descending. At post19, tHcy was not different from pre-exercise values. No values of hyperhomocysteinemia were observed at any sampling point and intensity. In conclusion, acute exercise in sedentary individuals, even at HI, shows no negative effect on tHcy when at least 400 kcal are spent during exercise and the nutritional status for folate, B12, and B6 is adequate, since no hyperhomocysteinemia has been observed and basal concentrations were recovered in less than 24 h. This could be relevant for further informing healthy exercise recommendations. PMID:23236449

  18. Serum homocysteine and folate concentrations are associated with prevalent age-related hearing loss.

    PubMed

    Gopinath, Bamini; Flood, Victoria M; Rochtchina, Elena; McMahon, Catherine M; Mitchell, Paul

    2010-08-01

    Elevated total serum homocysteine (tHcy) concentrations associated with vitamin B-12 or folate deficiencies may adversely affect blood flow to the cochlea, leading to age-related hearing loss (presbycusis). However, only 2 small cross-sectional studies have assessed the link between folate, vitamin B-12, or tHcy and presbycusis. We aimed to determine both the cross-sectional and longitudinal association between serum concentrations of folate, vitamin B-12, or tHcy and risk of age-related hearing loss. The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss (1997-1999 to 2002-2004). Presbycusis was measured in 2956 participants (aged >or=50 y) and was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0, and 4.0 kHz >25 dB hearing level (HL). Serum concentrations of folate, vitamin B-12, and tHcy were determined from blood samples. Participants with elevated tHcy (>20 micromol/L) concentrations had a 64% increased likelihood of prevalent hearing loss (>25 dB HL) [multivariate-adjusted odds ratio (OR) 1.64; 95% CI, 1.06-2.53]. Low serum folate levels (<11 nmol/L) increased the odds of prevalent mild hearing loss (>25-40 dB HL), multivariate-adjusted [OR 1.37 (CI 1.04-1.81)]. Serum vitamin B-12, however, was not significantly associated with prevalent hearing loss. Serum folate, vitamin B-12, and tHcy concentrations were also not significantly associated with an increased risk of incident hearing loss. Serum concentrations of tHcy and folate were associated with age-related hearing loss cross-sectionally, but no temporal links were observed, which could be due to insufficient study power. Further, large prospective studies will be required in the future to assess these associations.

  19. Plasma S-adenosylhomocysteine is a better biomarker of atherosclerosis than homocysteine in apolipoprotein E-deficient mice fed high dietary methionine.

    PubMed

    Liu, Chi; Wang, Qing; Guo, Honghui; Xia, Min; Yuan, Qin; Hu, Yan; Zhu, Huilian; Hou, Mengjun; Ma, Jing; Tang, Zhihong; Ling, Wenhua

    2008-02-01

    Homocysteine (Hcy) and S-adenosylhomocysteine (AdoHcy) are critical intermediates of methionine metabolism. To investigate which, if either, of these compounds is more closely related to atherosclerosis, we fed 5 groups of apolipoprotein E (apoE)-deficient mice different diets for 8 wk to induce changes in their plasma Hcy and AdoHcy concentrations. These included an AIN-93G control diet (C), this C diet supplemented with methionine (M), the M diet deficient in folates, vitamin B-6, and vitamin B-12 (M-V), this M diet supplemented with these B vitamins (M+V), and a C diet deficient in B vitamins (C-V). Compared with controls, mice fed the C-V diet had a moderate elevation in their plasma total Hcy (tHcy) levels; however, their plasma AdoHcy concentration and atherosclerotic lesion areas were not different. In contrast, the mice fed the M+V diet had larger atherosclerotic lesion areas and elevated plasma AdoHcy concentrations but their plasma tHcy concentration did not differ from that of the group C mice. The plasma AdoHcy concentration and aortic sinus lesion areas were positively correlated (r = 0.866; P < 0.001). We observed a negative correlation between the plasma AdoHcy concentration and both the DNA methyltransferase activity (r = -0.792; P < 0.001) and global DNA methylation status (r = -0.824; P < 0.001) in the aortic tissue. Hence, our study suggests that plasma AdoHcy is a better biomarker of atherosclerosis than Hcy and may accelerate the development of atherosclerotic lesions in apoE-deficient mice that have been fed a high methionine diet. The mechanisms underlying this effect may be related to the AdoHcy-mediated inhibition of DNA methylation in the aortic tissue. PMID:18203897

  20. Concomitant Effects of Ramadan Fasting and Time-Of-Day on Apolipoprotein AI, B, Lp-a and Homocysteine Responses during Aerobic Exercise in Tunisian Soccer Players

    PubMed Central

    Hammouda, Omar; Chtourou, Hamdi; Aloui, Asma; Chahed, Henda; Kallel, Choumous; Miled, Abdelhedi; Chamari, Karim; Chaouachi, Anis; Souissi, Nizar

    2013-01-01

    Objective To examine the time-of-day and Ramadan fasting (RF) effects on serum apolipoprotein-AI (Apo-AI) and B (Apo-B), lipoprotein particles-a (Lp-a), high-sensitive C-reactive-protein (hs-CRP), and homocysteine (Hcy) during the Yo-Yo intermittent recovery test (YYIRT). Design Performance and biochemical measures were completed at two times-of-day (07:00 and 17:00 h), 1-week before RF (BR), the second week of RF (SWR), and the fourth week of RF (ER). Setting For each session, subjects performed the YYIRT, and blood samples were taken before and 3-min after the test for biochemical measures. Participants Fifteen soccer players. Main Outcome Measures Total distance during the YYIRT, core temperature, body composition, dietary intakes, lipid (HDL-C, LDL-C, Apo-AI, B and Lp-a) and inflammatory (hs-CRP and Hcy) profiles. Results Performances during the YYIRT were higher in the evening than the morning BR (P < 0.05), but this fluctuation was not observed during RF. Moreover, LDL-C, ApoB, and Lp-a were stable throughout the daytime BR. However, during RF, they decreased at 17:00 h (P < 0.05). Likewise, HDL-C and Apo-AI increased after the exercise and were higher at 17:00 h BR (P < 0.001). Moreover, these parameters increased during RF (P < 0.01). Furthermore, Hcy and hs-CRP increased during the exercise (P < 0.01) with higher evening levels BR. During ER, the diurnal pattern of Hcy was inversed (P < 0.001). Conclusions This study concluded that caloric restriction induced by RF seems to ameliorate lipid and inflammatory markers of cardiovascular health during intermittent exercise performed in the evening. PMID:24244572

  1. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials

    PubMed Central

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A; Sofat, Reecha; Ricketts, Sally L; Cooper, Jackie; Breteler, Monique MB; Bautista, Leonelo E; Sharma, Pankaj; Whittaker, John C; Smeeth, Liam; Fowkes, F Gerald R; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A; Singleton, Andrew B; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B; Rich, Stephen S; Matarin, Mar; Norman, Paul E; Flicker, Leon; Almeida, Osvaldo P; van Bockxmeer, Frank M; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J; Bobak, Martin; Sterne, Jonathan AC; Smith, George Davey; Talmud, Philippa J; van Duijn, Cornelia; Humphries, Steve E; Price, Jackie F; Ebrahim, Shah; Lawlor, Debbie A; Hankey, Graeme J; Meschia, James F; Sandhu, Manjinder S; Hingorani, Aroon D; Casas, Juan P

    2011-01-01

    Summary Background The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. Methods We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). Findings The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar

  2. Metabolic syndrome and serum homocysteine in patients with bipolar disorder and schizophrenia treated with second generation antipsychotics.

    PubMed

    Vuksan-Ćusa, Bjanka; Jakovljević, Miro; Sagud, Marina; Mihaljević Peleš, Alma; Marčinko, Darko; Topić, Radmila; Mihaljević, Sanea; Sertić, Jadranka

    2011-08-30

    There is accumulating evidence for an increased prevalence of metabolic syndrome (MetS) in bipolar patients, which is comparable to the prevalence of MetS in patients with schizophrenia. Hyperhomocysteinaemia has emerged as an independent and graded risk factor for the development of cardiovascular disease (CVD), which is, at the same time, the primary clinical outcome of MetS. The aim of this study was to ascertain if the presence of MetS was associated with hyperhomocysteinaemia in patients with bipolar disorder (N=36) and schizophrenia (N=46) treated with second-generation antipsychotics (SGA). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria and the cut-off point for hyperhomocysteinaemia was set up at 15 μmoll(-1). Results of the study indicated that the presence of the MetS is statistically significantly associated with the elevated serum homocysteine in all participants. As hyperhomocysteinaemia has emerged as an independent risk factor for psychiatric disorder and CVD, it could be useful to include fasting homocysteine serum determination in the diagnostic panels of psychiatric patients to obtain a better assessment of their metabolic risk profile. PMID:21216014

  3. Similarities in the epidemiology of neural tube defects and coronary heart disease: is homocysteine the missing link?

    PubMed Central

    Stone, D. H.; McCarron, P.; Smith, G. D.

    1999-01-01

    It is hypothesised that a single aetiological pathway could explain both the strong ecological association between the birth prevalence of neural tube defects (NTD) and coronary heart disease (CHD) mortality and the potential efficacy of dietary measures, especially increased folic acid intake, in their prevention. The epidemiological similarities between NTD and CHD are strong and consistent suggesting that the relation is real rather than artefactual. It is suggested that this epidemiological association reflects a shared aetiology arising from the role of disturbed homocysteine metabolism in the pathogenesis of both conditions. Current public health measures designed to increase the intake of periconceptional folic acid in women, reinforced by a broadening of this policy to target both sexes throughout life, will (if successful) result in a reduction in both the birth prevalence of NTD and the incidence of CHD, although not necessarily contemporaneously. If disordered homocysteine metabolism is the cause of both NTD and CHD, this has implications for future research and preventive strategies for these serious and often lethal diseases.   PMID:10656088

  4. Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: An analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid ...

  5. Transient Decrease in Circulatory Testosterone and Homocysteine Precedes the Development of Metabolic Syndrome Features in Fructose-Fed Sprague Dawley Rats

    PubMed Central

    Sakamuri, Anil; Pitla, Sujatha; Putcha, Uday Kumar; Jayapal, Sugeedha; Pothana, Sailaja; Vadakattu, Sai Santosh

    2016-01-01

    Background. Increased fructose consumption is linked to the development of metabolic syndrome (MS). Here we investigated the time course of development of MS features in high-fructose-fed Sprague Dawley rats along with circulatory testosterone and homocysteine levels. Methods. Rats were divided into control and experimental groups and fed with diets containing 54.5% starch and fructose, respectively, for 4, 12, and 24 weeks. Plasma testosterone and homocysteine levels were measured along with insulin, glucose, and lipids. Body composition, insulin resistance, and hepatic lipids were measured. Results. Increase in hepatic triglyceride content was first observed in metabolic disturbance followed by hypertriglyceridemia and systemic insulin resistance in fructose-fed rats. Hepatic lipids were increased in time-dependent manner by fructose-feeding starting from 4 weeks, but circulatory triglyceride levels were increased after 12 weeks. Fasting insulin and Homeostatis Model Assessment of Insulin Resistance (HOMA-IR) were increased after 12 weeks of fructose-feeding. Decreased visceral adiposity, circulatory testosterone, and homocysteine levels were observed after 4 weeks of fructose-feeding, which were normalized at 12 and 24 weeks. Conclusions. We conclude that transient decrease in circulatory testosterone and homocysteine levels and increased hepatic triglyceride content are the earliest metabolic disturbances that preceded hypertriglyceridemia and insulin resistance in fructose-fed SD rats.

  6. Plasma homocysteine level is a risk factor for osteoporotic fractures in elderly patients

    PubMed Central

    Zhu, Yuefeng; Shen, Jie; Cheng, Qun; Fan, Yongqian; Lin, Weilong

    2016-01-01

    Objective To study the relationship of plasma homocysteine (Hcy), bone turnover biomarkers (BTB), and bone mineral density (BMD) with osteoporotic fracture (OPF) in elderly people. Methods Eighty-two patients (aged 65 years or older) admitted to our orthopedics department between October 2014 and May 2015 were randomly divided into three groups: 1) OPF group: 39 cases with the mean age 81.82±5.49 years, which included 24 females and 15 males; 2) high-energy fracture (HEF) group: 22 cases with the mean age 78.88±5.75 years, which included 16 females and six males; 3) non-bone-fracture group: 21 cases with mean age 79.75±5.47 years without bone fracture, which included 14 females and seven males. Plasma Hcy, BTB, and BMD were measured. Analysis of variance and multiple regression analysis were used in the statistical analysis. Results There was no significant difference in either age or sex among the three groups. There were significant differences in plasma Hcy and hip BMD between the OPF and HEF groups; there was also significant difference in plasma Hcy, 25-(OH) Vit D, and hip BMD between the OPF and non-fracture groups. There was no difference in lumbar spine BMD between the OPF group and the other two groups. There was no significant difference in plasma Hcy, 25-(OH) Vit D, hip or lumbar spine BMD between the HEF and non-fracture group. There was no significant difference in procollagen type I N-propeptide of type I collagen, serum C-terminal cross-linking telopeptide of type I collagen, and parathyroid hormone among the three groups. Plasma Hcy was linearly correlated with age and serum C-terminal cross-linking telopeptide of type I collagen, but not correlated with either hip or lumbar spine BMD or any other BTBs. Conclusion In this study, we found that the plasma Hcy level in elderly patients with OPF is higher than that of nonosteoporotic patients. It is not correlated with BMD, but positively correlated with bone resorption markers. An increased Hcy

  7. Serum Homocysteine Concentration Is Significantly Associated with Inflammatory/Immune Factors

    PubMed Central

    Yang, Xiaobo; Zhang, Haiying; Qin, Xue; Hu, Yanling; Mo, Zengnan

    2015-01-01

    Recent studies suggest that serum homocysteine (HCY) level is correlated to inflammatory/immune factors that influence the development and progression of many diseases, such as cardiovascular disease. However, the association between serum HCY level and inflammatory/immune factors in healthy populations has not been systematically investigated. This study was conducted based on the Fangchenggang Area Male Health and Examination Survey (FAMHES) project. After comprehensive baseline analysis, we could not find any significant association between HCY level and inflammatory/immune factors. However, in the next linear regression analysis, serum C4 [age-adjusted: Beta = -0.053, 95%CI = (-3.798, -0.050), P = 0.044; multivariate adjusted: Beta = -0.064, 95%CI = (-4.271, -0.378), P = 0.019] and C-reactive protein (CRP) concentration [unadjusted: Beta = 0.056, 95%CI = (0.037, 0.740), P = 0.030] were positively related with HCY. In further binary regression analysis, a significant correlation was confirmed for C4 and HCY [age-adjusted: OR = 0.572, 95%CI = (0.359, 0.911); multivariate adjusted: OR = 0.558, 95%CI = (0.344, 0.905)]. In order to discover more potential associations, multivariate logistic regression analysis was applied and suggested that HCY and C4 were significantly correlated [age-adjusted: OR = 0.703, 95%CI = (0.519, 0.951); multivariate adjusted: OR = 0.696, 95%CI = (0.509, 0.951)]. In addition, immunoglobulin M (IgM) may influence the HCY level to some extent [unadjusted: OR = 1.427, 95%CI = (1.052, 1.936); age-adjusted: OR = 1.446, 95%CI = (1.061, 1.970); multivariate adjusted: OR = 1.447, 95%CI = (1.062, 1.973)]. Combining our results with recent studies, we propose that C4, CRP, and IgM in serum are significantly associated with HCY concentration. Further studies are needed on the mechanism of the interaction, especially among cardiovascular disease subjects. PMID:26367537

  8. Homocysteine levels in morbidly obese patients: its association with waist circumference and insulin resistance.

    PubMed

    Vayá, Amparo; Rivera, Leonor; Hernández-Mijares, Antonio; de la Fuente, Miguel; Solá, Eva; Romagnoli, Marco; Alis, R; Laiz, Begoña

    2012-01-01

    The association between morbid obesity and hyperhomocysteinemia (HH) remains controversial and the nature of this relationship needs to be clarified as several metabolic, lipidic, inflammatory and anthropometric alterations that accompany morbid obesity may be involved. In 66 morbidly obese patients, 47 women and 19 men aged 41 ± 12 years and 66 normo-weight subjects, 43 women and 23 men, aged 45 ± 11 years, we determined homocysteine (Hcy) levels along with lipidic, anthropometric, inflammatory and insulin resistance markers. In addition, we investigated the effect of Metabolic Syndrome (MS) and its components on Hcy levels. Obese patients had statistically higher Hcy levels than controls: 12.76 ± 5.30 μM vs. 10.67 ± 2.50 μM; p = 0.006. Moreover, morbidly obese subjects showed higher waist circumference, glucose, insulin, HOMA, leptin, triglycerides, fibrinogen, C reactive protein (CRP) (p < 0.001, respectively), and lower vitamin B12 (p = 0.002), folic acid and HDL-cholesterol (p < 0.001, respectively). In the multivariate regression analysis, waist circumference, glucose, leptin and folic acid levels were independent predictors for Hcy values (p < 0.050). When obese patients were classified as having MS or not, no differences in Hcy levels were found between the two groups (p = 0.752). Yet when we analysed separately each MS component, only abdominal obesity was associated with Hcy levels (p = 0.031). Moreover when considering glucose >110 mg/dL (NCEP-ATPIII criteria) instead of glucose intolerance >100 mg/dl (updated ATPIII criteria), it also was associated with HH (p = 0.042). These results were confirmed in the logistic regression analysis where abdominal obesity and glucose >115 mg/dL constitute independent predictors for HH (OR = 3.2; CI: 1.23-13.2; p = 0.032, OR: 4.6; CI: 1.7-22.2; p = 0.016, respectively). The results of our study indicate that increased Hcy levels are related mostly with abdominal obesity and with insulin resistance. Thus, HH may

  9. [Homocysteine related vitamins and lifestyles in the elderly people: The SENECA study].

    PubMed

    Varela-Moreiras, G; Escudero, J M; Alonso-Aperte, E

    2007-01-01

    The SENECA study started in 1988 and consisted of a random age- and sex-stratified sample of inhabitants of 19 European towns. A total of 2.100 elderly people were finally able to be included in the study. The present study includes results for total plasma homocysteine (tHcy) and the related vitamins folate, B12 and B6. Other style factors as alcohol consumption or smoking have been also evaluated. The lowest values for tHcy corresponded to Mediterranean countries (Portugal, Spain, and Greece), compared to central or northern european countries (Netherland or Belgium (differences higher than 4 micromol/l). In addition, an interesting north-south gradient is observed, with the lowest values for tHcy corresponding to Betanzos (Spain), 12.38 micromol/l followed by both centers in Portugal, whereas the highest concentrations are found in Maki (Poland), 21.92 pmol/I and Culemborg (Netherlands), 20.41 mircromol/l. The mean tHcy concentration for all the European centers was 15.98 micromol/l. Effect of sex has been also evaluated: those countries with the lowest tHcy concentration (i.e. Spain or Portugal) show significant (p < 0.01) higher tHcy concentration in men vs women, whereas these differences by sex are not observed in countries with the highest tHcy values. The effect of "aging" within the same individuals after ten years of follow up was also evaluated: a significant difference was observed for the same individuals in the 10-years period. Plasma folic acid was compared to tHcy values, resulting also in marked differences between north and southern countries. Plasma vitamin B12 also shows a close pattern. Either plasma folate or vitamin B12 were shown as strong predictors of tHcy. This effect was not observed for plasma vitamin B6. Total alcohol intake was positively and significantly (p < 0.01) correlated with tHcy ("no" intake corresponded with the lowest tHcy, 14.3 micromol/l vs "high" intake-over 30 g/d-with the highest tHcy, 17 micromol/l). The type of

  10. Plasma Amyloid-β Peptides and Homocysteine in Depression in the Homebound Elderly

    PubMed Central

    Qiu, Wei Qiao; Sun, Xiaoyan; Mwamburi, D. Mkaya; Haker, Jacqueline; Lisle, David; Rizal, Abishek; Lin, Yu-min; Qiao, Liyan; Summergrad, Paul; Folstein, Marshal; Rosenberg, Irwin

    2011-01-01

    Objectives Both plasma amyloid-β peptide 40 (Aβ40) and homocysteine (tHcy) are linked to vascular disease, which is related to depression in the elderly. We sought to study whether the relationship between tHcy and plasma Aβ40 differs in those with and without depression. Study Design and Methods In a cross-sectional study of 1058 homebound elders, vascular depression was defined as a score ≥ 16 on the Center for Epidemiological Studies Depression scale (CES-D) along with self-reported cardiovascular disease (CVD). Plasma Aβ40 and Aβ42, and serum tHcy and creatinine were measured. Results Elders with high tHcy had higher concentrations of plasma Aβ40 (median: 147.5 vs. 123.1 pg/ml, P < 0.0001) and Aβ42 (median: 20.2 vs. 16.6 pg/ml, P < 0.0001) than those with low tHcy. In elders with depression, the relationship between logarithm of plasma Aβ40 (LogAβ40), but not LogAβ42, and tHcy was significant (β = +0.010, SE = 0.004, P = 0.007); in contrast, this relationship was not observed in those without depression. Subjects with vascular depression had the highest concentration of tHcy (mean ± SD: 12.8 ± 4.6 vs. 11.7 ± 4.5 vs. 11.9 + 5.5, P = 0.008) compared to those without CVD and those without depression. Depressed subjects without CVD had the lowest concentration of plasma Aβ42 (median: 15.5 vs. 19.1 vs. 18.7, P = 0.01) compared to those with CVD and those without depression. Conclusions Vascular depression, which is associated with tHcy and Aβ40 in blood, appears to be different from depression that is associated with low plasma Aβ42. This suggests that reducing tHcy and Aβ40 may be an adjunct treatment for vascular depression. PMID:23766866

  11. Valproic acid increases expression of methylenetetrahydrofolate reductase (MTHFR) and induces lower teratogenicity in MTHFR deficiency.

    PubMed

    Roy, Marc; Leclerc, Daniel; Wu, Qing; Gupta, Sapna; Kruger, Warren D; Rozen, Rima

    2008-10-01

    Valproate (VPA) treatment in pregnancy leads to congenital anomalies, possibly by disrupting folate or homocysteine metabolism. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme of folate interconversion and homocysteine metabolism, we addressed the possibility that VPA might have different teratogenicity in Mthfr(+/+) and Mthfr(+/-) mice and that VPA might interfere with folate metabolism through MTHFR modulation. Mthfr(+/+) and Mthfr(+/-) pregnant mice were injected with VPA on gestational day 8.5; resorption rates and occurrence of neural tube defects (NTDs) were examined on gestational day 14.5. We also examined the effects of VPA on MTHFR expression in HepG2 cells and on MTHFR activity and homocysteine levels in mice. Mthfr(+/+) mice had increased resorption rates (36%) after VPA treatment, compared to saline treatment (10%), whereas resorption rates were similar in Mthfr(+/-) mice with the two treatments (25-27%). NTDs were only observed in one group (VPA-treated Mthfr(+/+)). In HepG2 cells, VPA increased MTHFR promoter activity and MTHFR mRNA and protein (2.5- and 3.7-fold, respectively). Consistent with cellular MTHFR upregulation by VPA, brain MTHFR enzyme activity was increased and plasma homocysteine was decreased in VPA-treated pregnant mice compared to saline-treated animals. These results underscore the importance of folate interconversion in VPA-induced teratogenicity, since VPA increases MTHFR expression and has lower teratogenic potential in MTHFR deficiency. PMID:18615588

  12. Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application.

    PubMed

    Delport, Darnielle; Schoeman, Renata; van der Merwe, Nicole; van der Merwe, Lize; Fisher, Leslie R; Geiger, Dieter; Kotze, Maritha J

    2014-06-01

    Low folate intake in the presence of the functional MTHFR 677 C > T (rs1801133) polymorphism is an important cause of elevated homocysteine levels previously implicated in major depressive disorder (MDD) and many other chronic diseases. In this study the clinical relevance and inter-relationship of these aspects were evaluated in 86 South African patients diagnosed with MDD and 97 population-matched controls participating in a chronic diseases screening program. A questionnaire-based clinical and nutrition assessment was performed, homocysteine levels determined, and all study participants genotyped for MTHFR 677 C > T (rs1801133) using allele-specific TaqMan technology. The folate score was found to be significantly lower in the patient group compared to controls (p = 0.003) and correlated with increased body mass index (BMI), particularly in females with MDD (p = 0.009). BMI was significantly higher in the MDD patients compared with controls after adjustment for age and sex (p = 0.015), but this association was no longer significant after further adjustment for the level of folate intake in the diet. In MDD patients but not controls, the minor T-allele of MTHFR 677 C > T was associated with increased BMI (p = 0.032), which in turn correlated significantly with increased homocysteine levels. The significant association between BMI and homocysteine levels was observed in both the MDD patient (p = 0.049) and control (p = 0.018) study groups. The significantly higher homocysteine levels observed in MDD patients compared to controls after adjustment for age and sex (p = 0.030), therefore appears to be mediated by the effects of MTHFR 677 C > T and low folate intake on BMI. Detection of the low-penetrance MTHFR 677 C > T mutation reinforces the importance of folate intake above the recommended daily dose to prevent or restore dysfunction of the methylation pathway.

  13. Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine.

    PubMed

    Blasko, Imrich; Jellinger, Kurt; Kemmler, Georg; Krampla, Wolfgang; Jungwirth, Susanne; Wichart, Ildigo; Tragl, Karl Heinz; Fischer, Peter

    2008-01-01

    The changes of plasma amyloid beta (Abeta42) protein, homocysteine and medial temporal lobe atrophy (MTA) were studied by the transition from cognitive health to mild cognitive impairment (MCI) and to Alzheimer's disease (AD) in a prospective cohort of individuals aged 75 years. MTA but not plasma Abeta42 measured at baseline predicted which persons remained cognitively healthy (CH) and who developed AD 2.5 years later. The increase of plasma Abeta42 over time significantly distinguished between persons who remained CH on the one hand and MCI converters and AD converters out of cognitive health on the other (CH-to-MCI and CH-to-AD converters). Although both groups showed similar increase of Abeta42 levels, CH-to-AD converters had a higher increase of homocysteine compared to CH-to-MCI converters or to persons remaining CH. In comparison to all cognitive subgroups, the AD converters from MCI at baseline showed the smallest increase of Abeta42 levels and rather no increase of homocysteine. In logistic regression analysis, the increase of plasma Abeta42 but not change of MTA significantly predicted the conversion from CH to MCI, and changes of MTA and homocysteine but not of plasma Abeta42 predicted the conversion from CH to AD. The increase of plasma Abeta42 correctly allocated CH-to-MCI and CH-to-AD converters with low (63%) specificity (for both) and low (60%) sensitivity (54% for AD group). These results indicate that (1) plasma Abeta42 alone is not suitable as a biomarker for AD, (2) in the course of cognitive deterioration of the AD-type the increase of plasma Abeta42 seems to be an initial event, (3) similar to cerebrospinal fluid, changes of plasma Abeta42 may reflect the transition from cognitive health to AD, and (4) whether persons with MCI develop AD may depend on an accumulation of further toxic metabolites such as homocysteine.

  14. High serum homocysteine levels correlate with a decrease in the blood flow velocity of the ophthalmic artery in highway toll collectors.

    PubMed

    Memişoğullari, Ramazan; Yüksel, Harun; Coskun, Abdurrahman; Yüksel, Hatice Kurt; Yazgan, Omer; Bilgin, Cahit

    2007-07-01

    Highway workers, such as policemen, automotive service companies, and toll collectors, are placed at risk of the accelerated atherosclerotic process, since recent studies have suggested that exposure to exhaust particles and ambient air pollution increases carotid intima-media thickness and reduces ocular blood flow velocity. Therefore, we assessed the relationship between serum homocysteine, a potential parameter for atherosclerosis, and the ocular blood flow velocity and the resistivity index in highway toll collectors. The peak systolic and end diastolic flow velocities and the resistivity index were measured in 22 toll collectors and 24 control subjects by color Doppler ultrasonography. The resistivity index, which is an indirect measure of the atherosclerotic process, was calculated: resistivity index = (peak systolic velocity - end diastolic velocity)/peak systolic velocity. Serum homocysteine levels were determined by fluorometric high-performance liquid chromatography. In the highway toll collectors, the serum homocysteine level (14.4 +/- 4.8 micromol/l; p < 0.005) and the resistivity index of the ophthalmic artery (0.741 +/- 0.015; p < 0.05) were higher and the ophthalmic blood flow velocity (33.0 +/- 3.0 cm/s; p < 0.001) was lower than those in the controls (10.6 +/- 3.1 micromol/l; 0.728 +/- 0.023; 36.8 +/- 2.2 cm/s; respectively). There were significant correlations between the serum homocysteine level and ophthalmic artery resistivity index in both highway toll collectors (p < 0.001) and controls (p < 0.005). Exposure to exhaust particles might increase the serum homocysteine level, which in turn could lead to the decreased ocular blood flow and the increased resistivity index. PMID:17592212

  15. Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients: Primary Results from the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial

    PubMed Central

    Bostom, Andrew G.; Carpenter, Myra A.; Kusek, John W.; Levey, Andrew S.; Hunsicker, Lawrence; Pfeffer, Marc A.; Selhub, Jacob; Jacques, Paul F.; Cole, Edward; Gravens-Mueller, Lisa; House, Andrew A.; Kew, Clifton; McKenney, Joyce L.; Pacheco-Silva, Alvaro; Pesavento, Todd; Pirsch, John; Smith, Stephen; Solomon, Scott; Weir, Matthew

    2015-01-01

    Background Kidney transplant recipients, like other patients with chronic kidney disease (CKD), experience excess risk of cardiovascular disease (CVD) and elevated total homocysteine (tHcy) concentrations. Observational studies of patients with CKD suggest increased homocysteine is a risk factor for CVD. The impact of lowering total homocysteine (tHcy) levels in kidney transplant recipients is unknown. Methods and Results In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing tHcy concentrations reduced the rate of the primary composite arteriosclerotic CVD outcome (myocardial infarction, stroke, CVD death, resuscitated sudden death, coronary artery or renal artery revascularization, lower extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n= 547 total events; hazards ratio [95% confidence interval] = 0.99 [0.84–1.17]), or secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86–1.26]) or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93–1.43]) compared to the low dose multivitamin. Conclusions Treatment with a high dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level. PMID:21482964

  16. S-Adenosylmethionine and S-adenosylhomocystein metabolism in isolated rat liver. Effects of L-methionine, L-homocystein, and adenosine.

    PubMed

    Hoffman, D R; Marion, D W; Cornatzer, W E; Duerre, J A

    1980-11-25

    The effects of varying concentrations of L-methionine, L-homocysteine, and adenosine on the tissue levels of S-adenosylmethionine (AdoMet) and S-adenosyl-homocystein (AdoHcy) were investigated in perfused liver. In the normal liver, the intracellular concentration of AdoMet was dependent upon the availability of methionine. In the presence of high concentrations of methionine the maximum level of AdoMet attainable was 300 nmol/g of liver. The exogenous concentration of methionine did not alter the hepatic concentration of AdoHcy (8 to 20 nmol/g) while adenosine or homocysteine blocked hydrolysis of AdoHcy resulting in elevated levels of AdoHcy (400 to 600 nmol/g) and AdoMet (300 to 600 nmol/g). The addition of both adenosine (4mM) and homocysteine (3.4 mM) to the perfusate further increased the levels of AdoHcy (4 mumol/g) and AdoMet (1.2 mumol/g). As the concentration of AdoHcy increased, significant amounts of this compound were released into the perfusate, while AdoMet was not detected. Under all conditions where AdoHcy accumulated in the cell, a concomitant increase in the AdoMet level occurred. Apparently AdoHcy acts as a positive effector of the S-adenosylmethionine synthase. The hepatocytes did not take up significant amounts of [methyl-14C]AdoMet from the perfusate nor were any [14C]methyl groups from this compound incorporated into histones, DNA, or phospholipids. In contrast, [14C]methyl groups were readily incorporated into these macromolecules from exogenous [methyl-14C]methionine. The addition of adenosine (4 mM) and homocystein (3.4 mM) shifted the AdoMet:AdoHcy ratio from 8.2 to 0.3. Under these conditions, transmethylation was inhibited markedly.

  17. Influence of 5,10-methylenetetrahydrofolate reductase gene polymorphism on plasma homocysteine concentration in patients with end-stage renal disease.

    PubMed

    Lee, H A; Choi, J S; Ha, K S; Yang, D H; Chang, S K; Hong, S Y

    1999-08-01

    The purpose of this study is to observe the influence of the methylenetetrahydrofolate reductase (MTHFR) gene (677C-->T substitution) on plasma homocysteine levels in end-stage renal disease (ESRD) patients who received a relatively large amount of folate (2 mg/d) and are undergoing hemodialysis. A cross-sectional study of plasma homocysteine, vitamin B(12), and folate was performed in patients with ESRD. The study population for the MTHFR gene study included 312 healthy subjects and 106 patients with ESRD undergoing hemodialysis. The C677T transition in the MTHFR gene was detected by HinF 1 restriction enzyme analysis and subsequent electrophoresis in a 3% agarose gel. The genotype of the MTHFR gene in 106 patients with ESRD was homozygous C677T mutation (VV) in 17 patients (16.1%) and heterozygous (AV) in 63 patients (58.4%); 26 patients (24.5%) did not carry this mutation (AA). The mean levels of homocysteine, vitamin B(12), and folate in the patients with ESRD were 23.3 +/- 14.0 mmol/L, 620.2 +/- 98.5 pmol/L, and 138.6 +/- 55.6 nmol/L, respectively. There was no significant difference in homocysteine levels among the three genotypes: 28.2 +/- 19.4 mmol/L for VV, 22.7 +/- 14.9 mmol/L for AV, and 23.4 +/- 11.1 mmol/L for AA genotype (P > 0.05). There was no difference in genotype distribution between the patient groups of less than 25th and greater than 75th percentiles, classified according to plasma homocysteine levels (P = 0.47). In conclusion, with high-dose folate supplementation, the hyperhomocysteinemia in patients with ESRD does not seem to be caused by the 677C-->T mutation in the MTHFR gene. PMID:10430972

  18. Characterization of homocysteine γ-lyase from submerged and solid cultures of Aspergillus fumigatus ASH (JX006238).

    PubMed

    El-Sayed, Ashraf S; Khalaf, Salwa A; Aziz, Hani A

    2013-04-01

    Among 25 isolates, Aspergillus fumigatus ASH (JX006238) was identified as a potent producer of homocysteine gamma- lyase. The nutritional requirements to maximize the enzyme yield were optimized under submerged (SF) and solid-state fermentation (SSF) conditions, resulting in a 5.2- and 2.3-fold increase, respectively, after the last purification step. The enzyme exhibited a single homogenous band of 50 kDa on SDS-PAGE, along with an optimum pH of 7.8 and pH stability range of 6.5 to 7.8. It also showed a pI of 5.0, as detected by pH precipitation with no glycosyl residues. The highest enzyme activity was obtained at 37-40 degrees C, with a Tm value of 70.1 degrees C. The enzyme showed clear catalytic and thermal stability below 40 degrees C, with T1/2 values of 18.1, 9.9, 5.9, 3.3, and 1.9 h at 30 degrees C, 35 degrees C, 40 degrees C, 50 degrees C, and 60 degrees C, respectively. Additionally, the enzyme Kr values were 0.002, 0.054, 0.097, 0.184, and 0.341 S-1 at 30 degrees C, 35 degrees C, 40 degrees C, 50 degrees C, and 60 degrees C, respectively. The enzyme displayed a strong affinity to homocysteine, followed by methionine and cysteine when compared with non-S amino acids, confirming its potency against homocysteinuriarelated diseases, and as an anti-cardiovascular agent and a specific biosensor for homocysteinuria. The enzyme showed its maximum affinity for homocysteine (Km 2.46 mM, Kcat 1.39 × 10(-3) s(-1)), methionine (Km 4.1 mM, Kcat 0.97 × 10(-3) s(-1)), and cysteine (Km 4.9 m M, Kcat 0.77 × 10(-3) s(-1)). The enzyme was also strongly inhibited by hydroxylamine and DDT, confirming its pyridoxal 5'-phosphate (PLP) identity, yet not inhibited by EDTA. In vivo, using Swiss Albino mice, the enzyme showed no detectable negative effects on platelet aggregation, the RBC number, aspartate aminotransferase, alanine aminotransferase, or creatinine titer when compared with negative controls. PMID:23568204

  19. Plasma homocysteine in adolescents depends on the interaction between methylenetetrahydrofolate reductase genotype, lipids and folate: a seroepidemiological study

    PubMed Central

    Gil-Prieto, Ruth; Hernández, Valentín; Cano, Beatriz; Oya, Manuel; Gil, Ángel

    2009-01-01

    Background Many publications link high homocysteine levels to cardiovascular disease. In Spain there is little information on the prevalence of hyperhomocysteinaemia and associated vitamin factors among the general population, and less still among children. Cardiovascular risk factors in the childhood population may be related to the appearance of cardiovascular disease at adult age. The aim of this study is to establish a definition of hyperhomocysteinaemia in adolescents and to analyze the influence of vitamin and metabolic factors in homocysteine levels in this population group. Methods Descriptive, cross-sectional epidemiological study to estimate serum homocysteine, vitamin B12 and folate levels, as well as plasma total, HDL- and LDL- cholesterol in a schoolgoing population aged 13 to 17 years in Madrid, Spain. Spearman correlation analysis was performed to ascertain quantitative comparison, Pearson's χ2 test (frequency < 5, Fisher) was used for comparison of prevalences, Mann-Whitney U and Kruskal-Wallis test were used for comparison of means and Bonferroni correction was used for post-hoc tests. A multivariate logistic regression model was performed in the multivariate analysis. Results Based on the classic values for definition of hyperhomocysteinaemia in adults, prevalence of hyperhomocysteinaemia in the study population was: 1.26% for 15 μmol/L; and 2.52% for 12 μmol/L. Deficits in HDL cholesterol and serum folate levels yielded adjusted Odds Ratios (OR) for hyperhomocysteinemia of 2.786, 95% CI (1.089-7.126), and 5.140, 95% CI (2.347-11.256) respectively. Mutation of the methylenetetrahydrofolate reductase (MTHFR) C677T genotype also raises the risk of hyperhomocysteinaemia (CC→CT: OR = 2.362; 95% CI (1.107-5.042) CC→TT: OR = 6.124, 95% CI (2.301-16.303)) Conclusion A good definition of hyperhomocysteinaemia in adolescents is the 90th percentile, equivalent to 8.23 μmol/L. Risk factors for hyperhomocysteinaemia are cHDL and folate deficiency, and

  20. Characterization of homocysteine γ-lyase from submerged and solid cultures of Aspergillus fumigatus ASH (JX006238).

    PubMed

    El-Sayed, Ashraf S; Khalaf, Salwa A; Aziz, Hani A

    2013-04-01

    Among 25 isolates, Aspergillus fumigatus ASH (JX006238) was identified as a potent producer of homocysteine gamma- lyase. The nutritional requirements to maximize the enzyme yield were optimized under submerged (SF) and solid-state fermentation (SSF) conditions, resulting in a 5.2- and 2.3-fold increase, respectively, after the last purification step. The enzyme exhibited a single homogenous band of 50 kDa on SDS-PAGE, along with an optimum pH of 7.8 and pH stability range of 6.5 to 7.8. It also showed a pI of 5.0, as detected by pH precipitation with no glycosyl residues. The highest enzyme activity was obtained at 37-40 degrees C, with a Tm value of 70.1 degrees C. The enzyme showed clear catalytic and thermal stability below 40 degrees C, with T1/2 values of 18.1, 9.9, 5.9, 3.3, and 1.9 h at 30 degrees C, 35 degrees C, 40 degrees C, 50 degrees C, and 60 degrees C, respectively. Additionally, the enzyme Kr values were 0.002, 0.054, 0.097, 0.184, and 0.341 S-1 at 30 degrees C, 35 degrees C, 40 degrees C, 50 degrees C, and 60 degrees C, respectively. The enzyme displayed a strong affinity to homocysteine, followed by methionine and cysteine when compared with non-S amino acids, confirming its potency against homocysteinuriarelated diseases, and as an anti-cardiovascular agent and a specific biosensor for homocysteinuria. The enzyme showed its maximum affinity for homocysteine (Km 2.46 mM, Kcat 1.39 × 10(-3) s(-1)), methionine (Km 4.1 mM, Kcat 0.97 × 10(-3) s(-1)), and cysteine (Km 4.9 m M, Kcat 0.77 × 10(-3) s(-1)). The enzyme was also strongly inhibited by hydroxylamine and DDT, confirming its pyridoxal 5'-phosphate (PLP) identity, yet not inhibited by EDTA. In vivo, using Swiss Albino mice, the enzyme showed no detectable negative effects on platelet aggregation, the RBC number, aspartate aminotransferase, alanine aminotransferase, or creatinine titer when compared with negative controls.

  1. Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer

    PubMed Central

    Vashi, Pankaj; Edwin, Persis; Popiel, Brenten; Lammersfeld, Carolyn; Gupta, Digant

    2016-01-01

    Background/Aims Normal or high serum vitamin B-12 levels can sometimes be seen in a B-12 deficient state, and can therefore be misleading. High levels of Methymalonic Acid (MMA) and Homocysteine (HC) have been identified as better indicators of B-12 deficiency than the actual serum B-12 level itself. We evaluated the prevalence of vitamin B-12 deficiency using appropriate cut-off levels of vitamin B-12, MMA and HC, and determined the relationship between serum levels of vitamin B-12, MMA and HC in cancer. Methods This is a cross-sectional study using a consecutive case series of 316 cancer patients first seen at Cancer Treatment Centers of America® (CTCA) at Midwestern Regional Medical Center between April 2014 and June 2014. All patients were evaluated at baseline for vitamin B-12 (pg/mL), MMA (nmol/L) and HC (μmol/L) levels. In accordance with previously published research, the following cut-offs were used to define vitamin B-12 deficiency: <300 pg/mL for vitamin B-12, >260 nmol/L for MMA and >12 μmol/L for HC. The relationship between B-12, MMA and HC was evaluated using Spearman's rho correlation coefficient and cross-tabulation analysis. Receiver Operating Characteristic (ROC) curves were estimated using the non-parametric method to further evaluate the diagnostic accuracy of vitamin B-12 using Fedosov quotient as the "gold standard". Results Mean age at presentation was 52.5 years. 134 (42.4%) patients were males while 182 (57.6%) were females. Median vitamin B-12, MMA and HC levels were 582.5 pg/mL, 146.5 nmol/L and 8.4 μmol/L respectively. Of 316 patients, 28 (8.9%) were vitamin B-12 deficient based on vitamin B-12 (<300pg/mL), 34 (10.8%) were deficient based on MMA (>260 nmol/L) while 55 (17.4%) were deficient based on HC (>12 μmol/L). Correlation analysis revealed a significant weak negative correlation between vitamin B-12 and MMA (rho = -0.22) as well as B-12 and HC (rho = -0.35). ROC curves suggested MMA to have the best discriminatory power in

  2. Serum levels of homocysteine, folate and vitamin B12 in patients with vitiligo before and after treatment with narrow band ultraviolet B phototherapy and in a group of controls.

    PubMed

    Ataş, Hatice; Cemil, Bengü Çevirgen; Gönül, Müzeyyen; Baştürk, Eda; Çiçek, Emel

    2015-07-01

    The association between vitamin B12, folate, homocysteine and vitiligo were studied in several studies, but the results are contradictory. Narrow-band ultraviolet B (NBUVB) phototherapy is now considered as a gold standard for the treatment of diffuse vitiligo. The effects of NBUVB phototherapy on both vitamin B12, folate and homocysteine levels have not been studied in vitiligo patients yet. Serum levels of vitamin B12, folate and homocysteine were measured in vitiligo patients and control group and also both before and after NBUVB phototherapy in vitiligo patients. While levels of homocysteine in patients with vitiligo were significantly higher than controls (16.9±8.4 vs. 10. 9±3.4 μmol/L; p<0,001) vitamin B12 and folate levels were not different (p>0.05). NBUVB phototherapy led to a 33.7±21.9% (0-75%) response in patients with vitiligo after 80 seccions. Treatment with NBUVB improved vitiligo and decreased serum levels of vitamin B12 (375±151 vs. 346±119 pg/ml, p=0.024), while serum levels of folate and homocysteine did not change significantly after treatment (p=0.914, p=0.127). Further studies are needed to clarify the influence of NBUVB phototherapy on folate, vitamin B12 and homocysteine levels in patients with vitiligo. Furthermore, studies with the analysis of skin levels of homocysteine rather than circulating levels may be useful to elucidate the effects of phototherapy on homocysteine levels.

  3. Homocysteine-lowering is not a primary target for cardiovascular disease prevention in chronic kidney disease patients.

    PubMed

    Suliman, Mohamed E; Lindholm, Bengt; Bárány, Peter; Qureshi, Abdul Rashid; Stenvinkel, Peter

    2007-01-01

    The homocysteine (Hcy) theory states that total homocysteine (tHcy) is a risk factor for atherosclerosis. Chronic kidney disease (CKD) is one of the most frequent causes of hyperhomocysteinemia in the presence of high prevalence of cardiovascular disease (CVD). However, there is not yet any conclusive answer to the question whether Hcy may contribute to, or predict, cardiovascular events or mortality in CKD patients or whether it is just an innocent bystander biologically related to other potential risk factors for CVD. Moreover, tHcy levels in CKD are influenced by several commonly occurring confounding factors, such as inflammation and protein-energy wasting (PEW). These factors are also associated with morbidity and mortality and altogether this may explain why Hcy does not show up as a cardiovascular risk but in fact is reversely associated with clinical outcome. Thorough evaluation of such reverse association may not necessarily imply that the principles of Hcy being a contributor to vascular pathophysiology are different in CKD patients but rather indicate that other superimposed factors, such as PEW and inflammation, are more important. These confounders contribute significantly to the unacceptably high mortality rate in this patient population and may require nutritional and anti-inflammatory interventions to improve clinical outcome. So far, the results of recent folic acid intervention trials do not support the use of folic acid supplementation for lowering tHcy and improving survival in CKD patients. Although we are still waiting for the results from several ongoing controlled randomized trials in this area, future studies are needed to evaluate if thiol-exchange agents, besides folic acid, as part of a future multifactorial intervention regime targeting inflammation, PEW, oxidative stress as well as hyperhomocysteinemia may decrease CVD risk in this high-risk patient population.

  4. Determinants of Arsenic Metabolism: Blood Arsenic Metabolites, Plasma Folate, Cobalamin, and Homocysteine Concentrations in Maternal–Newborn Pairs

    PubMed Central

    Hall, Marni; Gamble, Mary; Slavkovich, Vesna; Liu, Xinhua; Levy, Diane; Cheng, Zhongqi; van Geen, Alexander; Yunus, Mahammad; Rahman, Mahfuzar; Pilsner, J. Richard; Graziano, Joseph

    2007-01-01

    Background In Bangladesh, tens of millions of people have been consuming waterborne arsenic for decades. The extent to which As is transported to the fetus during pregnancy has not been well characterized. Objectives We therefore conducted a study of 101 pregnant women who gave birth in Matlab, Bangladesh. Methods Maternal and cord blood pairs were collected and concentrations of total As were analyzed for 101 pairs, and As metabolites for 30 pairs. Maternal urinary As metabolites and plasma folate, cobalamin, and homocysteine levels in maternal cord pairs were also measured. Household tube well–water As concentrations exceeded the World Health Organization guideline of 10 μg/L in 38% of the cases. Results We observed strong associations between maternal and cord blood concentrations of total As (r = 0.93, p < 0.0001). Maternal and cord blood arsenic metabolites (n = 30) were also strongly correlated: in dimethylarsinate (DMA) (r = 0.94, p < 0.0001), monomethylarsonate (r = 0.80, p < 0.0001), arsenite (As+3) (r = 0.80, p < 0.0001), and arsenate (As+5) (r = 0.89, p < 0.0001). Maternal homocysteine was a strong predictor of %DMA in maternal urine, maternal blood, and cord blood (β = −6.2, p < 0.02; β = −10.9, p < 0.04; and β = −13.7, p < 0.04, respectively). Maternal folate was inversely associated with maternal blood As5+ (β = 0.56, p < 0.05), and maternal cobalamin was inversely associated with cord blood As5+ (β = −1.2, p < 0.01). Conclusions We conclude that exposure to all metabolites of inorganic As occurs in the prenatal period. PMID:17938743

  5. Maternal Methyl Donors Supplementation during Lactation Prevents the Hyperhomocysteinemia Induced by a High-Fat-Sucrose Intake by Dams

    PubMed Central

    Cordero, Paul; Milagro, Fermin I.; Campion, Javier; Martinez, J. Alfredo

    2013-01-01

    Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle. PMID:24351826

  6. Rosiglitazone attenuates NF-{kappa}B-dependent ICAM-1 and TNF-{alpha} production caused by homocysteine via inhibiting ERK{sub 1/2}/p38MAPK activation

    SciTech Connect

    Bai, Yong-Ping; Liu, Yu-Hui; Chen, Jia; Song, Tao; You, Yu; Tang, Zhen-Yan; Li, Yuan-Jian; Zhang, Guo-Gang . E-mail: xyzgg2006@sina.com

    2007-08-17

    Previous studies demonstrated an important interaction between nuclear factor-kappaB (NF-{kappa}B) activation and homocysteine (Hcy)-induced cytokines expression in endothelial cells and vascular smooth muscle cells. However, the underlying mechanism remains illusive. In this study, we investigated the effects of Hcy on NF-{kappa}B-mediated sICAM-1, TNF-{alpha} production and the possible involvement of ERK{sub 1/2}/p38MAPK pathway. The effects of rosiglitazone intervention were also examined. Our results show that Hcy increased the levels of sICAM-1 and TNF-{alpha} in cultured human umbilical vein endothelial cells (HUVECs) in a time- and concentration-dependent manner. This effect was significantly depressed by rosiglitazone and different inhibitors (PDTC, NF-{kappa}B inhibitor; PD98059, MEK inhibitor; SB203580, p38MAPK specific inhibitor; and staurosporine, PKC inhibitor). Next, we investigated the effect of Hcy on ERK{sub 1/2}/p38MAPK pathway and NF-{kappa}B activity in HUVECs. The results show that Hcy activated both ERK{sub 1/2}/p38MAPK pathway and NF-{kappa}B-DNA-binding activity. These effects were markedly inhibited by rosiglitazone as well as other inhibitors (SB203580, PD98059, and PDTC). Further, the pretreatment of staurosporine abrogated ERK{sub 1/2}/p38MAPK phosphorylation, suggesting that Hcy-induced ERK{sub 1/2}/p38MAPK activation is associated with PKC activity. Our results provide evidence that Hcy-induced NF-{kappa}B activation was mediated by activation of ERK{sub 1/2}/p38MAPK pathway involving PKC activity. Rosiglitazone reduces the NF-{kappa}B-mediated sICAM-1 and TNF-{alpha} production induced by Hcy via inhibition of ERK{sub 1/2}/p38MAPK pa0011thw.

  7. [The role of homocysteine and methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase polymorphisms in the development of cardiovascular diseases and hypertension].

    PubMed

    Marosi, Krisztina; Agota, Annamária; Végh, Veronika; Joó, József Gábor; Langmár, Zoltán; Kriszbacher, Ildikó; Nagy, Zsolt B

    2012-03-25

    Cardiovascular diseases (CVDs) are the leading causes of death in the developed countries. Elevated homocysteine level is as an independent risk factor of CVDs. The C677T and A1298C variants of methylenetetrahydrofolate reductase gene (MTHFR) have been shown to influence folate and homocysteine metabolisms. However, the relationship between MTHFR polymorphisms and hyperhomocysteinemia has not been well established yet. The gene variants were also reported to be associated with CVDs. In addition, the C677T polymorphisms may play a role in the development of hypertension. Recent research evidence has suggested that MTHFR variants might be independently linked to CVDs and hypertension, because of the involvement of the MTHFR enzyme product (5-methyl-tetrahydrofolate /5-MTHF) in the regulation of endothelial functions. Further research is required to investigate the association between gene polymorphisms of folate-metabolizing enzymes and CVDs, and to identify the possible role of the relevant gene variants in the molecular pathogenesis of hyperhomocysteinemia.

  8. Increased Glutamate and Homocysteine and Decreased Glutamine Levels in Autism: A Review and Strategies for Future Studies of Amino Acids in Autism

    PubMed Central

    Ghanizadeh, Ahmad

    2013-01-01

    There are many reports about the significant roles of some amino acids in neurobiology and treatment of autism. This is a critical review of amino acids levels in autism. No published review article about the level of amino acids in autism was found. The levels of glutamate and homocystein are increased in autism while the levels of glutamine and tryptophan are decreased. Findings regarding the plasma levels of taurine and lysine are controversial. The urinary levels of homocysteine and essential amino acids in both the untreated and treated autistic children are significantly less than those in the controls. The current literature suffers from many methodological shortcomings which needed to be considered in future studies. Some of them are age, gender, developmental level, autism symptoms severity, type of autism spectrum disorders, medical comorbidities, intelligent quotient, diet, concomitant medications, body mass index, and technical method of assessment of amino acids. PMID:24167375

  9. Increased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism.

    PubMed

    Ghanizadeh, Ahmad

    2013-01-01

    There are many reports about the significant roles of some amino acids in neurobiology and treatment of autism. This is a critical review of amino acids levels in autism. No published review article about the level of amino acids in autism was found. The levels of glutamate and homocystein are increased in autism while the levels of glutamine and tryptophan are decreased. Findings regarding the plasma levels of taurine and lysine are controversial. The urinary levels of homocysteine and essential amino acids in both the untreated and treated autistic children are significantly less than those in the controls. The current literature suffers from many methodological shortcomings which needed to be considered in future studies. Some of them are age, gender, developmental level, autism symptoms severity, type of autism spectrum disorders, medical comorbidities, intelligent quotient, diet, concomitant medications, body mass index, and technical method of assessment of amino acids. PMID:24167375

  10. Consumption of wheat aleurone-rich foods increases fasting plasma betaine and modestly decreases fasting homocysteine and LDL-cholesterol in adults.

    PubMed

    Price, Ruth K; Keaveney, Edel M; Hamill, Lesley L; Wallace, Julie M W; Ward, Mary; Ueland, Per M; McNulty, Helene; Strain, J J; Parker, Michael J; Welch, Robert W

    2010-12-01

    There is strong evidence that whole-grain foods protect against heart disease. Although underlying mechanisms and components are unclear, betaine, found at high levels in wheat aleurone, may play a role. We evaluated the effects of a diet high in wheat aleurone on plasma betaine and related measures. In a parallel, single-blinded intervention study, 79 healthy participants (aged 45-65 y, BMI ≥ 25 kg/m(2)) incorporated either aleurone-rich cereal products (27 g/d aleurone) or control products balanced for fiber and macronutrients into their habitual diets for 4 wk. Fasting blood samples were taken at baseline and postintervention (4 wk) from participants. Compared with the control, the aleurone products provided an additional 279 mg/d betaine and resulted in higher plasma betaine (P < 0.001; intervention effect size: 5.2 μmol/L) and lower plasma total homocysteine (tHcy) (P = 0.010; -0.7 μmol/L). Plasma dimethylglycine and methionine, which are products of betaine-mediated homocysteine remethylation, were also higher (P < 0.001; P = 0.027) relative to control. There were no significant effects on plasma choline or B vitamins (folate, riboflavin, and vitamin B-6). However, LDL cholesterol was lower than in the control group (P = 0.037). We conclude that incorporating aleurone-rich products into the habitual diet for 4 wk significantly increases plasma betaine concentrations and lowers tHcy, which is attributable to enhanced betaine-homocysteine methyltransferase-mediated remethylation of homocysteine. Although this supports a role for betaine in the protective effects of whole grains, concomitant decreases in LDL suggest more than one component or mechanism may be responsible.

  11. Is the C677T polymorphism in methylenetetrahydrofolate reductase gene or plasma homocysteine a risk factor for diabetic peripheral neuropathy in Chinese individuals?

    PubMed

    Wang, Hongli; Fan, Dongsheng; Hong, Tianpei

    2012-10-25

    The present study enrolled 251 diabetic patients, including 101 with neuropathy and 150 without neuropathy. Of the 150 patients, 100 had no complications, such as retinopathy, nephropathy, or neuropathy. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to identify methylenetetrahydrofolate reductase gene variants. Plasma homocysteine levels were also measured. Homocysteine levels and the frequency of hyperhomocysteinemia were significantly higher in patients with diabetic peripheral neuropathy compared with diabetic patients without neuropathy (P < 0.05). In logistic regression analysis with neuropathy as the dependent variable, the frequency of C677T in methylenetetrahydrofolate reductase was significantly higher in patients with diabetic peripheral neuropathy compared with patients without diabetic complications. Homocysteine levels were significantly higher in patients with diabetic peripheral neuropathy carrying the 677T allele and low folic acid levels. In conclusion, hyperhomocysteinemia is an independent risk factor for diabetic neuropathy in Chinese patients with diabetes. The C677T polymorphism in methylenetetrahydrofolate reductase and low folic acid levels may be risk factors for diabetic peripheral neuropathy in Chinese patients with diabetes.

  12. Homocysteine and the C677T Gene Polymorphism of Its Key Metabolic Enzyme MTHFR Are Risk Factors of Early Renal Damage in Hypertension in a Chinese Han Population.

    PubMed

    Yun, Lin; Xu, Rui; Li, Guohua; Yao, Yucai; Li, Jiamin; Cong, Dehong; Xu, Xingshun; Zhang, Lihua

    2015-12-01

    The combined hyperhomocysteinemia condition is a feature of the Chinese hypertensive population. This study used the case-control method to investigate the association between plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR), and early renal damage in a hypertensive Chinese Han population.A total of 379 adult essential hypertensive patients were selected as the study subjects. The personal information, clinical indicators, and the C677T gene polymorphism of MTHFR were texted. This study used the urine microalbumin/urine creatinine ratio (UACR) as a grouping basis: the hypertension without renal damage group (NRD group) and the hypertension combined with early renal damage group (ERD group).Early renal damage in the Chinese hypertensive population was associated with body weight, systolic pressure, diastolic pressure, urea nitrogen, serum creatinine, cystatin C, uric acid, aldosterone, and glomerular filtration rate. The homocysteine level and the UACR in the TT genotype group were higher than those in the CC genotype group. The binary logistic regression analysis results showed that after sex and age were adjusted, the MTHFR C677T gene polymorphism was correlated with early renal damage in hypertension in both the recessive model and in the additive model.Plasma homocysteine and the C677T gene polymorphism of its key metabolic enzyme MTHFR might be independent risk factors of early renal damage in the hypertensive Chinese Han population.

  13. Polymorphism in the methylenetetrahydrofolate reductase (C677T) gene and homocysteine levels: a comparison in Brazilian patients with coronary arterial disease, ischemic stroke and peripheral arterial obstructive disease.

    PubMed

    Sabino, Adriano; Fernandes, Ana Paula; Lima, Luciana Moreira; Ribeiro, Daniel Dias; Sousa, Marinez Oliveira; de Castro Santos, Maria Elizabeth Rennó; Mota, Ana Paula Lucas; Dusse, Luci Maria Sant'Ana; das Graças Carvalho, Maria

    2009-01-01

    This study aimed to compare plasma levels of total homocysteine (tHcy) in different arterial events as well as to investigate an association between homocysteine levels and C677T polymorphism in Brazilian patients. A total of 145 subjects were enrolled in this study including 43 patients with coronary arterial disease (CAD), 21 with ischemic stroke (IS), 44 with peripheral arterial obstructive disease (PAOD) and 37 control subjects. A preliminary analysis showed significant difference for tHcy plasma levels between patients with CAD (P = 0.003) or PAOD (P = 0.03) compared to controls. However, after adjustment for sex, age, total cholesterol, LDL, diabetes, tabagism or C677T polymorphism, no significant differences were detected in tHcy levels among patients groups and controls. No significant correlation was demonstrated for C677T polymorphism and homocysteine levels. These results indicate that increased Hcy levels may not be considered an independent risk factor for atherothrombotic diseases in Brazilian patients. PMID:18040753

  14. Long-term HIV-1 infection induces an antiviral state in primary macrophages.

    PubMed

    Pujantell, Maria; Badia, Roger; Ramirez, Cristina; Puig, Teresa; Clotet, Bonaventura; Ballana, Ester; Esté, José A; Riveira-Muñoz, Eva

    2016-09-01

    HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte-derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-β, and transcription of interferon-stimulated genes including CXCL10. Infected macrophages showed increased expression of p21 and subsequent inactivation of cyclin-CDK2 activity leading to a hypo-phosphorylated active retinoblastoma protein (pRb) and deactivation of E2F1-dependent transcription and CDK1 downregulation. Additionally, HIV-1 infection limited deoxynucleotide pool by downregulation of the ribonucleotide reductase subunit R2 (RNR2) and reactivation of the HIV-1 restriction factor SAMHD1 together with increased cell death. In conclusion, HIV-1 induced an innate antiviral mechanism associated to IFN-I production, interferon stimulated gene activation, and p21-mediated G2/M arrest leading to elevated levels of cell death in monocyte derived macrophages. Upregulation of MDA5 and Rig-I may serve as targets for the development of antiviral strategies leading to the elimination of HIV-1 infected cells. PMID:27510577

  15. Folic Acid and Vitamins D and B12 Correlate With Homocysteine in Chinese Patients With Type-2 Diabetes Mellitus, Hypertension, or Cardiovascular Disease.

    PubMed

    Mao, Xudong; Xing, Xubin; Xu, Rong; Gong, Qing; He, Yue; Li, Shuijun; Wang, Hongfu; Liu, Cong; Ding, Xin; Na, Rishu; Liu, Zhiwen; Qu, Yi

    2016-02-01

    Elevated serum homocysteine has been shown to be a risk factor for hypertension, cardiovascular disease (CVD), and type-2 diabetes mellitus (T2DM).We characterized the relationships between the serum levels of homocysteine, folic acid, and vitamins D2, D3, and B12 in patients with T2DM, CVD, and hypertension in Shanghai, China. The levels of these serum biochemical markers were determined for 9311 Chinese patients (mean age: 79.50 ± 13.26 years) with T2DM (N = 839), hypertension (N = 490), or CVD (N = 7925). The demographic and serum biochemical data were compared using an analysis of variance. We performed stratified analyses using Pearson linear regression to investigate correlations between the different variables in the T2DM, CVD, and hypertension groups and in patients aged < 50, 50 to 64, 65 to 80, and ≥80 years. A subgroup analysis was also performed to identify correlations between the serum biochemical markers. Stratified chi-squared analyses were performed based on the levels of folic acid and total vitamin D.In all 3 patient groups, elevated levels of vitamin D2 and homocysteine were observed, whereas the levels of folic acid and vitamins D3 and B12 were lower than the reference range for each serum marker (P < 0.05 for all). The linear regression and stratified analyses showed that the highest levels of folic acid and vitamins D2 and D3 correlated with the lowest level of homocysteine in T2DM, CVD, and hypertension patients (P < 0.05 for all), whereas the highest level of vitamin B12 correlated with a lowest level of homocysteine in CVD patients only (P < 0.05).Our results indicate that the contributions of both vitamin D2 and vitamin D3 should be considered in investigations of the effects of vitamin D supplements in T2DM, CVD, and hypertension patients. Our findings warrant future studies of the benefits of vitamin D and folic acid supplements for reducing the risk of T2DM, CVD, and hypertension in elderly Chinese

  16. Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians.

    PubMed

    Kumudini, Nadella; Uma, Addepally; Naushad, Shaik Mohammad; Mridula, Rukmini; Borgohain, Rupam; Kutala, Vijay Kumar

    2014-05-01

    This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, p<0.0001) and MTRR 66 A>G (r=0.31, p<0.0001) whereas an inverse correlation was observed with cSHMT 1420 C>T polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35-4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07-0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

  17. Overexpression of HDAC1 induces cellular senescence by Sp1/PP2A/pRb pathway

    SciTech Connect

    Chuang, Jian-Ying; Hung, Jan-Jong

    2011-04-15

    Highlights: {yields} Overexpression of HDAC1 induces Sp1 deacetylation and raises Sp1/p300 complex formation to bind to PP2Ac promoter. {yields} Overexpression of HDAC1 strongly inhibits the phosphorylation of pRb through up-regulation of PP2A. {yields} Overexpressed HDAC1 restrains cell proliferaction and induces cell senescence though a novel Sp1/PP2A/pRb pathway. -- Abstract: Senescence is associated with decreased activities of DNA replication, protein synthesis, and cellular division, which can result in deterioration of cellular functions. Herein, we report that the growth and division of tumor cells were significantly repressed by overexpression of histone deacetylase (HDAC) 1 with the Tet-off induced system or transient transfection. In addition, HDAC1 overexpression led to senescence through both an accumulation of hypophosphorylated active retinoblastoma protein (pRb) and an increase in the protein level of protein phosphatase 2A catalytic subunit (PP2Ac). HDAC1 overexpression also increased the level of Sp1 deacetylation and elevated the interaction between Sp1 and p300, and subsequently that Sp1/p300 complex bound to the promoter of PP2Ac, thus leading to induction of PP2Ac expression. Similar results were obtained in the HDAC1-Tet-off stable clone. Taken together, these results indicate that HDAC1 overexpression restrained cell proliferation and induced premature senescence in cervical cancer cells through a novel Sp1/PP2A/pRb pathway.

  18. Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state.

    PubMed

    Dell'edera, Domenico; Tinelli, Andrea; Milazzo, Giusi Natalia; Malvasi, Antonio; Domenico, Carone; Pacella, Elena; Pierluigi, Compagnoni; Giuseppe, Tarantino; Marcello, Guido; Francesco, Lomurno; Epifania, Annunziata Anna

    2013-08-01

    The role of hyperhomocysteinemia (HHcy) as a cardiovascular risk factor remains a matter of debate, while it correlates with folates, it demonstrates inverse correlation with plasma homocysteine (Hcy) levels and vitamin B12 levels and reduces plasma Hcy levels following supplementation with multivitamins. The purpose of this study was to demonstrate that administering multivitamins at specific doses for 90 days restores normal plasma Hcy levels in women who are homozygous for the thermolabile variant of 5,10 methylenetetrahydrofolate reductase (MTHFR C677T). We enrolled 106 healthy females aged between 30 and 42 years, who were non-smokers, non-vegetarian, normotensive and who had no history of food abuse in the previous months. Only females were enrolled in order to rule out any bias due to the variation in Hcy plasma concentrations between males and females. Patient blood sampling was performed in order to determine plasma Hcy, serum folic acid and vitamin B12 levels. Furthermore, molecular characterization of the C677T polymorphism present in the MTHFR gene, was also performed. The results of this study demonstrated that supplementation with specific multivitamins restores normal plasma Hcy levels, regardless of the MTHFR genotype. Furthermore, it is unnecessary to adminster high doses of folate to reduce plasma Hcy levels, and administering high doses of folate may cause pro-inflammatory and pro-proliferative effects. PMID:23818036

  19. Assessment of Folic Acid Supplementation in Pregnant Women by Estimation of Serum Levels of Tetrahydrofolic Acid, Dihydrofolate Reductase, and Homocysteine.

    PubMed

    Naithani, Manisha; Saxena, Vartika; Mirza, Anissa Atif; Kumari, Ranjeeta; Sharma, Kapil; Bharadwaj, Jyoti

    2016-01-01

    Background. Status of folic acid use in pregnant women of the hilly regions in North India was little known. This study was carried out to assess the folic acid use and estimate folate metabolites in pregnant women of this region. Materials and Methods. This cross-sectional study is comprised of 76 pregnant women, whose folic acid supplementation was assessed by a questionnaire and serum levels of homocysteine, tetrahydrofolic acid (THFA), and dihydrofolate reductase (DHFR) were estimated using Enzyme Linked Immunoassays. Results. The study data revealed awareness of folic acid use during pregnancy was present in 46.1% and 23.7% were taking folic acid supplements. The study depicted that there was no statistically significant difference between serum levels of THFA and DHFR in pregnant women with and without folic acid supplements (p = 0.790). Hyperhomocysteinemia was present in 15.78% of the participants. Conclusion. Less awareness about folic acid supplementation and low use of folic acid by pregnant women were observed in this region. Sufficient dietary ingestion may suffice for the escalated requirements in pregnancy, but since this cannot be ensured, hence folic acid supplementation should be made as an integral part of education and reproductive health programs for its better metabolic use, growth, and development of fetus.

  20. Relationship between plasma total homocysteine level and dietary caffeine and vitamin B6 intakes in pregnant women.

    PubMed

    Shiraishi, Mie; Haruna, Megumi; Matsuzaki, Masayo; Ota, Erika; Murayama, Ryoko; Sasaki, Satoshi; Yeo, SeonAe; Murashima, Sachiyo

    2014-06-01

    A high total homocysteine (tHcy) level during pregnancy is a risk factor for adverse perinatal outcomes, such as fetal growth restriction and preeclampsia. Caffeine is assumed to increase tHcy levels by acting as a vitamin B6 antagonist. The objective of this study was to examine a relationship between circulating tHcy levels and dietary caffeine and vitamin B6 intakes in pregnant Japanese women. A total of 321 healthy women with singleton pregnancies were recruited in metropolitan Tokyo, from June to December 2008, resulting in the final number included in the study as 254. Dietary caffeine intakes did not correlate with plasma tHcy levels. When we analyzed the data according to caffeinated beverages, caffeinated tea consumption was positively associated with plasma tHcy levels only among the women with a high intake of vitamin B6 , after controlling for confounding factors (P = 0.029). No correlation between coffee consumption and plasma tHcy levels was found. Pregnant Japanese women might need to cut down the consumption of caffeinated tea as well as take sufficient vitamin B6 in order to prevent the tHcy levels from increasing.

  1. A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations.

    PubMed

    Pintó, Xavier; Vilaseca, M Antonia; Balcells, Susana; Artuch, Rafael; Corbella, Emili; Meco, José F; Vila, Ramon; Pujol, Ramon; Grinberg, Daniel

    2005-01-01

    Background & Aims: At least 500 mug of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 mug of folate or with one 500 mug capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: -15.9 to -1.2) and synthetic folic acid capsules by 8% (95% CI: -13.3 to -2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.

  2. An aldehyde group-based P-acid probe for selective fluorescence turn-on sensing of cysteine and homocysteine.

    PubMed

    Yang, Chunlei; Wang, Xiu; Shen, Lei; Deng, Wenping; Liu, Haiyun; Ge, Shenguang; Yan, Mei; Song, Xianrang

    2016-06-15

    A highly sensitive and selective turn on fluorescent probe P-acid-aldehyde (P-CHO) is developed for the determination of cysteine (Cys) and homocysteine (Hcy). The probe is designed and synthesized by incorporating the specific functional group aldehyde group for thiols into a stable π-conjugated material 4,4'-(2,5-dimethoxy-1,4-phenylene) bis(ethyne-2,1-diyl) dibenzoic acid (P-acid). The probe fluorescence is quenched through donor photoinduced electron transfer (d-PET) between the fluorophore (P-acid) and the recognition group (aldehyde group). In the presence of thiols, Cys and Hcy can selectively react with aldehyde group of the probe because the inhibition of d-PET between fluorophore and recognition group. Therefore, a turn-on fluorescent sensor was established for the fluorescence recovery. Under the optimized conditions, the fluorescence response of probe is directly proportional to the concentration of Cys in the range of 4-95 NM L(-1), with a detection limit 3.0 nM. In addition, the sensing system exhibits good selectively toward Cys and Hcy in the presence of other amino acids. It has been successfully applied for bioimaging of Cys and Hcy in living cells with low cell toxicity.

  3. Homocysteine as a predictive biomarker in early diagnosis of renal failure susceptibility and prognostic diagnosis for end stages renal disease.

    PubMed

    Amin, Hatem K; El-Sayed, Mohamed-I Kotb; Leheta, Ola F

    2016-09-01

    Glomerular filtration rate and/or creatinine are not accurate methods for renal failure prediction. This study tested homocysteine (Hcy) as a predictive and prognostic marker for end stage renal disease (ESRD). In total, 176 subjects were recruited and divided into: healthy normal group (108 subjects); mild-to-moderate impaired renal function group (21 patients); severe impaired renal function group (7 patients); and chronic renal failure group (40 patients) who were on regular hemodialysis. Blood samples were collected, and serum was separated for analysis of total Hcy, creatinine, high sensitive C-reactive protein (CRP), serum albumin, and calcium. Data showed that Hcy level was significantly increased from normal-to-mild impairment then significantly decreases from mild impairment until the patient reaches severe impairment while showing significant elevation in the last stage of chronic renal disease. Creatinine level was increased in all stages of kidney impairment in comparison with control. CRP level was showing significant elevation in the last stage. A significant decrease in both albumin and calcium was occurred in all stages of renal impairment. We conclude Hcy in combination with CRP, creatinine, albumin, and calcium can be used as a prognostic marker for ESRD and an early diagnostic marker for the risk of renal failure.

  4. A Simple and Effective Ratiometric Fluorescent Probe for the Selective Detection of Cysteine and Homocysteine in Aqueous Media.

    PubMed

    Na, Risong; Zhu, Meiqing; Fan, Shisuo; Wang, Zhen; Wu, Xiangwei; Tang, Jun; Liu, Jia; Wang, Yi; Hua, Rimao

    2016-01-01

    Biothiols such as cysteine (Cys) and homocysteine (Hcy) are essential biomolecules participating in molecular and physiological processes in an organism. However, their selective detection remains challenging. In this study, ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (NL) was synthesized as a ratiometric fluorescent probe for the rapid and selective detection of Cys and Hcy over glutathione (GSH) and other amino acids. The fluorescence intensity of the probe in the presence of Cys/Hcy increased about 3-fold at a concentration of 20 equiv. of the probe, compared with that in the absence of these chemicals in aqueous media. The limits of detection of the fluorescent assay were 0.911 μM and 0.828 μM of Cys and Hcy, respectively. ¹H-NMR and MS analyses indicated that an excited-state intramolecular proton transfer is the mechanism of fluorescence sensing. This ratiometric probe is structurally simple and highly selective. The results suggest that it has useful applications in analytical chemistry and diagnostics. PMID:27527138

  5. Assessment of Folic Acid Supplementation in Pregnant Women by Estimation of Serum Levels of Tetrahydrofolic Acid, Dihydrofolate Reductase, and Homocysteine

    PubMed Central

    Saxena, Vartika; Mirza, Anissa Atif; Kumari, Ranjeeta; Sharma, Kapil; Bharadwaj, Jyoti

    2016-01-01

    Background. Status of folic acid use in pregnant women of the hilly regions in North India was little known. This study was carried out to assess the folic acid use and estimate folate metabolites in pregnant women of this region. Materials and Methods. This cross-sectional study is comprised of 76 pregnant women, whose folic acid supplementation was assessed by a questionnaire and serum levels of homocysteine, tetrahydrofolic acid (THFA), and dihydrofolate reductase (DHFR) were estimated using Enzyme Linked Immunoassays. Results. The study data revealed awareness of folic acid use during pregnancy was present in 46.1% and 23.7% were taking folic acid supplements. The study depicted that there was no statistically significant difference between serum levels of THFA and DHFR in pregnant women with and without folic acid supplements (p = 0.790). Hyperhomocysteinemia was present in 15.78% of the participants. Conclusion. Less awareness about folic acid supplementation and low use of folic acid by pregnant women were observed in this region. Sufficient dietary ingestion may suffice for the escalated requirements in pregnancy, but since this cannot be ensured, hence folic acid supplementation should be made as an integral part of education and reproductive health programs for its better metabolic use, growth, and development of fetus. PMID:27064332

  6. Parkinson's Disease and Homocysteine: A Community-Based Study in a Folate and Vitamin B12 Deficient Population

    PubMed Central

    Tiandong, Wang; Yang, Li; Huaxing, Meng; Guowen, Min; Yalan, Fang

    2016-01-01

    Background. Homocysteine (Hcy) levels were higher in patients with Parkinson's disease (PD). This could be partially explained by levodopa treatment. Whether untreated PD patients have higher Hcy levels is contradictory. Methods. A community-based study was conducted using a two-stage approach for subjects ≥ 55 years to find PD patients in 3 towns of Lüliang City. Blood samples were collected. Serum Hcy, folate, and vitamin B12 concentrations were measured. For each untreated PD patient, 5 controls were selected matched with age and sex to evaluate the relationship between Hcy levels and PD. Results. Of 6338 eligible residents, 72.7% participated in the study. 31 PD cases were identified. The crude prevalence of PD for people ≥ 55 years was 0.67%. Blood samples were collected from 1845 subjects, including 17 untreated PD patients. There was no difference for concentrations of serum Hcy, folate, and vitamin B12 between cases and controls (P > 0.05). In univariate and multivariate analysis, there was significant inverse relation between PD and current smoking (P < 0.05). No other factor was significant statistically. Conclusions. The prevalence of PD was comparable to earlier studies in China. Hyperhomocysteinemia was not a risk factor of PD, as well as folate and vitamin B12 deficiency. PMID:27656311

  7. Parkinson's Disease and Homocysteine: A Community-Based Study in a Folate and Vitamin B12 Deficient Population.

    PubMed

    Wei, Zhang; Tiandong, Wang; Yang, Li; Huaxing, Meng; Guowen, Min; Yalan, Fang; Xiaoyuan, Niu

    2016-01-01

    Background. Homocysteine (Hcy) levels were higher in patients with Parkinson's disease (PD). This could be partially explained by levodopa treatment. Whether untreated PD patients have higher Hcy levels is contradictory. Methods. A community-based study was conducted using a two-stage approach for subjects ≥ 55 years to find PD patients in 3 towns of Lüliang City. Blood samples were collected. Serum Hcy, folate, and vitamin B12 concentrations were measured. For each untreated PD patient, 5 controls were selected matched with age and sex to evaluate the relationship between Hcy levels and PD. Results. Of 6338 eligible residents, 72.7% participated in the study. 31 PD cases were identified. The crude prevalence of PD for people ≥ 55 years was 0.67%. Blood samples were collected from 1845 subjects, including 17 untreated PD patients. There was no difference for concentrations of serum Hcy, folate, and vitamin B12 between cases and controls (P > 0.05). In univariate and multivariate analysis, there was significant inverse relation between PD and current smoking (P < 0.05). No other factor was significant statistically. Conclusions. The prevalence of PD was comparable to earlier studies in China. Hyperhomocysteinemia was not a risk factor of PD, as well as folate and vitamin B12 deficiency.

  8. L-DOPA treatment in MPTP-mouse model of Parkinson's disease potentiates homocysteine accumulation in substantia nigra.

    PubMed

    Bhattacharjee, Nivedita; Mazumder, Muhammed Khairujjaman; Paul, Rajib; Choudhury, Amarendranath; Choudhury, Sabanum; Borah, Anupom

    2016-08-15

    One of the intermediates of methionine cycle, the homocysteine (Hcy), elevates in plasma of Parkinson's disease (PD) patients undergoing L-DOPA (3,4-dihydroxyphenylalanine) therapy and has been regarded as a risk factor of the disease. Several evidences pointed out that Hcy causes degeneration of dopaminergic neurons. In rodent, elevated level of Hcy in brain or infusion of the same directly into the substantia nigra (SN) potentiates dopaminergic neurodegeneration. However, the influence of L-DOPA therapy on the levels of Hcy in dopamine-rich regions of the brain (striatum and SN) of experimental models of PD is not known. The present study, for the first time, tested the hypothesis that L-DOPA treatment in experimental mouse model of PD potentiates Hcy accumulation in the dopamine-rich regions of the brain. We found a significant elevation of Hcy level in nigrostriatum in naïve as well as parkinsonian mice as a result of chronic L-DOPA treatment. Interestingly, L-DOPA treatment significantly elevates Hcy level in nigra but not in striatum of parkinsonian mice, when compared with L-DOPA naïve group. However, there is no significant decrease in the number of dopaminergic neurons in SN region in the parkinsonian mice given L-DOPA treatment. Thus, the present study demonstrates that L-DOPA treatment potentiates the level of Hcy in the SN without causing aggravated neurodegeneration in parkinsonian mice model.

  9. Parkinson's Disease and Homocysteine: A Community-Based Study in a Folate and Vitamin B12 Deficient Population.

    PubMed

    Wei, Zhang; Tiandong, Wang; Yang, Li; Huaxing, Meng; Guowen, Min; Yalan, Fang; Xiaoyuan, Niu

    2016-01-01

    Background. Homocysteine (Hcy) levels were higher in patients with Parkinson's disease (PD). This could be partially explained by levodopa treatment. Whether untreated PD patients have higher Hcy levels is contradictory. Methods. A community-based study was conducted using a two-stage approach for subjects ≥ 55 years to find PD patients in 3 towns of Lüliang City. Blood samples were collected. Serum Hcy, folate, and vitamin B12 concentrations were measured. For each untreated PD patient, 5 controls were selected matched with age and sex to evaluate the relationship between Hcy levels and PD. Results. Of 6338 eligible residents, 72.7% participated in the study. 31 PD cases were identified. The crude prevalence of PD for people ≥ 55 years was 0.67%. Blood samples were collected from 1845 subjects, including 17 untreated PD patients. There was no difference for concentrations of serum Hcy, folate, and vitamin B12 between cases and controls (P > 0.05). In univariate and multivariate analysis, there was significant inverse relation between PD and current smoking (P < 0.05). No other factor was significant statistically. Conclusions. The prevalence of PD was comparable to earlier studies in China. Hyperhomocysteinemia was not a risk factor of PD, as well as folate and vitamin B12 deficiency. PMID:27656311

  10. Ratiometric measurement of hydrogen sulfide and cysteine/homocysteine ratios using a dual-fluorophore fragmentation strategy.

    PubMed

    Hammers, Matthew D; Pluth, Michael D

    2014-07-15

    Hydrogen sulfide (H2S) is an integral signaling molecule in biology with complex generation, translocation, and metabolism processes that are intertwined with cellular thiols. Differentiating the complex interplay between H2S and biological thiols, however, remains challenging due to the difficulty of monitoring H2S and thiol levels simultaneously in complex redox environments. As a step toward unraveling the complexities of H2S and thiols in sulfur redox homeostasis, we present a dual-fluorophore fragmentation strategy that allows for the ratiometric determination of relative H2S and cysteine (Cys) or homocysteine (Hcy) concentrations, two important metabolites in H2S biosynthesis. The key design principle is based on a nitrobenzofurazan-coumarin (NBD-Coum) construct, which fragments into spectroscopically differentiable products upon nucleophilic aromatic substitution with either H2S or Cys/Hcy. Measurement of the ratio of fluorescence intensities from coumarin and the NBD-Cys or NBD-Hcy adducts generates a sigmoidal response with a dynamic range of 3 orders of magnitude. The developed scaffold displays a rapid response (<1 min) and is selective for sulfhydryl-containing nucleophiles over other reactive sulfur, oxygen, and nitrogen species, including alcohol- and amine-functionalized amino acids, polyatomic anionic sulfur species, NO, and HNO. Additionally, NBD-Coum is demonstrated to differentiate and report on different oxidative stress stimuli in simulated sulfur pools containing H2S, Cys, and cystine.

  11. Aerobic Physical Exercise Improved the Cognitive Function of Elderly Males but Did Not Modify Their Blood Homocysteine Levels

    PubMed Central

    Antunes, Hanna Karen M.; De Mello, Marco Túlio; de Aquino Lemos, Valdir; Santos-Galduróz, Ruth Ferreira; Camargo Galdieri, Luciano; Amodeo Bueno, Orlando Francisco; Tufik, Sergio; D'Almeida, Vânia

    2015-01-01

    Background Physical exercise influences homocysteine (Hcy) concentrations, cognitive function and the metabolic profile. The purpose of this study was to investigate the influence of regular physical exercise on Hcy levels, the metabolic profile and cognitive function in healthy elderly males before and after an endurance exercise program. Methods Forty-five healthy and sedentary volunteers were randomized into 2 groups: (1) a control group asked not to change their normal everyday activities and not to start any regular physical exercise program and (2) an experimental group trained at a heart rate intensity corresponding to ventilatory threshold 1 (VT-1) for 60 min/day 3 times weekly on alternate days for 6 months using a cycle ergometer. All volunteers underwent cognitive evaluations, blood sample analyses and ergospirometric assessments. Results A significant improvement in cognitive function was observed in the experimental group compared with the control group (p < 0.05). No significant changes in Hcy levels were observed in the experimental group (p > 0.05), but there was a significant increase in peak oxygen consumption and workload at VT-1 as well as a significant improvement in cholesterol, triglycerides, HDL, glucose, alkaline phosphatase, urea, T3, T4 and prostate-specific antigen compared with the control group (p < 0.05). Conclusion The data suggest that a physical exercise program does not reduce Hcy levels in healthy elderly males, although it improves the cardiovascular and metabolic profile as well as cognitive function. PMID:25759715

  12. Modulating the Copper-Sulfur Interaction in Type 1 Blue Copper Azurin by Replacing Cys112 with Nonproteinogenic Homocysteine

    PubMed Central

    Clark, Kevin M; Yu, Yang; Blackburn, Ninian; Lu, Yi

    2014-01-01

    The Cu-SCys interaction is known to play a dominant role in defining the type 1 (T1) blue copper center with respect to both its electronic structure and electron transfer function. Despite this importance, its role has yet to be probed by mutagenesis studies without dramatic change of its T1 copper character. We herein report replacement of the conserved Cys112 in azurin with the nonproteinogenic amino acid homocysteine. Based on electronic absorption, electron paramagnetic resonance, and extended x-ray absorption fine structural spectroscopic studies, this variant displays typical type 1 copper site features. Surprisingly, instead of increasing the strength of the Cu-sulfur interaction by the introduction of the extra methylene group, the Cys112Hcy azurin showed a decrease in the covalent interaction between SHcy and Cu(II) when compared with the WT SCys-Cu(II) interaction. This is likely due to geometric adjustment of the center that resulted in the copper ion moving out of the trigonal plane defined by two histidines and one Hcy and closer to Met121. These structural changes resulted in an increase of reduction potential by 35 mV, consistent with lower Cu-S covalency. These results suggest that the Cu-SCys interaction is close to being optimal in native blue copper protein. It also demonstrates the power of using nonproteinogenic amino acids in addressing important issues in bioinorganic chemistry. PMID:24707355

  13. Gold nanoparticle extraction followed by o-phthaldialdehyde derivatization for fluorescence sensing of different forms of homocysteine in plasma.

    PubMed

    Lai, Yi-Jhen; Tseng, Wei-Lung

    2012-03-15

    This study reports a selective and sensitive method for fluorescent detection of total, protein-bound, free, and free oxidized homocysteine (HCys) using tris(2-carboxyethyl)phosphine (TCEP) as a reducing agent, fluorosurfactant-capped gold nanoparticles (FSN-AuNP) as a preconcentrating probe, and o-phthaldialdehyde (OPA) as a derivatizing agent. TCEP was used to reduce the disulfide bonds of protein-bound and free oxidized HCys. FSN-AuNPs can extract HCys from a complicated complex because the FSN capping layer stabilizes the AuNPs in a high-salt solution and inhibits non-specific adsorption. HCys was selectively derivatized with OPA in the absence of a nucleophile. By taking advantage of these features, the selectivity of the proposed system is greater than 100-fold for HCys and homocystine (HCys-HCys disulfide; diHCys) compared to any aminothiols. The limits of detection for HCys and diHCys were 4.4 and 4.6 nM, respectively. Different forms of plasma HCys were determined by varying the order of disulfide reduction with TCEP.

  14. Impact of physical activity and cardiovascular fitness on total homocysteine concentrations in European adolescents: The HELENA study.

    PubMed

    Benser, Jasmin; Valtueña, Jara; Ruiz, Jonatan R; Mielgo-Ayuso, Juan; Breidenassel, Christina; Vicente-Rodriguez, German; Ferrari, Marika; Widhalm, Kurt; Manios, Yannis; Sjöström, Michael; Molnar, Denes; Gómez-Martínez, Sonia; Kafatos, Antony; Palacios, Gonzalo; Moreno, Luis A; Castillo, Manuel J; Stehle, Peter; González-Gross, Marcela

    2015-01-01

    We examined the association of physical activity (PA), cardiovascular fitness (CVF) and fatness with total homocysteine (tHcy) concentrations in European adolescents. The present study comprised 713 European adolescents aged 14.8 ± 1.2 y (females 55.3%) from the multicenter HELENA cross-sectional study. PA was assessed through accelerometry, CVF by the 20-m shuttle run test, and body fat by skinfold thicknesses with the Slaughter equation. Plasma folate, cobalamin, and tHcy concentrations were measured. To examine the association of tHcy with PA, CVF, and fatness after controlling for a set of confounders including age, maturity, folate, cobalamin, creatinine, smoking, supplement use, and methylenetetrahydrofolate reductase 677 genotype (CC 47%, CT 43%, TT 10%), bivariate correlations followed by multiple regression models were performed. In the bivariate correlation analysis, tHcy concentrations were slightly negatively correlated (p<0.05) with CVF in females (measured both by stages: r=-0.118 and by VO2max: r=-0.102) and positively with body mass index (r=0.100). However, daily time spent with moderate and vigorous PA showed a weak positive association with tHcy in females (p<0.05). tHcy concentrations showed a tendency to decrease with increasing CVF and increase with increasing BMI in female European adolescents. However, tHcy concentrations were positively associated with moderate and vigorous PA in female European adolescents.

  15. Hypertrophy of IMC of carotid artery in Parkinson's disease is associated with L-DOPA, homocysteine, and MTHFR genotype.

    PubMed

    Nakaso, Kazuhiro; Yasui, Kenichi; Kowa, Hisanori; Kusumi, Masayoshi; Ueda, Keigo; Yoshimoto, Yuko; Takeshima, Takao; Sasaki, Kiyohiro; Nakashima, Kenji

    2003-03-15

    In recent years, an intense interest has developed in the association between Parkinson's disease (PD) and hyperhomocysteinemia. Homocysteine (Hcy) is a neuronal excitotoxic amino acid, and is well known as a risk factor for vascular diseases. Some reports suggest that the administration of L-DOPA may promote hyperhomocysteinemia and idiopathic atherosclerosis. In this study, we report that a mild hypertrophy of the intima-media complex (IMC) of the carotid artery, which has been established as a marker for systemic atherosclerosis, is observed in PD patients compared with normal subjects. PD patients that were treated with L-DOPA for long durations showed a hypertrophic IMC, while the patients that were not treated with L-DOPA did not show any hypertrophic changes in the IMC. These hypertrophic changes were observed primarily in patients with a Hoehn-Yahr stage of 3-5. PD patients with hypertrophic IMC of the carotid artery also exhibited elevated plasma levels of Hcy associated with the C677T genotype of 5,10-methylenetetrahydrofolate reductase (MTHFR). Moreover, a prolonged duration of treatment with L-DOPA in patients with MTHFR T/T genotype enhanced the hypertrophy of IMC, compared with patients with the C/C or C/T genotype. These results suggest that hyperhomocysteinemia promoted by the C677T genotype of MTHFR and prolonged treatment with L-DOPA enhances atherosclerosis in PD patients and affects their general condition.

  16. RelA-Induced Interferon Response Negatively Regulates Proliferation

    PubMed Central

    Kochupurakkal, Bose S.; Wang, Zhigang C.; Hua, Tony; Culhane, Aedin C.; Rodig, Scott J.; Rajkovic-Molek, Koraljka; Lazaro, Jean-Bernard; Richardson, Andrea L.; Biswas, Debajit K.; Iglehart, J. Dirk

    2015-01-01

    Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors. PMID:26460486

  17. Role of plasma homocysteine levels and MTHFR polymorphisms on IQ scores in children and young adults with epilepsy treated with antiepileptic drugs.

    PubMed

    Di Rosa, Gabriella; Lenzo, Patrizia; Parisi, Eleonora; Neri, Milena; Guerrera, Silvia; Nicotera, Antonio; Alibrandi, Angela; Germanò, Eva; Caccamo, Daniela; Spanò, Maria; Tortorella, Gaetano

    2013-12-01

    Homocysteine (Hcy) is a sulfur-containing amino acid involved in methionine metabolism. High plasma total Hcy (tHcy) has been quite frequently reported in patients with epilepsy treated with antiepileptic drugs (AEDs) mainly related to plasma folate reduction induced by AEDs themselves. The role of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene (MTHFR) on the increase of plasma tHcy in patients with epilepsy taking AEDs is still controversial. Cognitive impairment may be associated with epilepsy either as the result of the epileptic syndrome per se or as a side effect induced by the AEDs. High plasma tHcy levels were associated with lower cognitive performances in patients affected by Alzheimer's disease and mild cognitive impairment and in healthy elderly. We searched for a correlation between plasma tHcy levels with the intelligence quotient (IQ) scores in a population of children and young adults with epilepsy treated with old and/or newer AEDs. The study group encompassed 179 patients (92 M, 51.5%) followed at our Unit of Child Neuropsychiatry and aged between 4 and 25years (mean+SD: 14.03±4.25). The inclusion criteria included the following: 1) diagnosis of epilepsy of "unknown cause" (cryptogenic) according to the ILAE classification, 2) age older than 3years, 3) stabilized antiepileptic treatment for at least 6months, and 4) clinical records of cognitive tests, plasma tHcy value, and results of MTHFR polymorphisms. Patients' mean tHcy value was 9.71±3.13μM/L (tHcy<9μM/L as our laboratory cutoff in nonepileptic controls). The mean TIQ score was 85.22 (SD±24.12); the mean VIQ score was 86.32 (SD±20.86); and the mean PIQ score was 86.94 (SD±21.51). C677T and A1298C MTHFR polymorphisms were detected in 74/92 (80%) examined patients and distributed into the following: CT (22.3%), TT (14.9%), CC (10.3%) for C677T, AC (16%), CC (1.1%), and AA (30.3%) for A1298C. Plasma tHcy levels were not significantly related to the IQ scores

  18. Higher intake of vitamin B-6 and dairy products and lower intake of green and oolong tea are independently associated with lower serum homocysteine concentration in young Japanese women.

    PubMed

    Murakami, Kentaro; Sasaki, Satoshi; Uenishi, Kazuhiro

    2013-08-01

    Little is known about the relation of modifiable dietary factors to circulating homocysteine concentrations, particularly in young adults and non-Western populations. We investigated the hypothesis that intakes of nutrients and foods are associated with serum homocysteine concentration in a group of young Japanese women. This cross-sectional study included 1050 female Japanese dietetic students aged 18 to 22 years. Dietary intake was assessed using a validated, self-administered, comprehensive diet history questionnaire. Fasting blood samples were collected, and serum homocysteine concentrations were measured. Adjustment was made for survey year, region, municipality level, current smoking, current alcohol drinking, dietary supplement use, physical activity, body mass index, energy intake, and intakes of other nutrients or foods. After adjustment for nondietary confounding factors, intakes of all B vitamins (folate, vitamin B-6, vitamin B-12, and riboflavin) were inversely associated with homocysteine concentration. However, only vitamin B-6 remained significant after further adjustment for other B vitamins. Marine-origin n-3 polyunsaturated fatty acid intake showed an inverse association, but this was not independent of intakes of B vitamins. For foods, pulses, fish and shellfish, and vegetables were independently and inversely associated with homocysteine concentration, but these associations disappeared after adjustment for intakes of other foods. Conversely, an inverse association for dairy products and a positive association for green and oolong tea remained even after adjustment for other foods. To conclude, in a group of young Japanese women, higher intake of vitamin B-6 and dairy products and lower intake of green and oolong tea were independently associated with lower serum homocysteine concentration.

  19. Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice.

    PubMed

    Martínez-Vega, Raquel; Partearroyo, Teresa; Vallecillo, Néstor; Varela-Moreiras, Gregorio; Pajares, María A; Varela-Nieto, Isabel

    2015-12-01

    Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid-high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss.

  20. 5,10-methylene tetrahydrofolate reductase C677T gene polymorphism, homocysteine concentration and the extent of premature coronary artery disease in southern Iran.

    PubMed

    Senemar, Sara; Saffari, Babak; Sharifkazemi, Mohammad Bagher; Bahari, Marzieh; Jooyan, Najmeh; Dehaghani, Elham Davoudi; Yavarian, Majid

    2013-01-01

    Elevated level of plasma homocysteine (Hcy) has been identified as an independent risk factor for coronary artery disease (CAD). Furthermore, numerous studies have documented the influences of a common polymorphism (C677T) of methylenetetrahydrofolate reductase (MTHFR) on homocysteine levels. However the relationship between this mutation and cardiovascular diseases (CVD) has remained as a controversial issue. The present study was undertaken to investigate the relationship between C677T polymorphism of MTHFR gene, plasma total Hcy levels and the number of affected vessels as a criterion for the extent of CAD. MTHFR genotypes and plasma homocysteine (HCY) concentrations were examined in 231 patients and 300 healthy subjects who underwent diagnostic coronary angiography. A multiple linear regression analysis was performed to identify the predictors of Hcy levels whereas logistic regression model was built to determine the association of Hcy quartiles with the risk of CAD adjusted for risk factors. The prevalence of MTHFR genotypes was similar between CAD patients and non-CAD individuals while the geometric mean of Hcy values was significantly higher in patient group (14.13 ± 4.11 μmol/l) than in control group (10.19 ± 3.52 μmol/l) (P < 0.001). Moreover, unlike the MTHFR polymorphism, Hcy concentration increased with increasing number of stenosed vessels and the CAD risk increased about 2 folds in the top two Hcy quartiles (≥ 17.03 and 13.20-17.02 μmol/l) compared with the lowest quartile (≤ 9.92 μmol/l) after controlling for conventional risk factors (P<0.001 for both). Our data suggest that hyperhomocysteinaemia (HHcy) is significantly associated to CAD risk increase as well as to the extent of coronary atherosclerosis. PMID:26417236

  1. DNA/nickel oxide nanoparticles/osmium(III)-complex modified electrode toward selective oxidation of l-cysteine and simultaneous detection of l-cysteine and homocysteine.

    PubMed

    Sharifi, Ensiyeh; Salimi, Abdollah; Shams, Esmaeil

    2012-08-01

    The modification of glassy carbon (GC) electrode with electrodeposited nickel oxide nanoparticles (NiOxNPs) and deoxyribonucleic acid (DNA) is utilized as a new efficient platform for entrapment of osmium (III) complex. Surface morphology and electrochemical properties of the prepared nanocomposite modified electrode (GC/DNA/NiOxNPs/Os(III)-complex) were investigated by FESEM, cyclic voltammetry and electrochemical impedance spectroscopy techniques. Cyclic voltammetric results indicated the excellent electrocatalytic activity of the resulting electrode toward oxidation of l-cysteine (CySH) at reduced overpotential (0.1 V vs. Ag/AgCl). Using chronoamperometry to CySH detection, the sensitivity and detection limit of the biosensor are obtained as 44 μA mM(-1) and 0.07 μM with a concentration range up to 1000 μM. The electrocatalytic activity of the modified electrode not only for oxidation of low molecular-mass biothiols derivatives such as, glutathione, l-cystine, l-methionine and electroactive biological species ( dopamine, uric acid, glucose) is negligible but also for very similar biothiol compound (homocysteine) no recognizable response is observed at the applied potential window. Furthermore, the simultaneous voltammetric determination of l-cysteine and homocysteine compounds without any separation or pretreatment process was reported for the first time in this work. Finally, the applicability of sensor for the analysis of CySH concentration in complex serum samples was successfully demonstrated. Highly selectivity, excellent electrocatalytic activity and stability, remarkable antifouling property toward thiols and their oxidation products, as well as the ability for simultaneous detection of l-cysteine and homocysteine are remarkably advantageous of the proposed DNA based biosensor.

  2. [Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries].

    PubMed

    Klenkova, N A; Kapustin, S I; Saltykova, N B; Shmeleva, V M; Blinov, M N

    2009-01-01

    Under study were features of allele polymorphism of genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A 2756G), methionine synthase reductase (MTRR A66G) and methylenetetrahydrofolate dehydrogenase (MTHFD G1958A) in patients with atherosclerosis of the lower extremity arteries (ALEA). Patients with hyperhomocysteinemia (HHcy) had statistically significant increase of allele MTHFR 677T and MTRR 66GG as compared both with the control group and with the group of patients without HHcy. It suggests that polymorphism of genes involved in homocystein and folate metabolism might affect the risk of HHcy in patients with ALEA. PMID:20209990

  3. Functional COMT Val158Met Polymorphism, Risk of Acute Coronary Events and Serum Homocysteine: The Kuopio Ischaemic Heart Disease Risk Factor Study

    PubMed Central

    Voutilainen, Sari; Tuomainen, Tomi-Pekka; Korhonen, Maarit; Mursu, Jaakko; Virtanen, Jyrki K.; Happonen, Pertti; Alfthan, Georg; Erlund, Iris; North, Kari E.; Mosher, M.J.; Kauhanen, Jussi; Tiihonen, Jari; Kaplan, George A.; Salonen, Jukka T.

    2007-01-01

    Background The role of circulating levels of total homocysteine tHcy in the development of coronary heart disease (CHD) is still under debate. One reason for conflicting results between previous studies on homocysteine and heart diseases could be consequence of different interactions between homocysteine and genes in different study populations. Many genetic factors play a role in folate-homocysteine metabolism, like functional polymorphism (Val108Met) in the Catechol-O-methyltransferase (COMT) gene. Methodology and Findings Our aim was to examine the role of COMT Val158Met polymorphism and interaction of this polymorphism with serum tHcy and folate concentration on the risk of acute coronary and events in middle-aged men from eastern Finland. A population-based prospective cohort of 792 men aged 46–64 years was examined as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 9.3 years, there were 69 acute coronary events in men with no previous history of CHD. When comparing the COMT low activity genotype with the others, we found an age and examination year adjusted hazard rate ratio (HRR) of 1.73 (95% confidence interval (CI), 1.07–2.79), and an age, examination year, serum LDL and HDL cholesterol, and triglyceride concentration, systolic blood pressure and smoking adjusted HRR of 1.77 (95% CI, 1.05–2.77). Although serum tHcy concentration was not statistically significantly associated with acute coronary events (HRR for the highest third versus others 1.52, 95% CI, 0.93–2.49), subjects with both high serum tHcy and the COMT low activity genotype had an additionally increased adjusted risk of HRR 2.94 (95% CI 1.50–5.76) as compared with other men. Conclusions This prospective cohort study suggests that the functional COMT Val158Met polymorphism is associated with increased risk of acute coronary events and it may interact with high serum tHcy levels. PMID:17264883

  4. [Features of allele polymorphism of genes involved in homocysteine and folate metabolism in patients with atherosclerosis of the lower extremity arteries].

    PubMed

    Klenkova, N A; Kapustin, S I; Saltykova, N B; Shmeleva, V M; Blinov, M N

    2009-01-01

    Under study were features of allele polymorphism of genes of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A 2756G), methionine synthase reductase (MTRR A66G) and methylenetetrahydrofolate dehydrogenase (MTHFD G1958A) in patients with atherosclerosis of the lower extremity arteries (ALEA). Patients with hyperhomocysteinemia (HHcy) had statistically significant increase of allele MTHFR 677T and MTRR 66GG as compared both with the control group and with the group of patients without HHcy. It suggests that polymorphism of genes involved in homocystein and folate metabolism might affect the risk of HHcy in patients with ALEA.

  5. Crystal structures of Mycobacterium tuberculosis S-adenosyl-L-homocysteine hydrolase in ternary complex with substrate and inhibitors

    SciTech Connect

    Reddy, Manchi C.M.; Kuppan, Gokulan; Shetty, Nishant D.; Owen, Joshua L.; Ioerger, Thomas R.; Sacchettini, James C.

    2009-12-01

    S-adenosylhomocysteine hydrolase (SAHH) is a ubiquitous enzyme that plays a central role in methylation-based processes by maintaining the intracellular balance between S-adenosylhomocysteine (SAH) and S-adenosylmethionine. We report the first prokaryotic crystal structure of SAHH, from Mycobacterium tuberculosis (Mtb), in complex with adenosine (ADO) and nicotinamide adenine dinucleotide. Structures of complexes with three inhibitors are also reported: 3{prime}-keto aristeromycin (ARI), 2-fluoroadenosine, and 3-deazaadenosine. The ARI complex is the first reported structure of SAHH complexed with this inhibitor, and confirms the oxidation of the 3{prime} hydroxyl to a planar keto group, consistent with its prediction as a mechanism-based inhibitor. We demonstrate the in vivo enzyme inhibition activity of the three inhibitors and also show that 2-fluoradenosine has bactericidal activity. While most of the residues lining the ADO-binding pocket are identical between Mtb and human SAHH, less is known about the binding mode of the homocysteine (HCY) appendage of the full substrate. We report the 2.0 {angstrom} resolution structure of the complex of SAHH cocrystallized with SAH. The most striking change in the structure is that binding of HCY forces a rotation of His363 around the backbone to flip out of contact with the 5{prime} hydroxyl of the ADO and opens access to a nearby channel that leads to the surface. This complex suggests that His363 acts as a switch that opens up to permit binding of substrate, then closes down after release of the cleaved HCY. Differences in the entrance to this access channel between human and Mtb SAHH are identified.

  6. Genetic and Lifestyle Variables Associated with Homocysteine Concentrations and the Distribution of Folate Derivatives in Healthy Premenopausal Women

    PubMed Central

    Summers, Carolyn M.; Mitchell, Laura E.; Stanislawska-Sachadyn, Anna; Baido, Shirley F.; Blair, Ian A.; Von Feldt, Joan M.; Whitehead, Alexander S.

    2014-01-01

    Background Low folate and high homocysteine (Hcy) concentrations are associated with pregnancy-related pathologies such as spina bifida. Polymorphisms in folate/Hcy metabolic enzymes may contribute to this potentially pathogenic biochemical phenotype. Methods The study comprised 26 Caucasian and 23 African-American premenopausal women. Subjects gave fasting blood samples for biochemical phenotyping and genotyping. Total Hcy (tHcy) and both plasma and red blood cell (RBC) folate derivatives [i.e. tetrahydrofolate (THF), 5-methylTHF (5-MTHF), and 5,10-methenylTHF (5,10-MTHF)] were measured using stable isotope dilution liquid chromatography, multiple reaction monitoring, mass spectrometry. Eleven polymorphisms from nine folate/Hcy pathway genes were genotyped. Tests of association between genetic, lifestyle, and biochemical variables were applied. Results In African American women, tHcy concentrations were associated (p<0.05) with total RBC folate, RBC 5-MTHF, B12, and polymorphisms in methionine synthase (MTR) and thymidylate synthase (TYMS). In Caucasian women, tHcy concentrations were not associated with total folate levels, but were associated (p<0.05) with RBC THF, ratios of RBC 5-MTHF: THF, and polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and MTR . In African Americans, folate derivative levels were associated with smoking, B12, and polymorphisms in MTR, TYMS, methionine synthase reductase (MTRR), and reduced folate carrier1 (RFC1). In Caucasians, folate derivative levels were associated with vitamin use, B12, and polymorphisms in MTHFR, TYMS, and RFC1. Conclusions Polymorphisms in the folate/Hcy pathway are associated with tHcy and folate derivative levels. In African American and Caucasian women, different factors are associated with folate/Hcy phenotypes and may contribute to race-specific differences in the risks of a range of pregnancy-related pathologies. PMID:20544798

  7. Big-endothelin 1 (big ET-1) and homocysteine in the serum of dogs with chronic kidney disease.

    PubMed

    Rossi, Gabriele; Giordano, Alessia; Breda, Sara; Lisi, Chiara; Roura, Xavier; Zatelli, Andrea; Paltrinieri, Saverio

    2013-10-01

    This study was aimed at determining the serum concentration of homocysteine (Hcy) and big endothelin-1 (big ET-1, the precursor of endothelin) in dogs with chronic kidney disease (CKD) with and without hypertension, proteinuria and inflammation, in order to explore their role as biomarkers of hypertension associated with CKD. Hcy and big ET-1 were measured using an enzyme-linked immunosorbent assay and an enzymatic cyclic reaction, respectively, in dogs with CKD staged, as proposed by the International Renal Interest Society (IRIS), using serum creatinine, urinary protein to creatinine (UPC) ratio and systolic blood pressure, and classified as affected or not by inflammation based on the serum concentration of C-reactive protein (CRP). Serum Hcy was significantly higher in dogs of IRIS stages II, III and IV compared with controls and in proteinuric compared with non-proteinuric dogs. No differences relating to the degree of hypertension or to the CRP concentration were found. Serum big ET-1 significantly increased in dogs of IRIS stage IV compared with controls, in proteinuric compared with non-proteinuric dogs, in dogs with severe hypertension compared with those without hypertension, and in dogs with increased CRP compared to those with normal CRP concentrations. Hcy only correlated with serum creatinine but big ET-1 significantly correlated with serum creatinine, UPC ratio, systolic blood pressure, and increased CRP. In conclusion, both Hcy and big ET-1 increase in dogs with CKD. Although further research is needed, big ET-1, but not Hcy, may also be considered as a biomarker of hypertension.

  8. Prognostic Value of Elevated Homocysteine Levels in Korean Patients with Coronary Artery Disease: A Propensity Score Matched Analysis

    PubMed Central

    Kwon, Sung Woo; Kim, Jong-Youn; Suh, Young Ju; Lee, Dae Hyung; Yoon, Young Won; Lee, Byoung Kwon; Jung, Young-Hak; Choi, Eui-Young; Hong, Bum-Kee; Rim, Se-Joong

    2016-01-01

    Background and Objectives We sought to determine whether an elevated homocysteine (Hcy) level is associated with a worse prognosis in Korean patients with coronary artery disease (CAD). Subjects and Methods A total of 5839 patients (60.4% male, mean age 61.3±11.2 years) with CAD were enrolled from 2000 to 2010 at Gangnam Severance Hospital. CAD was diagnosed by invasive coronary angiography. Laboratory values including Hcy level were obtained on the day of coronary angiography and analyses were performed shortly after sampling. Patients were divided into two groups according to their Hcy levels. Baseline risk factors, coronary angiographic findings, length of follow-up, and composite endpoints including cardiac death (CD) and non-fatal myocardial infarction (NFMI) were recorded. 1:1 propensity score matched analysis was also performed. Results Over a mean follow-up period of 4.4±2.5 years, there were 132 composite endpoints (75 CD and 57 NFMI) with an event rate of 2.3%. Mean Hcy level was 9.9±4.3 µmol/L (normal Hcy 7.9±1.5 µmol/L and elevated Hcy 13.9±5.1 µmol/L). Kaplan-Meier survival analysis showed an association of elevated Hcy level with worse prognosis (p<0.0001). In addition, a multivariate Cox regression analysis showed an association of elevated Hcy level with worse prognosis for both the entire cohort (hazard ratio [HR] 2.077, 95% confidence interval [CI] 1.467-2.941, p<0.0001) and the propensity score matched cohort (HR 1.982, 95% CI 1.305-3.009, p=0.001). Conclusion Elevated Hcy level is associated with worse outcomes in Korean patients with CAD. PMID:27014345

  9. Role of B₁₂ and homocysteine status in determining BMD and bone turnover in young Indians.

    PubMed

    Haroon, Nisha Nigil; Marwaha, Raman K; Godbole, Madan M; Gupta, Sushil K

    2012-01-01

    Vitamin B(12) (B(12)) deficiency and hyperhomocysteinemia (HHcy) are independent risk factors for low bone mineral density (BMD) and fracture risk. We studied the role of HHcy and B(12) deficiency in determining the peak bone mass in Indians. Randomly selected 151 healthy young adult subjects (females 100, mean age: 26 yr) underwent evaluation of dietary intake of calcium and B(12); sun exposure; estimation of BMD by dual-energy X-ray absorptiometry at total hip, forearm, and lumbar spine; serum 25(OH)D(3); intact parathyroid hormone; B(12); homocysteine (Hcy); and bone turnover markers (BTMs) serum crosslaps, N-mid osteocalcin, and bone-specific alkaline phosphatase. Hypovitaminosis D (serum 25OHD(3)<20 ng/mL) and serum ALP level >150 IU/L were seen in 83% and 27%, respectively. Median serum B(12) and Hcy levels were 140 pg/mL (interquartile range [IQR]: 72-230 pg/mL) and 18 μmol/L (IQR 14-32 μmol/L); B(12) deficiency (serum B(12)<200 pg/mL) and HHcy (serum Hcy>30 μmol/L) were present in 71% and 68%, respectively. Low BMD (Z-score <-2.0) was present in 17% of subjects. There was no significant correlation between serum Hcy, folate, B(12), BTM, and BMD. BMD was predicted by height, weight, and body mass index. Young Indian healthy adults have high prevalence of hypovitaminosis D, B(12) deficiency, and HHcy. There is no correlation of serum B(12), folate, and Hcy status with BTMs and BMD in young, healthy, vegetarian Indian adults. Anthropometric variables predict BMD in young Indians.

  10. Low erythrocyte catalase enzyme activity is correlated with high serum total homocysteine levels in tunisian patients with acute myocardial infarction

    PubMed Central

    2013-01-01

    Background An imbalance between pro-oxidants and antioxidant systems has been suggested to be implicated in the physiopathology of acute myocardial infarction (AMI). We aimed to evaluate the antioxidant capacity in Tunisian patients and to assess the possible relationship between erythrocyte catalase enzyme activity and hyperhomocysteinaemia. Methods 108 patients with AMI and 81 healthy subjects were enrolled in this study. Catalase erythrocyte enzyme activity was determined spectrophotometrically whereas “total antioxidant status” (TAS) concentration was measured by a commercially available method. Serum total homocysteine (tHcy) level was determined by a fluorescence polarization immunoassay (FPIA). Lipid peroxidation was measured with a fluorimetric method as “thiobarbituric acid reactive substances” (TBARS). Results Compared with healthy subjects, patients with AMI had significantly lower catalase activity (P<0.001), TAS concentrations (P<0.001), and significantly higher serum tHcy (P<0.001) and TBARS levels (P<0.001). Erythrocyte catalase enzyme activity was negatively correlated with serum tHcy and TBARS while serum tHcy and TBARS were in positive correlation. Furthermore, the unbalance between pro-oxidants and antioxidants seems to be more aggravated in patients with Q wave AMI compared to patients with non-Q wave AMI. Conclusion Our results suggest the involvement of hyperhomocysteinaemia in the drop of erythrocyte catalase activity related to myocardial ischemia reperfusion. Hyperhomocysteinaemia may increase the myocardial wall dysfunction under ischemia reperfusion by excessive production of reactive oxygen species which is made evident by increased lipid peroxidation. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1623509866881834 PMID:23631751

  11. Effect of losartan with folic acid on plasma homocysteine and vascular ultrastructural changes in spontaneously hypertensive rats.

    PubMed

    Zhu, Lihe; Yu, Jiong; Jia, Baofu; Zhao, Feng; Tang, Mengmeng; Hu, Lufeng; Lin, Feiyan

    2015-01-01

    Elevated homocysteine (Hcy) is a high risk factor of hypertension due to its function in endothelial dysfunction. Its level in the blood is strongly influenced by folic acid. In order to investigate the effects of losartan with folic acid on plasma level of Hcy and vascular ultrastructural changes, thirty spontaneously hypertensive rats (SHR) involved and randomly divided into three groups (n=10): SHR-C group (control), SHR-L group (losartan 25 mg · kg(-1) · d(-1)), SHR-L+Y group (losartan 25 mg · kg(-1) · d(-1) + folic acid 0.4 mg · kg(-1) · d(-1)). Another 10 Wistar Rats involved as WKY-C group for normal control. The level of plasma Hcy was measured dynamically by LS-MS, the vascular ultrastructural changes were analyzed by light and electron microscopy. Moreover, the thickness and area of aorta was measured. The results showed the Hcy levels in four groups were WKY-C 7.49 ± 1.95 μmol/L; SHR-C 8.45 ± 1.90 μmol/L; SHR-L 8.28 ± 2.11 μmol/L; SHR-L+Y 7.53 ± 2.02 μmol/L at 80 days. There was no significant change for plasma Hcy (P>0.05). The morphological change showed the subendothelial space didn't increased significantly, the endothelial cells have a more smooth and intact cellular membrane in SHR-L+Y group. In conclusion, Losartan combined with folic acid could improve arterial endothelial structure in SHR which has no significant correlation with plasma Hcy.

  12. Opposite effects of plasma homocysteine and the methylenetetrahydrofolate reductase C677T mutation on carotid artery geometry in asymptomatic adults.

    PubMed

    Demuth, K; Moatti, N; Hanon, O; Benoit, M O; Safar, M; Girerd, X

    1998-12-01

    Studies of symptomatic patients have identified hyperhomocysteinemia as an independent risk factor for vascular disease. In case-control studies, a point mutation (C677T) in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) has also been linked to an increased risk of vascular disease through its effect on homocysteinemia. Our aim was to extend these observations to asymptomatic subjects by studying the influence of both homocysteinemia and its mutation on carotid artery geometry. We examined 144 subjects free of atherosclerotic lesions. Fasting homocysteinemia was measured by high-performance liquid chromatography with fluorometric detection. MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. Carotid artery geometry was characterized by internal diameter and intima-media thickness, as assessed by a high-resolution echo-tracking system. Subjects in the upper homocysteine tertile had a greater carotid internal diameter than did subjects in the middle and lower tertiles (6516+/-770 versus 6206+/-641 and 5985+/-558 microm, respectively; P<0.001). Subjects homozygous for the mutation had a smaller carotid artery internal diameter than did subjects heterozygous or homozygous for the wild-type allele (5846+/-785 versus 6345+/-673 and 6199+/-671 microm, respectively; P<0.05). Homocysteinemia was not significantly increased in subjects homozygous for the mutation. In multivariate regression analysis, homocysteinemia was independently and positively associated with lumen diameter (P=0.0008) and wall thickness (P=0.020). Conversely, homozygosity for the mutation was negatively associated with internal diameter (P=0.009). These preliminary data suggest that mildly elevated homocysteinemia and homozygosity for the MTHFR C677T mutation are associated with opposite preclinical modifications of carotid artery geometry. If confirmed, these results may have important implications for new treatment strategies for vascular disease

  13. Neurotoxic injury pathways in differentiated mouse motor neuron–neuroblastoma hybrid (NSC-34D) cells in vitro—Limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity

    SciTech Connect

    Hemendinger, Richelle A.; Brooks, Benjamin Rix

    2012-01-15

    The neuroblastoma–spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H{sub 2}O{sub 2}) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC{sub 50} = 0.01 μM), followed by Thaps (TC{sub 50} = 0.9 μM) and H{sub 2}O{sub 2} (TC{sub 50} = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC{sub 50} = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H{sub 2}O{sub 2}- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. -- Highlights: ► Calcium-dependent neurotoxins are potent cell death inducers in NSC-34D cells. ► Riluzole provides neurorescue against Thaps-induced NSC-34D cell death. ► Riluzole had no effect on neurotoxicity by STS, H{sub 2}O{sub 2} and Hcy. ► Riluzole reduces NSC-34D cell death independent of

  14. Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine.

    PubMed

    Troen, Aron M; Chao, Wei-Hsun; Crivello, Natalia A; D'Anci, Kristen E; Shukitt-Hale, Barbara; Smith, Don E; Selhub, Jacob; Rosenberg, Irwin H

    2008-12-01

    Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

  15. Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

    PubMed

    Mälarstig, Anders; Buil, Alfonso; Souto, Juan Carolos; Clarke, Robert; Blanco-Vaca, Francisco; Fontcuberta, Jordi; Peden, John; Andersen, Malin; Silveira, Angela; Barlera, Simona; Seedorf, Udo; Watkins, Hugh; Almasy, Laura; Hamsten, Anders; Soria, José Manuel

    2009-08-13

    Total plasma homocysteine concentration (tHcy) is a biomarker for atherothrombotic disease, but causality remains uncertain. Polymorphisms in the genes involved in methionine metabolism explain only a small fraction of the heritability of tHcy levels. In a genome-wide association study, we examined the genetic determinants of tHcy using a 2-stage design. First, 283 437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 persons recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR 677C>T SNP (beta = 0.10, P = .0001). Second, a replication analysis of these 17 SNPs was performed in patients with premature myocardial infarction (n = 1238). Novel associations were found for SNPs near the ZNF366 gene (lead SNP rs7445013; discovery stage: adjusted beta = -0.12, P = 5.30 x 10(-6), replication stage: adjusted beta = -0.13, P = .004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted beta = 0.11, P = 5.5 x 10(-6), replication stage: adjusted beta = 0.10, P = .005). These associations were independent of known confounders, including creatinine clearance and plasma fibrinogen concentration. Our findings implicate novel pathways in homocysteine metabolism, and highlight the need for investigation of the associated genes in the etiology of vascular diseases.

  16. The effects of long-term resistance exercise on the relationship between neurocognitive performance and GH, IGF-1, and homocysteine levels in the elderly

    PubMed Central

    Tsai, Chia-Liang; Wang, Chun-Hao; Pan, Chien-Yu; Chen, Fu-Chen

    2015-01-01

    This study aimed to investigate the effects of a long-term resistance exercise intervention on executive functions in healthy elderly males, and to further understand the potential neurophysiological mechanisms mediating the changes. The study assessed forty-eight healthy elderly males randomly assigned to exercise (n = 24) or control (n = 24) groups. The assessment included neuropsychological and neuroelectric measures during a variant of the oddball task paradigm, as well as growth hormone (GH), insulin-like growth factor-1 (IGF-1), and homocysteine levels at baseline and after either a 12 month intervention of resistance exercise training or control period. The results showed that the control group had a significantly lower accuracy rate and smaller P3a and P3b amplitudes in the oddball condition after 12 months. The exercise group exhibited improved reaction times (RTs), sustained P3a and P3b amplitudes, increased levels of serum IGF-1, and decreased levels of serum homocysteine. The changes in IGF-1 levels were significantly correlated with the changes in RT and P3b amplitude of the oddball condition in the exercise group. In conclusion, significantly enhanced serum IGF-1 levels after 12 months of resistance exercise were inversely correlated with neurocognitive decline in the elderly. These findings suggest that regular resistance exercise might be a promising strategy to attenuate the trajectory of cognitive aging in healthy elderly individuals, possibly mediated by IGF-1. PMID:25713518

  17. A Phospholipid-Protein Complex from Antarctic Krill Reduced Plasma Homocysteine Levels and Increased Plasma Trimethylamine-N-Oxide (TMAO) and Carnitine Levels in Male Wistar Rats

    PubMed Central

    Bjørndal, Bodil; Ramsvik, Marie S.; Lindquist, Carine; Nordrehaug, Jan E.; Bruheim, Inge; Svardal, Asbjørn; Nygård, Ottar; Berge, Rolf K.

    2015-01-01

    Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC’s content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis. PMID:26371012

  18. The matricellular protein CCN1 suppresses lung cancer cell growth by inducing senescence via the p53/p21 pathway.

    PubMed

    Jim Leu, Shr-Jeng; Sung, Jung-Sung; Chen, Mei-Yu; Chen, Chih-Wei; Cheng, Jian-Yu; Wang, Tse-Yen; Wang, Jeng-Jung

    2013-09-01

    CCN1, a secreted matrix-associated molecule, is involved in multiple cellular processes. Previous studies have indicated that expression of CCN1 correlates inversely with the aggressiveness of non-small-cell lung carcinoma (NSCLC); however, the underlying mechanisms remain elusive. Using three NSCLC cell line systems, here we show that long-term treatment of cells with the recombinant CCN1 protein led to a permanent cell cycle arrest in G1 phase; cells remained viable as judged by apoptotic assays. CCN1-treated NSCLC cells acquired a phenotype characteristic of senescent cells, including an enlarged and flattened cell shape and expression of the senescence-associated β-galactosidase. Immunoblot analysis showed that addition of CCN1 increased the abundance of hypo-phosphorylated Rb, as well as accumulation of p53 and p21. Silencing the expression of p53 or p21 by lentivirus-mediated shRNA production in cells blocked the CCN1-induced senescence. Furthermore, a CCN1 mutant defective for binding integrin α6β1 and co-receptor heparan sulfate proteoglycans was incapable of senescence induction. Our finding that direct addition of CCN1 induces senescence in NSCLC cells provides a potential novel strategy for therapeutic intervention of lung cancers.

  19. Genome-wide meta-analysis of homocysteine and methionine metabolism identifies five one carbon metabolism loci and a novel association of ALDH1L1 with ischemic stroke

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Circulating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the ...

  20. Combined cobalamin and iron deficiency anemia: a diagnostic approach using a model based on age and homocysteine assessment.

    PubMed

    Remacha, Angel F; Sardà, M P; Canals, C; Queraltò, J M; Zapico, E; Remacha, J; Carrascosa, C

    2013-04-01

    Macrocytosis, the hallmark of cobalamin/folate deficiency anemia, is frequently absent. Clinicians have to be aware of coexisting conditions that can mask the macrocytosis expression of megaloblastic anemia, especially iron deficiency. The objective of this work was to investigate the degree of overlap between iron deficiency anemia (IDA) and cobalamin deficiency and to develop a predictive model for differentiating IDA from combined deficiency. A prospective case and control study was carried out to investigate vitamin B12 and folate status in iron deficiency anemia. A total of 658 patients were recruited, 41 of whom (6.2 %) were excluded. The remaining 617 subjects consisted of 130 controls and 487 with IDA. Low vitamin B12 (LB12) was considered when serum vitamin B12 was ≤200 pmol/L. High serum homocysteine (Hcy) was defined by Hcy >17 μM/L. A multivariate analysis (including a logistic regression) was performed to develop a diagnostic model. Low vitamin B12 levels were found in 17.8 % of IDA subjects. Ten out of 11 subjects (91 %) with IDA and serum vitamin B12 (B12) ≤100 pmol/L showed vitamin B12 deficiency. Moreover, vitamin B12 deficiency was demonstrated in 48 % of cases with IDA and B12 between 101 and 150 pmol/L and in 40 % with IDA and B12 between 151 and 200 pmol/, respectively. As a result of multivariate logistic analysis, neutrophil counts and age predicted subjects with vitamin B12 ≤200 and Hcy >17 μmol/L, [Formula: see text]. Using the age of 60 as a cutoff, sensitivity was 91 % (39 out of the 43 patients with vitamin B12 deficiency and IDA were identified). In summary, low vitamin B12 was found in 18 % of patients with IDA. Vitamin B12 deficiency was demonstrated in many patients with LB12 and IDA. Age over 60 years was used to separate patients with combined deficiency (sensitivity 91 %). Therefore, for a diagnostic purpose, serum vitamin B12 should be evaluated in IDA patients over 60 years. This diagnostic model needs to

  1. Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)

    PubMed Central

    Lenz, Thomas; Poot, Peter; Gräbner, Olivia; Glinski, Mirko; Weinhold, Elmar; Dreger, Mathias; Köster, Hubert

    2010-01-01

    There is a variety of approaches to reduce the complexity of the proteome on the basis of functional small molecule-protein interactions such as affinity chromatography 1 or Activity Based Protein Profiling 2. Trifunctional Capture Compounds (CCs, Figure 1A) 3 are the basis for a generic approach, in which the initial equilibrium-driven interaction between a small molecule probe (the selectivity function, here S-adenosyl-L-homocysteine, SAH, Figure 1A) and target proteins is irreversibly fixed upon photo-crosslinking between an independent photo-activable reactivity function (here a phenylazide) of the CC and the surface of the target proteins. The sorting function (here biotin) serves to isolate the CC - protein conjugates from complex biological mixtures with the help of a solid phase (here streptavidin magnetic beads). Two configurations of the experiments are possible: "off-bead" 4 or the presently described "on-bead" configuration (Figure 1B). The selectivity function may be virtually any small molecule of interest (substrates, inhibitors, drug molecules). S-Adenosyl-L-methionine (SAM, Figure 1A) is probably, second to ATP, the most widely used cofactor in nature 5, 6. It is used as the major methyl group donor in all living organisms with the chemical reaction being catalyzed by SAM-dependent methyltransferases (MTases), which methylate DNA 7, RNA 8, proteins 9, or small molecules 10. Given the crucial role of methylation reactions in diverse physiological scenarios (gene regulation, epigenetics, metabolism), the profiling of MTases can be expected to become of similar importance in functional proteomics as the profiling of kinases. Analytical tools for their profiling, however, have not been available. We recently introduced a CC with SAH as selectivity group to fill this technological gap (Figure 1A). SAH, the product of SAM after methyl transfer, is a known general MTase product inhibitor 11. For this reason and because the natural cofactor SAM is used by

  2. Relationship of serum homocysteine level with nutritional status and HbA1c level in elderly inpatients

    PubMed Central

    Chen, Sheng-Fang; Cui, Chun-Li; Wu, Ping; Xie, Nan-Zi

    2013-01-01

    Background: Hyperhomocysteinemia is a risk factor for vascular diseases. This study aimed to investigate the serum total homocysteine (tHcy) level and nutritional status in elderly inpatients and determine the relationship between tHcy level and nutritional status. Methods: This cross sectional study was carried out in the Tongji hospital, and 142 subjects were consecutively recruited. Fasting blood was collected, and the liver and kidney function, blood glucose, glycosylated hemoglobin (HbA1c), plasma protein, lipid profile, folic acid, vitamin B12 and serum total tHcy were measured. Anthropometric measurements, grip strength and the shortened MNA form (MNA-SF) were used to assess the nutritional status. Results: Undernutrition was common in this population. Based on MNA-SF scores, 34.2% of subjects were at risk of malnutrition, and malnourished subjects accounted for 4.9%. The mean tHcy was 14.10±5.46 μmol/l, and the prevalence of hyperhomocysteinemia was 32.4% (46/142). Hyperhomocysteinemia was a risk factor of cerebral infarction (RR=1.636, 95% CI: 1.169-2.288); Serum tHcy was negatively correlated with serum folic acid, vitamin B12 and MNA-SF score (r=-0.348,P=0.000; r=-0.236, P=0.005; r=-0.208, P=0.014), and positively with BMI within normal range (18.5-23.9; r=0.232, P=0.044). Serum tHcy was negatively correlated with HbA1c, (r=-0.196, P=0.021) and positively with serum creatinine (r=0.327, P=0.000), but unrelated to fasting blood glucose (r=-0.098, P=0.250). Multivariate stepwise regression analysis showed serum folic acid, serum creatinine, MNA-SF score and HbA1c were independent determinants of serum tHcy. Conclusion: Elderly subjects have higher serum tHcy level. Compromised renal function, poor nutritional status and lower blood glucose are likely to influence the serum tHcy level. PMID:24179571

  3. Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis

    PubMed Central

    Deminice, Rafael; Silva, Talita Capoani Vieira; de Oliveira, Vitor Hugo Fernando

    2015-01-01

    AIM: To evaluate the association between the levels of homocysteine (Hcy), folate, vitamin B12 in human immunodeficiency virus (HIV)-infected patients who were treated with antiretroviral therapy (ART) or not treated with ART. METHODS: The PubMed and Scielo databases were searched. Eligible studies regarding plasma Hcy level in HIV-infected patients were firstly identified. After careful analysis by two independent researches, the identified articles were included in the review according to two outcomes (1) Hcy, folate and vitamin B12 blood concentration in HIV-infected subjects vs health controls and; (2) Hcy blood concentration in HIV-infected subjects under ART vs not treated with ART. RevMan (version 5.2) was employed for data synthesis. RESULTS: A total of 12 studies were included in outcome 1 (1649 participants, 932 cases and 717 controls). Outcome 1 meta-analysis demonstrated higher plasma Hcy (2.05 µmol/L; 95%CI: 0.10 to 4.00, P < 0.01) and decreased plasma folate concentrations (-2.74 ng/mL; 95%CI: -5.18 to -0.29, P < 0.01) in HIV-infected patients compared to healthy controls. No changes in vitamin B12 plasma concentration were observed between groups. All studies included in the outcome 2 meta-analysis (1167 participants; 404 HIV-infected exposed to ART and 757 HIV-infected non-ART patients) demonstrated higher mean Hcy concentration in subjects HIV-infected under ART compared to non-ART HIV subjects (4.13 µmol/L; 95%CI: 1.34 to 6.92, P < 0.01). CONCLUSION: This meta-analysis demonstrated that the levels of Hcy and folate, but not vitamin B12, were associated with HIV infection. In addition, Hcy levels were higher in HIV-infected patients who were under ART compared to HIV-infected patients who were not exposed to ART. Our results suggest that hyperhomocysteinemia should be included among the several important metabolic disturbances that are associated with ART in patients with HIV infection. PMID:25964880

  4. Profiling of methyltransferases and other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS).

    PubMed

    Lenz, Thomas; Poot, Peter; Gräbner, Olivia; Glinski, Mirko; Weinhold, Elmar; Dreger, Mathias; Köster, Hubert

    2010-01-01

    There is a variety of approaches to reduce the complexity of the proteome on the basis of functional small molecule-protein interactions such as affinity chromatography (1) or Activity Based Protein Profiling (2). Trifunctional Capture Compounds (CCs, Figure 1A) (3) are the basis for a generic approach, in which the initial equilibrium-driven interaction between a small molecule probe (the selectivity function, here S-adenosyl-(L)-homocysteine, SAH, Figure 1A) and target proteins is irreversibly fixed upon photo-crosslinking between an independent photo-activable reactivity function (here a phenylazide) of the CC and the surface of the target proteins. The sorting function (here biotin) serves to isolate the CC - protein conjugates from complex biological mixtures with the help of a solid phase (here streptavidin magnetic beads). Two configurations of the experiments are possible: "off-bead" (4) or the presently described "on-bead" configuration (Figure 1B). The selectivity function may be virtually any small molecule of interest (substrates, inhibitors, drug molecules). S-Adenosyl-(L)-methionine (SAM, Figure 1A) is probably, second to ATP, the most widely used cofactor in nature (5, 6). It is used as the major methyl group donor in all living organisms with the chemical reaction being catalyzed by SAM-dependent methyltransferases (MTases), which methylate DNA (7), RNA (8), proteins (9), or small molecules (10). Given the crucial role of methylation reactions in diverse physiological scenarios (gene regulation, epigenetics, metabolism), the profiling of MTases can be expected to become of similar importance in functional proteomics as the profiling of kinases. Analytical tools for their profiling, however, have not been available. We recently introduced a CC with SAH as selectivity group to fill this technological gap (Figure 1A). SAH, the product of SAM after methyl transfer, is a known general MTase product inhibitor (11). For this reason and because the natural

  5. Effect of vitamin B deprivation during pregnancy and lactation on homocysteine metabolism and related metabolites in brain and plasma of mice offspring.

    PubMed

    da Silva, Vanessa Cavalcante; Fernandes, Leandro; Haseyama, Eduardo Jun; Agamme, Ana Luiza Dias Abdo; Guerra Shinohara, Elvira Maria; Muniz, Maria Tereza Cartaxo; D'Almeida, Vânia

    2014-01-01

    Epidemiological and experimental studies indicate that the altered fetal and neonatal environment influences physiological functions and may increase the risk of developing chronic diseases in adulthood. Because homocysteine (Hcy) metabolic imbalance is considered a risk factor for neurodegenerative diseases, we investigated whether maternal Vitamin B deficiency during early development alters the offspring's methionine-homocysteine metabolism in their brain. To this end, the dams were submitted to experimental diet one month before and during pregnancy or pregnancy/lactation. After birth, the offspring were organized into the following groups: control (CT), deficient diet during pregnancy and lactation (DPL) and deficient diet during pregnancy (DP). The mice were euthanized at various stages of development. Hcy, cysteine, glutathione (GSH), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), folate and cobalamin concentrations were measured in the plasma and/or brain. At postnatal day (PND) 0, total brain of female and male offspring exhibited decreased SAM/SAH ratios. Moreover, at PND 28, we observed decreased GSH/GSSG ratios in both females and males in the DPL group. Exposure to a Vitamin B-deficient diet during the ontogenic plasticity period had a negative impact on plasma folate and brain cortex SAM concentrations in aged DPL males. We also observed decreased plasma GSH concentrations in both DP and DPL males (PND 210). Additionally, this manipulation seemed to affect the female and male offspring differently. The decreased plasma GSH concentration may reflect redox changes in tissues and the decreased brain cortex SAM may be involved in changes of gene expression, which could contribute to neurodegenerative diseases over the long term. PMID:24695104

  6. S-Adenosyl-S-carboxymethyl-l-homocysteine: a novel cofactor found in the putative tRNA-modifying enzyme CmoA

    SciTech Connect

    Byrne, Robert T.; Whelan, Fiona; Aller, Pierre; Bird, Louise E.; Dowle, Adam; Lobley, Carina M. C.; Reddivari, Yamini; Nettleship, Joanne E.; Owens, Raymond J.; Antson, Alfred A.; Waterman, David G.

    2013-06-01

    The putative methyltransferase CmoA is involved in the nucleoside modification of transfer RNA. X-ray crystallography and mass spectrometry are used to show that it contains a novel SAM derivative, S-adenosyl-S-carboxymethyl-l-homocysteine, in which the donor methyl group is replaced by a carboxymethyl group. Uridine at position 34 of bacterial transfer RNAs is commonly modified to uridine-5-oxyacetic acid (cmo{sup 5}U) to increase the decoding capacity. The protein CmoA is involved in the formation of cmo{sup 5}U and was annotated as an S-adenosyl-l-methionine-dependent (SAM-dependent) methyltransferase on the basis of its sequence homology to other SAM-containing enzymes. However, both the crystal structure of Escherichia coli CmoA at 1.73 Å resolution and mass spectrometry demonstrate that it contains a novel cofactor, S-adenosyl-S-carboxymethyl-l-homocysteine (SCM-SAH), in which the donor methyl group is substituted by a carboxymethyl group. The carboxyl moiety forms a salt-bridge interaction with Arg199 that is conserved in a large group of CmoA-related proteins but is not conserved in other SAM-containing enzymes. This raises the possibility that a number of enzymes that have previously been annotated as SAM-dependent are in fact SCM-SAH-dependent. Indeed, inspection of electron density for one such enzyme with known X-ray structure, PDB entry http://scripts.iucr.org/cgi-bin/cr.cgi?rm, suggests that the active site contains SCM-SAH and not SAM.

  7. Serum haematological and biochemical indices of oxidative stress and their relationship with DNA damage and homocysteine in Pakistani type II diabetic patients.

    PubMed

    Bukhari, Shazia Anwer; Javed, Sadia; Ali, Muhammad; Shahzadi, Andleeb; Rehman, Mahmoodur

    2015-05-01

    Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by chronic hyperglycaemia, higher glycated hemoglobin (HbA1C) as well as protein. Oxidative stress can cause damage to leukocytic DNA and enhancement of homocysteine (Hcy) level in sera of type 2 diabetic patients. Haematological and biochemical parameters are severely affected by oxidative stress, which results in damages to DNA and Hcy in these patients. Eighty DM patients and 80 normal subjects, after having their consent, were selected for the present study. Leukocytes were characterized for DNA damage by comet assay kit while, blood plasma was taken into account for biochemical indices using commercial test kits. Results indicated that DNA damage was strongly linked with erythrocyte sedimentation rate (ESR) (P<0.01), glycated hemoglobin (HbA1C) (P<0.0001), glycated serum protein (P<0.005), cholesterol (P<0.011), triglycerides (P<0.001), albumin (P<0.001), creatinine (P<0.006), urea (P<0.007) and ALT (P<0.02), and negatively associated with packed cell volume (PCV) (P<0.002) and hemoglobin (P<0.001). Homocysteine was strongly linked with ESR, HbA1C, glycated protein (P<0.002), cholesterol (P<0.016), triglycerides (P<0.0001), albumin, creatinine, urea, ALT and AST in diabetic patients. Hyc and DNA damages both were negatively linked with total hemoglobin and PCV. Both of these even in their normal range may have a role in the endothelium damage. Nutritional intervention to lower down Hyc and DNA damages in the Pakistani population may mitigate their effect and guarantee in maintenance of a healthy nation.

  8. Isozyme-specific enzyme inhibitors. 14. 5'(R)-C-[(L-homocystein-S-yl)methyl]adenosine 5'-(beta,gamma-imidotriphosphate), a potent inhibitor of rat methionine adenosyltransferases.

    PubMed

    Kappler, F; Vrudhula, V M; Hampton, A

    1987-09-01

    The title compound is a covalent adduct of L-methionine (Met) and beta,gamma-imido-ATP. In its synthesis the N-Boc derivative of 5'(R)-C-(aminomethyl)-N6-benzoyl-5'-O-tosyl-2',3'-O- isopropylidenadenosine was converted by the successive actions of CF3CO2H and HNO2 into the corresponding 5'(R)-C-hydroxymethyl derivative. Treatment of this with disodium L-homocysteinate led to attack of sulfur at C6', apparently via a 5',6'-epoxide, and to total stereoselective inversion at C5' to furnish, after debenzoylation, 5'(R)-C-(L-homocystein-S-ylmethyl)-2',3'-O-isopropylidene ade nosine. The 5' configuration was established by conversion of this into the known 5'(S)-C-methyl-2',3'-O-isopropylidene adenosine with Raney nickel. The alpha-amino acid residue was protected as an N-Boc methyl ester, after which the 5'-hydroxyl was phosphorylated with benzyl phosphate and dicyclohexylcarbodiimide. The phosphoanhydride bond with inorganic imidodiphosphate was then created by established methods. Finally, blocking groups were removed under conditions that gave the desired adduct with no racemization of its L-methionine residue. It was a potent inhibitor [KM(ATP)/Ki = 1080; KM(Met)/Ki = 7.7] of the M-2 (normal tissue) form of rat methionine adenosyltransferase and of the M-T (hepatoma tissue) form [KM(ATP)/Ki = 670; KM(Met)/Ki = 22]. Inhibitions were competitive with respect to ATP or to L-methionine, indicating a dual substrate site mode of binding to the enzyme forms.

  9. Rapamycin prevents cadmium-induced neuronal cell death via targeting both mTORC1 and mTORC2 pathways.

    PubMed

    Xu, Chong; Liu, Chunxiao; Liu, Lei; Zhang, Ruijie; Zhang, Hai; Chen, Sujuan; Luo, Yan; Chen, Long; Huang, Shile

    2015-10-01

    Cadmium (Cd), a toxic environmental contaminant, contributes to neurodegeneration. Rapamycin, a macrocyclic lactone, has shown preventive effect on Cd-induced neuronal cell death. However, the underlying mechanism is not fully understood. Here, we show that rapamycin prevented Cd-induced apoptotic cell death in neuronal cells. Coincidently, rapamycin markedly blocked Cd-induced phosphorylation of Akt, S6K1 and 4E-BP1 in the cells. Expression of a rapamycin-resistant and kinase-active mTOR (S2035T, mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR (S2035T/D2357E, mTOR-TE), conferred resistance to rapamycin inhibition of Cd-induced cell death, implying that the preventive effect of rapamycin on Cd-induced neurotoxicity is mTOR kinase activity-dependent. It appeared that both mTORC1 and mTORC2 were involved in the inhibitory activity of rapamycin, as silencing raptor, rictor or raptor/rictor enhanced rapamycin's blockage of Cd-induced cell death. Furthermore, downregulation of S6K1, ectopic expression of constitutively hypophosphorylated 4E-BP1 or dominant negative Akt, or co-treatment with Akt inhibitor also potentiated the rapamycin's inhibitory effect. The findings indicate that rapamycin prevents Cd-induced neuronal cell death via suppressing both mTORC1 and mTORC2 pathways. Our results highlight that rapamycin may be exploited for the prevention of Cd-induced neurodegenerative disorders.

  10. Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells.

    PubMed

    Ash, Dipankar; Subramanian, Manikandan; Surolia, Avadhesha; Shaha, Chandrima

    2015-01-01

    Nitric oxide (NO) has been shown to be effective in cancer chemoprevention and therefore drugs that help generate NO would be preferable for combination chemotherapy or solo use. This study shows a new evidence of NO as a mediator of acute leukemia cell death induced by fisetin, a promising chemotherapeutic agent. Fisetin was able to kill THP-1 cells in vivo resulting in tumor shrinkage in the mouse xenograft model. Death induction in vitro was mediated by an increase in NO resulting in double strand DNA breaks and the activation of both the extrinsic and the intrinsic apoptotic pathways. Double strand DNA breaks could be reduced if NO inhibitor was present during fisetin treatment. Fisetin also inhibited the downstream components of the mTORC1 pathway through downregulation of levels of p70 S6 kinase and inducing hypo-phosphorylation of S6 Ri P kinase, eIF4B and eEF2K. NO inhibition restored phosphorylation of downstream effectors of mTORC1 and rescued cells from death. Fisetin induced Ca(2+) entry through L-type Ca(2+) channels and abrogation of Ca(2+) influx reduced caspase activation and cell death. NO increase and increased Ca(2+) were independent phenomenon. It was inferred that apoptotic death of acute monocytic leukemia cells was induced by fisetin through increased generation of NO and elevated Ca(2+) entry activating the caspase dependent apoptotic pathways. Therefore, manipulation of NO production could be viewed as a potential strategy to increase efficacy of chemotherapy in acute monocytic leukemia.

  11. Myeloid differentiation and retinoblastoma phosphorylation changes in HL-60 cells induced by retinoic acid receptor- and retinoid X receptor-selective retinoic acid analogs.

    PubMed

    Brooks, S C; Kazmer, S; Levin, A A; Yen, A

    1996-01-01

    The ability of subtypes of retinoic acid receptors (RARs) and retinoid X receptors (RXRs) singly and in combination to elicit myeloid differentiation, G1/0-specific growth arrest, and retinoblastoma (RB) tumor suppressor protein dephosphorylation was determined in the human myeloblastic leukemia cell line HL-60 using subtype-selective retinoic acid (RA) analogs. RA analogs that selectively bind only to RARs (Am580 and/or TTNPB) or to RXRs (Ro 25-6603, SR11237, and/or SR11234) did not elicit the above-mentioned three cellular responses. In contrast, simultaneous treatment with both an RAR-selective ligand (Am580 or TTNPB) and an RXR-selective ligand (Ro 25-6603, SR11237, or SR11234) induced all three cellular processes. An RAR alpha-selective ligand used with an RXR-selective ligand generated the same responses as did all-trans RA or 9-cis RA, which affect both families of receptors, suggesting an important role for RAR alpha among RAR subtypes in eliciting cellular response. Consistent with this finding, the RAR alpha antagonist, Ro 41-5253, reduced the level of the cellular responses elicited by treatment with an RAR alpha-selective ligand plus RXR-selective ligand. The coupling of the shift of RB to its hypophosphorylated form with G1/0 arrest and differentiation in response to ligands is consistent with a possible role of RB as a downstream target or effector of RAR alpha and RXR in combination.

  12. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review.

    PubMed

    Ray, J G; Laskin, C A

    1999-09-01

    Placental infarction or abruption, recurrent pregnancy loss and pre-eclampsia are thought to arise due to defects within the placental vascular bed. Deficiencies of vitamin B12 and folate, or other abnormalities within the methionine-homocyst(e)ine pathway have been implicated in the development of such placental diseases. We conducted a systematic literature review to quantify the risk of placental disease in the presence of these metabolic defects. Studies were identified through OVID Medline between 1966 and February 1999. Terms relating to the measurement of vitamin B12, folic acid, methylenetetrahydrofolate reductase or homocyst(e)ine were combined with those of pre-eclampsia, placental abruption/infarction or spontaneous and habitual abortion. Human studies comprising both cases and controls and published in the English language were accepted. Their references were explored for other publications. Data were abstracted on the matching of cases with controls, the mean levels of folate, B12 or homocyst(e)ine in each group or the frequency of the homozygous state for the thermolabile variant of methylenetetrahydrofolate reductase. The definition of 'abnormal' for each exposure was noted and the presence or absence of the exposure of interest for each outcome was calculated as an absolute rate with a 95 per cent confidence interval. The crude odds ratios were calculated for each study and then pooled using a random effects model. Eighteen studies were finally included. Eight studies examined the risk of placental abruption/infarction in the presence of vitamin B12 or folate deficiency, or hyperhomocyst(e)inaemia. Folate deficiency was a prominent risk factor for placental abruption/infarction among four studies, though not statistically significant (pooled odds ratio 25.9, 95 per cent CI 0.9-736.3). Hyperhomocyst(e)inaemia was also associated with placental abruption/infarction both without (pooled odds ratio 5.3, 95 per cent CI 1.8-15.9) and with methionine

  13. Modulatory effect of curcumin on methionine-induced hyperlipidemia and hyperhomocysteinemia in albino rats.

    PubMed

    Kapoor, Puneet; Ansari, M Nazam; Bhandari, Uma

    2008-07-01

    The present study was designed to investigate the antioxidant effect of curcumin on methionine-induced hyperlipidemia and hyperhomocysteinemia in Wistar rats (200-250 g) of either sex. The vehicle control rats were treated with 1% Tween 80 in normal saline (2 ml/kg, po) for 30 days. Hyperlipidemia and hyperhomocysteinemia was induced by methionine administration (1 g/kg, po) for 30 days. A significant increase in total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C) and homocysteine levels in serum and thiobarbituric acid reactive substances (TBARS) levels in heart homogenates were observed with a concomitant decrease in serum high density lipoprotein (HDL-C) levels in pathogenic control (i.e. group II) rats, as compared to vehicle control (i.e. group I) rats. Further, curcumin (200 mg/kg, p.o.) treatment in methionine treated rats for 30 days significantly decreased the total cholesterol, triglycerides, LDL-C and homocysteine levels in serum and TBARS levels in heart homogenates and increased serum HDL-C levels, as compared to pathogenic control (i.e. group II) rats. The results of biochemical observations were supplemented by histopathological examination of rat's aortic section. The results of test drug were comparable to that obtained with folic acid (100 mg/kg, p.o.). The results suggest that curcumin has significant antihyperlipidemic and antihyperhomocysteinemic effect against methionine-induced hyperlipidemia and hyperhomocysteinemia in rats.

  14. Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase

    PubMed Central

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W.; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B.; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H.; Jaenisch, Rudolf

    2008-01-01

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung−/−) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung−/− embryonic fibroblasts, and conferred death of cultured Ung−/− hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung−/− but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung−/− mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency. PMID:18614692

  15. Oxyhalogen-sulfur chemistry: kinetics and mechanism of oxidation of N-acetyl homocysteine thiolactone by acidified bromate and aqueous bromine.

    PubMed

    Mbiya, Wilbes; Choi, Boyoung; Martincigh, Bice S; Morakinyo, Moshood K; Simoyi, Reuben H

    2013-12-12

    N-acetyl homocysteine thiolactone (NAHT), medically known as citiolone, can be used as a mucolytic agent and for the treatment of certain hepatic disorders. We have studied the kinetics and mechanisms of its oxidation by acidic bromate and aqueous bromine. In acidic bromate conditions the reaction is characterized by a very short induction period followed by a sudden and rapid formation of bromine and N-acetyl homocysteine sulfonic acid. The stoichiometry of the bromate-NAHT reaction was deduced to be: BrO3(-) + H2O + CH3CONHCHCH2CH2SCO → CH3CONHCHCH2CH2(SO3H)COOH + Br(-) (S1) while in excess bromate it was deduced to be: 6BrO3(-) + 5CH3CONHCHCH2CH2SCO + 6H(+) → 3Br2 + 5CH3CONHCHCH2CH2(SO3H)COOH + 2H2O (S2). For the reaction of NAHT with bromine, a 3:1 stoichiometric ratio of bromine to NAHT was obtained: 3Br2 + CH3CONHCHCH2CH2SCO + 4H2O → 6Br(-) + CH3CONHCHCH2CH2(SO3H)COOH + 6H(+) (S3). Oxidation occurred only on the sulfur center where it was oxidized to the sulfonic acid. No sulfate formation was observed. The mechanism involved an initial oxidation to a relatively stable sulfoxide without ring-opening. Further oxidation of the sulfoxide involved two pathways: one which involved intermediate formation of an unstable sulfone and the other involves ring-opening coupled with oxidation through to the sulfonic acid. There was oligooscillatory production of aqueous bromine. Bromide produced in S1 reacts with excess bromate to produce aqueous bromine. The special stability associated with the sulfoxide allowed it to coexist with aqueous bromine since its further oxidation to the sulfone was not as facile. The direct reaction of aqueous bromine with NAHT was fast with an estimated lower limit bimolecular rate constant of 2.94 ± 0.03 × 10(2) M(-1) s(-1).

  16. Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

    PubMed

    Fryer, Anthony A; Emes, Richard D; Ismail, Khaled M K; Haworth, Kim E; Mein, Charles; Carroll, William D; Farrell, William E

    2011-01-01

    Supplementation with folic acid during pregnancy is known to reduce the risk of neural tube defects and low birth weight. It is thought that folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. We examined the effects of folate on the human methylome using quantitative interrogation of 27,578 CpG loci associated with 14,496 genes at single-nucleotide resolution across 12 fetal cord blood samples. Consistent with previous studies, the majority of CpG dinucleotides located within CpG islands exhibited hypo-methylation while those outside CpG islands showed mid-high methylation. However, for the first time in human samples, unbiased analysis of methylation across samples revealed a significant correlation of methylation patterns with plasma homocysteine, LINE-1 methylation and birth weight centile. Additionally, CpG methylation significantly correlated with either birth weight or LINE-1 methylation were predominantly located in CpG islands. These data indicate that levels of folate-associated intermediates in cord blood reflect their influence and consequences for the fetal epigenome and potentially on pregnancy outcome. In these cases, their influence might be exerted during late gestation or reflect those present during the peri-conceptual period.

  17. In Vitro and In Vivo Enzyme Activity Screening via RNA-Based Fluorescent Biosensors for S-Adenosyl-l-homocysteine (SAH).

    PubMed

    Su, Yichi; Hickey, Scott F; Keyser, Samantha G L; Hammond, Ming C

    2016-06-01

    High-throughput enzyme activity screens are essential for target characterization and drug development, but few assays employ techniques or reagents that are applicable to both in vitro and live cell settings. Here, we present a class of selective and sensitive fluorescent biosensors for S-adenosyl-l-homocysteine (SAH) that provide a direct "mix and go" activity assay for methyltransferases (MTases), an enzyme class that includes several cancer therapeutic targets. Our riboswitch-based biosensors required an alternate inverted fusion design strategy, but retained full selectivity for SAH over its close structural analogue, the highly abundant methylation cofactor S-adenosyl-l-methionine (SAM). The level of ligand selectivity for these fluorescent biosensors exceeded that of commercial antibodies for SAH and proved critical to cellular applications, as we employed them to measure methylthioadenosine nucleosidase (MTAN) activity in live Escherichia coli. In particular, we were able to monitor in vivo increase of SAH levels upon chemical inhibition of MTAN using flow cytometry, which demonstrates high-throughput, single cell measurement of an enzyme activity associated with the biosynthesis of quorum sensing signal AI-2. Thus, this study presents RNA-based fluorescent biosensors as promising molecular reagents for high-throughput enzymatic assays that successfully bridge the gap between in vitro and in vivo applications. PMID:27191512

  18. Refolding of a fully functional flavivirus methyltransferase revealed that S-adenosyl methionine but not S-adenosyl homocysteine is copurified with flavivirus methyltransferase.

    PubMed

    Brecher, Matthew B; Li, Zhong; Zhang, Jing; Chen, Hui; Lin, Qishan; Liu, Binbin; Li, Hongmin

    2015-01-01

    Methylation of flavivirus RNA is vital for its stability and translation in the infected host cell. This methylation is mediated by the flavivirus methyltransferase (MTase), which methylates the N7 and 2'-O positions of the viral RNA cap by using S-adenosyl-l-methionine (SAM) as a methyl donor. In this report, we demonstrate that SAM, in contrast to the reaction by-product S-adenosyl-l-homocysteine, which was assumed previously, is copurified with the Dengue (DNV) and West Nile virus MTases produced in Escherichia coli (E. coli). This endogenous SAM can be removed by denaturation and refolding of the MTase protein. The refolded MTase of DNV serotype 3 (DNV3) displays methylation activity comparable to native enzyme, and its crystal structure at 2.1 Å is almost identical to that of native MTase. We characterized the binding of Sinefungin (SIN), a previously described SAM-analog inhibitor of MTase function, to the native and refolded DNV3 MTase by isothermal titration calorimetry, and found that SIN binds to refolded MTase with more than 16 times the affinity of SIN binding to the MTase purified natively. Moreover, we show that SAM is also copurified with other flavivirus MTases, indicating that purification by refolding may be a generally applicable tool for studying flavivirus MTase inhibition.

  19. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals

    PubMed Central

    Wu, Wei; Guo, Ye; Cui, Wei

    2015-01-01

    Background Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. Method Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. Results We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. Conclusion Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer. PMID:25985325

  20. There are no differences in IL-6, CRP and homocystein concentrations between women whose mothers had AD and women whose mothers did not have AD.

    PubMed

    Devčić, Sanja; Glamuzina, Ljubomir; Ruljancic, Nedjeljka; Mihanovic, Mate

    2014-12-30

    A wide range of recent studies have detected inflammation as one of the most influent factors in the appearance and spreading of neurodegenerative brain diseases. We aimed to understand the influence of Interleukin-6 (IL-6), C-reactive protein (CRP) and homocysteine (Hcy) on patients suffering from Alzheimer׳s disease (AD) and on their descendants. Three groups of subjects were analyzed: 55 patients suffering from AD, 51 middle-aged daughters of the patients of the first group, and 53 subjects without positive family history of AD. The results of the conducted research are in accordance with the present scientific knowledge, namely a statistically significant difference for examined parameters has been determined between women suffering from AD and their daughters and control group examinees. No difference was found in serum concentrations of IL-6, highly sensitive C-reactive protein (hsCRP) and Hcy between the groups of the middle-aged descendants of patients with AD and healthy controls without family history of AD. This finding supports the hypothesis that these markers may not play causal role in the development of AD. This is supported by the obtained positive correlation between IL-6 and hsCRP and IL-6 and Hcy in AD patients while there is no such correlation between female subjects with or without a family history of AD. PMID:25240941

  1. Quantitation of sulfur-containing amino acids, homocysteine, methionine and cysteine in dried blood spot from newborn baby by HPLC-fluorescence detection.

    PubMed

    Wada, Mitsuhiro; Kuroki, Mana; Minami, Yuu; Ikeda, Rie; Sekitani, Yui; Takamura, Noboru; Kawakami, Shigeru; Kuroda, Naotaka; Nakashima, Kenichiro

    2014-06-01

    Sulfur-containing amino acids (SAAs), homocysteine (Hcy), methionine (Met) and cysteine (Cys) in blood are related to homocystinuria, an inborn error of metabolism. In this study, an assay method with HPLC-fluorescence detection to quantify the SAAs in a dried blood spot was established and applied to samples from newborn babies (n=200). Sample pretreatment involving reduction, derivatization with 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole, and liquid-liquid extraction with ethyl acetate gave the separation of the derivatives with retention times within 12 min. The method was enough sensitive to determine the SAAs in a dried blood spot with 0.04-0.14 µm as the limit of detection at a signal-to-noise ratio of 3. However, the absolute recoveries were very low (5.7% for Hcy, 4.6% for Cys) except for Met (105.4%) owing to inefficient recovery of Hcy and Cys from the blood matrix. Other validation parameters such as accuracy (93.5-106.2%) and intra- (≤ 9.0%) and inter-day precisions (≤ 8.7%) were acceptable. The reliability of a dried blood spot as an analytical sample was estimated. Furthermore, the proposed method was successfully applied to dried blood spots prepared from newborn babies.

  2. [Comparative S-adenosyl-L-methionine and S-adenosyl-L-homocysteine content in the tissues of experimental tumors in the process of their growth].

    PubMed

    Orlov, E N

    1980-01-01

    Content of S-adenosyl-l-methionine (SAM) in rat tissues of Pliss lymphosarcoma, of sarcoma 180 and in adenocarcinoma 755 of mice varied within the limits of 27-57 nM/g, 60-64 nM/g and 32-40 nM/g of wet tissue, respectively, content of S-adenosyl-l-homocysteine (SAH) varied in the tumors studied within the limits of 19-28, 16-21 and 11-20 nM/g, respectively. In the tumor bearing mice the content of SAM was unaltered in liver tissue during the growth of sarcoma 180 or adenocarcinoma 755. Development of Pliss lymphosarcoma in rats was accompanied by a decrease in content of SAM in liver tissue. When the rate of Pliss lymphosarcoma growth was decreased, the content of SAH in the tumor was unaltered but the level of SAM was decreased about 2-fold and the ratio SAH/SAM was increased, correspondingly, approximately 2-fold. If the rate of growth of mice adenocarcinoma 755 was elevated, content of SAM in the tumor was increased but the SAH level was markedly decreased and the ratio SAH/SAM was decreased about 2-fold. Concentrations of SAH and SAM were unaltered in mice sarcoma 180 with the linear rate of growth from 0.15 to 1.6 g. The data obtained suggest that the rate of growth of the tumors studied correlated with relative and absolute content of SAM and SAH.

  3. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial.

    PubMed

    Mietus-Snyder, Michele L; Shigenaga, Mark K; Suh, Jung H; Shenvi, Swapna V; Lal, Ashutosh; McHugh, Tara; Olson, Don; Lilienstein, Joshua; Krauss, Ronald M; Gildengoren, Ginny; McCann, Joyce C; Ames, Bruce N

    2012-08-01

    Dietary intake modulates disease risk, but little is known how components within food mixtures affect pathophysiology. A low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins and minerals, fruit polyphenolics, β-glucan, docosahexaenoic acid) appropriate for deconstruction and mechanistic studies is described and evaluated in a pilot trial. The bar was developed in collaboration with the U.S. Department of Agriculture. Changes in cardiovascular disease and diabetes risk biomarkers were measured after 2 wk twice-daily consumption of the bar, and compared against baseline controls in 25 healthy adults. Plasma HDL-cholesterol (HDL-c) increased 6.2% (P=0.001), due primarily to a 28% increase in large HDL (HDL-L; P<0.0001). Total plasma homocysteine (Hcy) decreased 19% (P=0.017), and glutathione (GSH) increased 20% (P=0.011). The changes in HDL and Hcy are in the direction associated with decreased risk of cardiovascular disease and cognitive decline; increased GSH reflects improved antioxidant defense. Changes in biomarkers linked to insulin resistance and inflammation were not observed. A defined food-based supplement can, within 2 wk, positively impact metabolic biomarkers linked to disease risk. These results lay the groundwork for mechanistic/deconstruction experiments to identify critical bar components and putative synergistic combinations responsible for observed effects.

  4. A novel marker for terminal Schwann cells, homocysteine-responsive ER-resident protein, as isolated by a single cell PCR-differential display.

    PubMed

    Oda, Ryo; Yaoi, Takeshi; Okajima, Seiichiro; Kobashi, Hiroaki; Kubo, Toshikazu; Fushiki, Shinji

    2003-09-01

    Terminal Schwann cells (TSCs) that cover motor neuron terminals are known to play important roles in maintaining neuromuscular junctions, as well as in the repair process after nerve injury. However, molecular characteristics of TSCs remain unknown, because of the difficulties in analyzing them due to their paucity. We have established a method of selectively and efficiently collecting TSCs so that cDNA analysis can be done properly. The expression of 1-2% of whole mRNAs was compared between myelinating Schwann cells (MSCs) and TSCs, and it turned out that approximately one-third of the bands could be categorized as cell-type-specific bands. TSCs thus constitute a distinct entity from the viewpoint of gene expression. As one of the cDNA clones belonging to TSC-specific bands was identified homocysteine-responsive ER-resident protein (Herp), and in situ hybridization confirmed that Herp mRNA is expressed in TSCs on motor nerve terminals but not in MSCs, both in developing and adult rats. In conclusion, we have been able to identify Herp as a novel molecular marker for TSCs. PMID:12927800

  5. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

  6. Palm tocotrienol-rich fraction inhibits methionine-induced cystathionine β-synthase in rat liver.

    PubMed

    Kamisah, Yusof; Norsidah, Ku-Zaifah; Azizi, Ayob; Faizah, Othman; Nonan, Mohd Rizal; Asmadi, Ahmad Yusof

    2015-12-01

    Oxidative stress plays an important role in cardiovascular diseases. The study investigated the effects of dietary palm tocotrienol-rich fraction on homocysteine metabolism in rats fed a high-methionine diet. Forty-two male Wistar rats were randomly assigned to six groups. Five groups were fed with high-methionine diet (1%) for 10 weeks. Groups 2 to 5 were also given dietary folate (8 mg/kg) and three doses of palm tocotrienol-rich fraction (30, 60 and 150 mg/kg) from week 6 to week 10. The last group was only given basal rat chow. High-methionine diet increased plasma homocysteine after 10 weeks, which was prevented by the supplementations of folate and high-dose palm tocotrienol-rich fraction. Hepatic S-adenosyl methionine (SAM) content was unaffected in all groups but S-adenosyl homocysteine (SAH) content was reduced in the folate group. Folate supplementation increased the SAM/SAH ratio, while in the palm tocotrienol-rich fraction groups, the ratio was lower compared with the folate. Augmented activity of hepatic cystathionine β-synthase and lipid peroxidation content by high-methionine diet was inhibited by palm tocotrienol-rich fraction supplementations (moderate and high doses), but not by folate. The supplemented groups had lower hepatic lipid peroxidation than the high-methionine diet. In conclusion, palm tocotrienol-rich fraction reduced high-methionine-induced hyperhomocysteinaemia possibly by reducing hepatic oxidative stress in high-methionine-fed rats. It may also exert a direct inhibitory effect on hepatic cystathionine β-synthase.

  7. Association between folate intake from different food sources in Norway and homocysteine status in a dietary intervention among young male adults.

    PubMed

    Stea, Tonje Holte; Uglem, Solveig; Wandel, Margareta; Mansoor, Mohammad Azam; Frølich, Wenche

    2009-09-01

    The aim of the present investigation was to study the effect of a dietary intervention which combined nutrition information with increased availability of vegetables, fruits and wholegrain bread. The effect of the intervention was determined by changes in the intake of vegetables, fruits, wholegrain bread and estimated nutrients. Furthermore, the study investigated whether changes in relative contribution from different food sources of folate were related to changes in the concentration of plasma total homocysteine (p-tHcy). The 5-month intervention study included 376 male recruits from the Norwegian National Guard, Vaernes (intervention group) and 105 male recruits from the Norwegian National Guard, Heggelia (control group). The study resulted in an increase in the total consumption of vegetables, fruits, berries and juice (P < 0.001) and of wholegrain bread (P < 0.001). The participants in the intervention group showed a higher increase in the intake of dietary fibre (P < 0.001) and folate (P < 0.001) compared with the control group. The relative contribution of folate intake from fruits, vegetables and wholegrain bread was higher in the intervention group compared with the control group (P < 0.001 for all). The increased intake of folate from wholegrain bread was inversely associated with a reduced concentration of p-tHcy (P = 0.017). In summary, the dietary intervention resulted in an increased intake of vegetables, fruits and wholegrain bread and a subsequent increase in folate intake from these food components. Reduction in the concentration of p-tHcy was significantly related to an increased folate intake due to an increased consumption of wholegrain bread.

  8. Broadly Applicable Strategy for the Fluorescence Based Detection and Differentiation of Glutathione and Cysteine/Homocysteine: Demonstration in Vitro and in Vivo.

    PubMed

    Chen, Wenqiang; Luo, Hongchen; Liu, Xingjiang; Foley, James W; Song, Xiangzhi

    2016-04-01

    Glutathione (GSH), cysteine (Cys), and homocysteine (Hcy) are small biomolecular thiols that are present in all cells and extracellular fluids of healthy mammals. It is well-known that each plays a separate, critically important role in human physiology and that abnormal levels of each are predictive of a variety of different disease states. Although a number of fluorescence-based methods have been developed that can detect biomolecules that contain sulfhydryl moieties, few are able to differentiate between GSH and Cys/Hcy. In this report, we demonstrate a broadly applicable approach for the design of fluorescent probes that can achieve this goal. The strategy we employ is to conjugate a fluorescence-quenching 7-nitro-2,1,3-benzoxadiazole (NBD) moiety to a selected fluorophore (Dye) through a sulfhydryl-labile ether linkage to afford nonfluorescent NBD-O-Dye. In the presence of GSH or Cys/Hcy, the ether bond is cleaved with the concomitant generation of both a nonfluorescent NBD-S-R derivative and a fluorescent dye having a characteristic intense emission band (B1). In the special case of Cys/Hcy, the NBD-S-Cys/Hcy cleavage product can undergo a further, rapid, intramolecular Smiles rearrangement to form a new, highly fluorescent NBD-N-Cys/Hcy compound (band B2); because of geometrical constraints, the GSH derived NBD-S-GSH derivative cannot undergo a Smiles rearrangement. Thus, the presence of a single B1 or double B1 + B2 signature can be used to detect and differentiate GSH from Cys/Hcy, respectively. We demonstrate the broad applicability of our approach by including in our studies members of the Flavone, Bodipy, and Coumarin dye families. Particularly, single excitation wavelength could be applied for the probe NBD-OF in the detection of GSH over Cys/Hcy in both aqueous solution and living cells.

  9. Effect of a Klamath algae product ("AFA-B12") on blood levels of vitamin B12 and homocysteine in vegan subjects: a pilot study.

    PubMed

    Baroni, Luciana; Scoglio, Stefano; Benedetti, Serena; Bonetto, Chiara; Pagliarani, Silvia; Benedetti, Yanina; Rocchi, Marco; Canestrari, Franco

    2009-03-01

    Vitamin B12 is a critical nutrient that is often inadequate in a plant-based (vegan) diet, thus the inclusion of a reliable vitamin B12 source in a vegan diet is recommended as essential. Unfortunately, many natural sources of vitamin B12 have been proven to contain biologically inactive vitamin B12 analogues, inadequate for human supplementation. The aim of this non-randomized open trial was to determine whether supplementation with a natural Klamath algae-based product ("AFA-B12", Aphanizomenon flos-aquae algae plus a proprietary mix of enzymes) could favorably affect the vitamin B12 status of a group of 15 vegan subjects. By assessing blood concentration of vitamin B12, folate, and more importantly homocysteine (Hcy, a reliable marker in vegans of their B12 absorption), the vitamin B12 status of the participants at the end of the 3-month intervention period, while receiving the Klamath-algae supplement (T2), was compared with their vitamin B12 status at the end of the 3-month control period (T1), when they were not receiving any supplement, having stopped taking their usual vitamin B12 supplement at the beginning of the study (T0). Compared to the control period, in the intervention period participants improved their vitamin B12 status, significantly reducing Hcy blood concentration (p=0.003). In conclusion, the Klamath algae product AFA-B12 appears to be, in a preliminary study, an adequate and reliable source of vitamin B12 in humans.

  10. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and high plasma homocysteine in chronic hepatitis C (CHC) infected patients from the Northeast of Brazil

    PubMed Central

    2011-01-01

    Background/Aim Hyperhomocysteinemia due to Methylenetetrahydrofolate Reductase (MTHFR) gene, in particular the C677T (Ala222Val) polymorphism were recently associated to steatosis and fibrosis. We analyzed the frequency of MTHFR gene in a cross-sectional study of patients affected by Chronic Hepatitis C (CHC) from Northeast of Brazil. Method One hundred seven-four untreated patients with CHC were genotyped for the C677T MTHFR. Genomic DNA was extracted from peripheral blood cells and the C677T MTHFR polymorphism was identified by PCR-RFLP. The homocysteine (Hcy) levels were determined by chemiluminescence method. All patients were negative for markers of Wilson's disease, hemochromatosis and autoimmune diseases and have current and past daily alcohol intake less than 100 g/week. Results Among subjects infected with CHC genotype non-1 the frequency of MTHFR genotypes TT was 9.8% versus 4.4% genotype 1 (p = 0.01). Nevertheless, association was found between the MTHFR genotype TT × CT/CC polymorphism and the degree of steatosis and fibrosis in both hepatitis C genotype (p < 0.05). A significant difference was found on plasma Hcy levels in patients with steatosis regardless of HCV genotype (p = 0.03). Conclusion Our results indicate that plasma Hcy levels is highly prevalent in subjects with chronic hepatits C with steatosis regardless of HCV genotype and vitamin deficiency. The presence of genotype TT of MTHFR C677T polymorphism was more common in CHC genotype non-1 infected patient regardless of histopathological classification and genotype TT+CT frequencies were significant in the presence of fibrosis grade 1+2 and of steatosis in CHC infected patients from the northeast of Brazil regardless of HCV genotype. The genetic susceptibility of MTHFR C677T polymorphism should be confirmed in a large population. PMID:21854603

  11. Plasma C-reactive protein and homocysteine concentrations are related to frequent fruit and vegetable intake in Hispanic and non-Hispanic white elders.

    PubMed

    Gao, Xiang; Bermudez, Odilia I; Tucker, Katherine L

    2004-04-01

    Elevated C-reactive protein (CRP) and plasma total homocysteine (Hcy) were recently identified as risk factors for cardiovascular disease. However, few studies have related fruit and vegetable consumption to these markers of inflammation and B vitamin deficiency, particularly in the Hispanic population. We examined the relation of fruit and vegetable intake with plasma CRP and Hcy concentrations in a cross-sectional study. Subjects were 445 Hispanic elders and 154 neighborhood-based non-Hispanic white elders living in Massachusetts. Diet was assessed with a FFQ designed for this population. There were significant inverse dose-response associations between fruit and vegetable intake and plasma CRP (P for trend = 0.010) and Hcy (P for trend = 0.033) concentrations, after adjustment for potential confounders. The prevalence of high plasma CRP (> 10 mg/L), and high Hcy (>10.4 micromol/L for women and >11.4 micromol/L for men), was significantly greater among subjects in the lowest quartile of fruit and vegetable consumption relative to those in the highest quartile, 17.9 vs. 9.1% and 58.7 vs. 44.4%, respectively. With each additional serving of fruit and vegetable intake, adjusted odd ratios for high plasma CRP and Hcy were 0.79 (95% CI: 0.65 to 0.97) and 0.83 (95% CI: 0.72 to 0.96), respectively. Greater frequency of fruit and vegetable intake was associated with significantly lower plasma CRP and Hcy concentrations. Because both of these metabolites are known risk factors for CVD, these findings contribute to the evidence that a higher intake of fruit and vegetables may reduce the risk of CVD.

  12. Plasma-aminothiols status and inverse correlation of total homocysteine with B-vitamins in arsenic exposed population of West Bengal, India.

    PubMed

    Mukherjee, Ashit K; Manna, Sujoy K; Roy, Sanjit K; Chakraborty, Manisha; Das, Surajit; Naskar, Jnan P

    2016-09-18

    Chronic arsenic toxicity is a serious environmental health problem across the world. Bangladesh and India (particularly the state of West Bengal) are the worst affected countries with such problem. The present study reports plasma-aminothiols (p-aminothiols) like L-cysteine (L-Cys), cysteinyl glycine (Cys-gly), total homocysteine (t-Hcy) and glutathione (GSH) status, and the inverse relationship of t-Hcy with B-vitamins (B1, B6, B9 and B12) in arsenic exposed population of West Bengal, India. Reverse phase HPLC was used to measure p-aminothiols and serum B-vitamins in different arsenic exposed population. Arsenic in drinking water and urine were measured by flow injection analysis system - Atomic Absorption Spectrometry (FIAS-AAS) and Transversely heated graphite atomizer (THGA-AAS) techniques, respectively. Water arsenic exposure was >50 µg/L in 50% population, of which majority (33.58%) belong to the range of >50-500 µg/L and more than 8% were even >1000 µg/L. Urine arsenic (µg/g creatinine) levels increased with arsenic exposure. The variability among p-aminothiols was also observed with higher exposure to arsenic in drinking water. A significant difference between exposed and control population was noticed for plasma L-Cys. The difference of B-vitamins between the population exposed to <50 and >50 µg/L arsenic in drinking water was also found to be significant. B9 and B12 deficiency with increased consumption of arsenic in water corroborates the anemic conditions commonly observed among arsenic exposed population. The aminothiol status indicated oxidative stress in exposed population. This study demonstrated progressive increase in plasma t-Hcy as well as inverse relationships of serum B-vitamins with increased water arsenic concentration. PMID:27336853

  13. Effects of DL-homocysteine thiolactone on cardiac contractility, coronary flow, and oxidative stress markers in the isolated rat heart: the role of different gasotransmitters.

    PubMed

    Zivkovic, Vladimir; Jakovljevic, Vladimir; Pechanova, Olga; Srejovic, Ivan; Joksimovic, Jovana; Selakovic, Dragica; Barudzic, Nevena; Djuric, Dragan M

    2013-01-01

    Considering the adverse effects of DL-homocysteine thiolactone hydrochloride (DL-Hcy TLHC) on vascular function and the possible role of oxidative stress in these mechanisms, the aim of this study was to assess the influence of DL-Hcy TLHC alone and in combination with specific inhibitors of important gasotransmitters, such as L-NAME, DL-PAG, and PPR IX, on cardiac contractility, coronary flow, and oxidative stress markers in an isolated rat heart. The hearts were retrogradely perfused according to the Langendorff technique at a 70 cm H2O and administered 10  μM DL-Hcy TLHC alone or in combination with 30  μM L-NAME, 10  μM DL-PAG, or 10  μM PPR IX. The following parameters were measured: dp/dt max, dp/dt min, SLVP, DLVP, MBP, HR, and CF. Oxidative stress markers were measured spectrophotometrically in coronary effluent through TBARS, NO2, O2(-), and H2O2 concentrations. The administration of DL-Hcy TLHC alone decreased dp/dt max, SLVP, and CF but did not change any oxidative stress parameters. DL-Hcy TLHC with L-NAME decreased CF, O2(-), H2O2, and TBARS. The administration of DL-Hcy TLHC with DL-PAG significantly increased dp/dt max but decreased DLVP, CF, and TBARS. Administration of DL-Hcy TLHC with PPR IX caused a decrease in dp/dt max, SLVP, HR, CF, and TBARS.

  14. Gene-environment and gene-gene interactions of specific MTHFR, MTR and CBS gene variants in relation to homocysteine in black South Africans.

    PubMed

    Nienaber-Rousseau, Cornelie; Ellis, Suria M; Moss, Sarah J; Melse-Boonstra, Alida; Towers, G Wayne

    2013-11-01

    The methylenetetrahydrofolate reductase (MTHFR), cystathione-β-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 μmol/L; p<0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 μmol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p=0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p=0.003 and=0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 TT genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations. Therefore, some of the investigated genotypes affected Hcy; residential area changed the way in which the CBS T833C/844ins68 SNPs influenced Hcy concentrations highlighting the importance of environmental factors; and gene-gene interactions allude to epistatic effects.

  15. Effects of red grape juice consumption on high density lipoprotein-cholesterol, apolipoprotein AI, apolipoprotein B and homocysteine in healthy human volunteers.

    PubMed

    Khadem-Ansari, Mohammad H; Rasmi, Yousef; Ramezani, Fatemeh

    2010-01-01

    It has suggested that grape juice consumption has lipid- lowering effect and it is associated with a decreased risk of heart disease. We aimed to evaluate the effects of red grape juice (RGj) consumption on high density lipoprotein-cholesterol (HDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB) and homocysteine (Hcy) levels in healthy human volunteers. Twenty six healthy and nonsmoking males, aged between 25-60 years, who were under no medication asked to consume 150 ml of RGj twice per day for one month. Serum HDL-C, apoAI, apoB and plasma Hcy levels were measured before and after one month RGj consumption. HDL-C levels after RGj consumption were significantly higher than the corresponding levels before the RGj consumption (41.44 ± 4.50 and 44.37 ± 4.30 mg/dl; P<0.0001). Also, apoB was significantly increased after RGj consumption (149.0 ± 22.35 and 157.19 ± 18.60 mg/dl; P<0.002). But apoAI levels were not changed significantly before and after of RGj consumption (154.27 ± 21.55 and 155.35 ± 21.07 mg/dl; P>0.05). Hcy levels were decreased after RGj consumption (7.70 ± 2.80 and 6.20 ± 2.30 µmol/l; P<0.001). The present study demonstrates that RGj consumption can significantly increase serum HDL-C levels and decrease Hcy levels. These findings may have important implications for the prevention of atherosclerosis in healthy individuals. PMID:21633724

  16. Plasma-aminothiols status and inverse correlation of total homocysteine with B-vitamins in arsenic exposed population of West Bengal, India.

    PubMed

    Mukherjee, Ashit K; Manna, Sujoy K; Roy, Sanjit K; Chakraborty, Manisha; Das, Surajit; Naskar, Jnan P

    2016-09-18

    Chronic arsenic toxicity is a serious environmental health problem across the world. Bangladesh and India (particularly the state of West Bengal) are the worst affected countries with such problem. The present study reports plasma-aminothiols (p-aminothiols) like L-cysteine (L-Cys), cysteinyl glycine (Cys-gly), total homocysteine (t-Hcy) and glutathione (GSH) status, and the inverse relationship of t-Hcy with B-vitamins (B1, B6, B9 and B12) in arsenic exposed population of West Bengal, India. Reverse phase HPLC was used to measure p-aminothiols and serum B-vitamins in different arsenic exposed population. Arsenic in drinking water and urine were measured by flow injection analysis system - Atomic Absorption Spectrometry (FIAS-AAS) and Transversely heated graphite atomizer (THGA-AAS) techniques, respectively. Water arsenic exposure was >50 µg/L in 50% population, of which majority (33.58%) belong to the range of >50-500 µg/L and more than 8% were even >1000 µg/L. Urine arsenic (µg/g creatinine) levels increased with arsenic exposure. The variability among p-aminothiols was also observed with higher exposure to arsenic in drinking water. A significant difference between exposed and control population was noticed for plasma L-Cys. The difference of B-vitamins between the population exposed to <50 and >50 µg/L arsenic in drinking water was also found to be significant. B9 and B12 deficiency with increased consumption of arsenic in water corroborates the anemic conditions commonly observed among arsenic exposed population. The aminothiol status indicated oxidative stress in exposed population. This study demonstrated progressive increase in plasma t-Hcy as well as inverse relationships of serum B-vitamins with increased water arsenic concentration.

  17. Three-month variation of plasma pentraxin 3 compared with C-reactive protein, albumin and homocysteine levels in haemodialysis patients

    PubMed Central

    Sjöberg, Bodil; Snaedal, Sunna; Stenvinkel, Peter; Qureshi, Abdul Rashid; Heimbürger, Olof; Bárány, Peter

    2014-01-01

    Background Inflammatory markers vary considerably over time in haemodialysis (HD) patients, yet the variability is poorly defined. The aim of the study was to assess changes of plasma levels of pentraxin-3 (PTX-3), C-reactive protein (CRP), albumin and homocysteine (Hcy) over 3 months and the association between the changes in these biomarkers and mortality. Methods In 188 prevalent HD patients, inflammatory markers were measured at inclusion and after 3 months. Mortality was recorded during a median follow-up of 41 months. The changes of the biomarker levels were categorized according to change in tertile for the specific biomarker. The variation was calculated as the intra-class correlation (ICC). Mortality was analysed by Kaplan–Meier and Cox proportional hazards model. The predictive strength was calculated for single measurements and for the variation of each inflammatory marker. Results The intra-individual variation (low ICC) was largest for PTX-3 [ICC 0.44; 95% confidence interval (CI): 0.33–0.55], albumin (ICC 0.58; 95% CI: 0.49–0.67) and CRP (ICC 0.59; 95% CI: 0.51–0.68) and lowest for Hcy (ICC 0.81; 95% CI: 0.77–0.86). During follow-up, 88 patients died. Conclusions PTX-3 measurements are less stable and show higher variation within patients than CRP, albumin and Hcy. Persistently elevated PTX-3 levels are associated with high mortality. Moreover, in multivariate logistic regression we found that stable high PTX-3 adds to the mortality risk, even after inclusion of clinical factors and the three other biomarkers. The associations of decreasing albumin levels as well as low Hcy levels with worse outcome reflect protein-energy wasting. PMID:25852911

  18. Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults

    PubMed Central

    Lange, Leslie A.; Croteau-Chonka, Damien C.; Marvelle, Amanda F.; Qin, Li; Gaulton, Kyle J.; Kuzawa, Christopher W.; McDade, Thomas W.; Wang, Yunfei; Li, Yun; Levy, Shawn; Borja, Judith B.; Lange, Ethan M.; Adair, Linda S.; Mohlke, Karen L.

    2010-01-01

    Plasma homocysteine (Hcy) level is associated with cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. We performed a genome-wide association study for Hcy in 1786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP) (rs7422339, P = 4.7 × 10−13) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in the Hcy level. The widely studied MTHFR C677T SNP (rs1801133) was also highly significant (P = 8.7 × 10−10) and explained 1.6% of the trait variation. We also genotyped these two SNPs in 1679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with Hcy (P = 1.9 × 10−26) and explained ∼5.1% of the variation in the offspring. In contrast, the CPS1 variant was significant only in females (P = 0.11 in all; P = 0.0087 in females). Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with Hcy in the offspring (interaction P = 1.2 × 10−5). Furthermore, although there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring (interaction P = 0.0046), there was no significant evidence for an interaction in the mothers (P = 0.55). These data confirm a recent finding that CPS1 is a locus influencing Hcy levels in women and suggest that genetic effects on Hcy may differ across developmental stages. PMID:20154341

  19. Determination of reduced homocysteine in human serum by elemental labelling and liquid chromatography with ICP-MS and ESI-MS detection.

    PubMed

    Espina, Juan Gómez; Montes-Bayón, Maria; Blanco-González, Elisa; Sanz-Medel, Alfredo

    2015-10-01

    Analytical methods allowing sensitive determination of reduced homocysteine (rHcy), one of the so-called biothiols, in human serum is a topic of growing interest due to its close relation to several human disorders, mainly cardiovascular diseases. Although most widely used analytical strategies to determine total Hcy involve derivatization by means of fluorescent labels, this work proposes the use of ebselen, a Se-containing labelling agent to derivatize the reactive sulfhydryl group of the Hcy molecule in its "free" reduced form, which is more likely to play different roles in disease pathogenesis. Optimization of the derivatization and separation conditions by high-performance liquid chromatography (HPLC) to isolate the excess of derivatizing reagent is carried out here using UV/VIS detection. Further, the study of the Se labelling reaction by electrospray ionization tandem mass spectrometry (ESI-MS/MS) provides a stoichiometry of the derivative of 1:1. The main advantage of using ebselen as a labelling agent is the presence of the Se atom in the molecule that allows the use of inductively coupled plasma mass spectrometry (ICP-MS) as a sensitive and selective Se detector. The coupling of HPLC with ICP-MS provided excellent features for the determination of Se-derivatized rHcy (detection limit of 9.6 nM) in real samples. Quantification was accomplished by using post-column isotope dilution (ID) of Se in serum samples, after precipitation of the main serum proteins. Quantitative results for "free" rHcy turned out to be around 0.18-0.22 μM in serum samples from healthy individuals that could be directly analyzed without sample preconcentration. PMID:26362154

  20. Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers.

    PubMed

    Kasperczyk, Sławomir; Dobrakowski, Michał; Kasperczyk, Aleksandra; Romuk, Ewa; Rykaczewska-Czerwińska, Monika; Pawlas, Natalia; Birkner, Ewa

    2016-09-01

    N-Acetylcysteine (NAC) could be included in protocols designed for the treatment of lead toxicity. Therefore, in this study, we decided to investigate the influence of NAC administration on homocysteine (Hcy) levels, oxidative damage to proteins, and the levels of iron (Fe), transferrin (TRF), and haptoglobin (HPG) in lead (Pb)-exposed workers. The examined population (n = 171) was composed of male employees who worked with Pb. They were randomized into four groups. Workers who were not administered any antioxidants, drugs, vitamins, or dietary supplements were classified as the reference group (n = 49). The remaining three groups consisted of workers who were treated orally with NAC at three different doses (1 × 200, 2 × 200, or 2 × 400 mg) for 12 weeks. After the treatment, blood Pb levels significantly decreased in the groups receiving NAC compared with the reference group. The protein concentration was not affected by NAC administration. In contrast, Hcy levels significantly decreased or showed a strong tendency toward lower values depending on the NAC dose. Levels of the protein carbonyl groups were significantly decreased in all of the groups receiving NAC. Conversely, glutamate dehydrogenase activity was significantly elevated in all of the groups receiving NAC, while the level of protein thiol groups was significantly elevated only in the group receiving 200 mg of NAC. Treatment with NAC did not significantly affect Fe and TRF levels, whereas HPG levels showed a tendency toward lower values. Treatment with NAC normalized the level of Hcy and decreased oxidative stress as measured by the protein carbonyl content; this effect occurred in a dose-dependent manner. Moreover, small doses of NAC elevated the levels of protein thiol groups. Therefore, NAC could be introduced as an alternative therapy for chronic Pb toxicity in humans. PMID:25731901

  1. 1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione Induces G1 Cell Cycle Arrest and Autophagy in HeLa Cervical Cancer Cells

    PubMed Central

    Tsai, Jie-Heng; Hsu, Li-Sung; Huang, Hsiu-Chen; Lin, Chih-Li; Pan, Min-Hsiung; Hong, Hui-Mei; Chen, Wei-Jen

    2016-01-01

    The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose- and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer. PMID:27527160

  2. 1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione Induces G1 Cell Cycle Arrest and Autophagy in HeLa Cervical Cancer Cells.

    PubMed

    Tsai, Jie-Heng; Hsu, Li-Sung; Huang, Hsiu-Chen; Lin, Chih-Li; Pan, Min-Hsiung; Hong, Hui-Mei; Chen, Wei-Jen

    2016-01-01

    The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose- and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer. PMID:27527160

  3. Mechanisms of Hyperhomocysteinemia Induced Skeletal Muscle Myopathy after Ischemia in the CBS−/+ Mouse Model

    PubMed Central

    Veeranki, Sudhakar; Tyagi, Suresh C.

    2015-01-01

    Although hyperhomocysteinemia (HHcy) elicits lower than normal body weights and skeletal muscle weakness, the mechanisms remain unclear. Despite the fact that HHcy-mediated enhancement in ROS and consequent damage to regulators of different cellular processes is relatively well established in other organs, the nature of such events is unknown in skeletal muscles. Previously, we reported that HHcy attenuation of PGC-1α and HIF-1α levels enhanced the likelihood of muscle atrophy and declined function after ischemia. In the current study, we examined muscle levels of homocysteine (Hcy) metabolizing enzymes, anti-oxidant capacity and focused on protein modifications that might compromise PGC-1α function during ischemic angiogenesis. Although skeletal muscles express the key enzyme (MTHFR) that participates in re-methylation of Hcy into methionine, lack of trans-sulfuration enzymes (CBS and CSE) make skeletal muscles more susceptible to the HHcy-induced myopathy. Our study indicates that elevated Hcy levels in the CBS−/+ mouse skeletal muscles caused diminished anti-oxidant capacity and contributed to enhanced total protein as well as PGC-1α specific nitrotyrosylation after ischemia. Furthermore, in the presence of NO donor SNP, either homocysteine (Hcy) or its cyclized version, Hcy thiolactone, not only increased PGC-1α specific protein nitrotyrosylation but also reduced its association with PPARγ in C2C12 cells. Altogether these results suggest that HHcy exerts its myopathic effects via reduction of the PGC-1/PPARγ axis after ischemia. PMID:25608649

  4. Mechanisms of hyperhomocysteinemia induced skeletal muscle myopathy after ischemia in the CBS-/+ mouse model.

    PubMed

    Veeranki, Sudhakar; Tyagi, Suresh C

    2015-01-01

    Although hyperhomocysteinemia (HHcy) elicits lower than normal body weights and skeletal muscle weakness, the mechanisms remain unclear. Despite the fact that HHcy-mediated enhancement in ROS and consequent damage to regulators of different cellular processes is relatively well established in other organs, the nature of such events is unknown in skeletal muscles. Previously, we reported that HHcy attenuation of PGC-1α and HIF-1α levels enhanced the likelihood of muscle atrophy and declined function after ischemia. In the current study, we examined muscle levels of homocysteine (Hcy) metabolizing enzymes, anti-oxidant capacity and focused on protein modifications that might compromise PGC-1α function during ischemic angiogenesis. Although skeletal muscles express the key enzyme (MTHFR) that participates in re-methylation of Hcy into methionine, lack of trans-sulfuration enzymes (CBS and CSE) make skeletal muscles more susceptible to the HHcy-induced myopathy. Our study indicates that elevated Hcy levels in the CBS-/+ mouse skeletal muscles caused diminished anti-oxidant capacity and contributed to enhanced total protein as well as PGC-1α specific nitrotyrosylation after ischemia. Furthermore, in the presence of NO donor SNP, either homocysteine (Hcy) or its cyclized version, Hcy thiolactone, not only increased PGC-1α specific protein nitrotyrosylation but also reduced its association with PPARγ in C2C12 cells. Altogether these results suggest that HHcy exerts its myopathic effects via reduction of the PGC-1/PPARγ axis after ischemia. PMID:25608649

  5. Analysis of the transcobalamin II 776C>G (259P>R) single nucleotide polymorphism by denaturing HPLC in healthy elderly: associations with cobalamin, homocysteine and holo-transcobalamin II.

    PubMed

    Wans, Stefan; Schüttler, Katrin; Jakubiczka, Sibylle; Müller, Andreas; Luley, Claus; Dierkes, Jutta

    2003-11-01

    A relatively new method for the detection of single nucleotide polymorphisms is the use of denaturing high-performance liquid chromatography (DHPLC). DHPLC was used to analyse the transcobalamin II 776C>G polymorphism in DNA from 159 healthy elderly. Furthermore, cobalamin, folate, homocysteine and holo-transcobalamin II (holo-TC II) were measured. The allele frequency of the G-allele was 17% with n = 55 harbouring the CC genotype, n = 77 being heterozygous and n = 27 showing the GG genotype. Holo-TC II concentrations were significantly decreased in patients harbouring the GG genotype. There was no effect on cobalamin, methylmalonyl-CoA, folate or homocysteine concentrations. A new G>A variant at nucleotide position 810 in the TC II gene was detected by an altered peak pattern in the DHPLC and further elucidated by direct sequencing. The TC II G810A variant is a silent mutation without replacement of the corresponding amino acid (alanine) at position 270 in the TC II protein and was only found as a heterozygous genotype in a single patient. The new variant would have been undetected by other methods used for single nucleotide polymorphism detection, e.g., restriction fragment length polymorphism analysis. The results suggest that the common TC II 776C>G polymorphism has no major influence on vitamin B12 metabolism.

  6. Effect of Nrf2 activators on release of glutathione, cysteinylglycine and homocysteine by human U373 astroglial cells.

    PubMed

    Steele, Megan L; Fuller, Stacey; Patel, Mili; Kersaitis, Cindy; Ooi, Lezanne; Münch, Gerald

    2013-01-01

    Neurons rely on the release and subsequent cleavage of GSH to cysteinylglycine (CysGly) by astrocytes in order to maintain optimal intracellular GSH levels. In neurodegenerative diseases characterised by oxidative stress, neurons need an optimal GSH supply to defend themselves against free radicals released from activated microglia and astroglia. The rate of GSH synthesis is controlled largely by the activity of γ-glutamyl cysteine ligase. Expression of γ-glutamyl cysteine ligase and of the Xc- system, which facilitates cystine uptake, is regulated by the redox-sensitive transcription factor, nuclear factor erythroid-2-related factor 2 (Nrf2). Compounds that can activate the Nrf2-ARE pathway, referred to as 'Nrf2 activators' are receiving growing attention due to their potential as GSH-boosting drugs. This study compares four known Nrf2 activators, R-α-Lipoic acid (LA), tert-butylhydroquinone (TBHQ), sulforaphane (SFN) and Polygonum cuspidatum extract containing 50% resveratrol (PC-Res) for their effects on astroglial release of GSH and CysGly. GSH levels increased dose-dependently in response to all four drugs. Sulforaphane produced the most potent effect, increasing GSH by up to 2.4-fold. PC-Res increased GSH up to 1.6-fold, followed by TBHQ (1.5-fold) and LA (1.4-fold). GSH is processed by the ectoenzyme, γ-glutamyl transpeptidase, to form CysGly. Once again, SFN produced the most potent effect, increasing CysGly by up to 1.7-fold, compared to control cells. TBHQ and PC-Res both induced fold increases of 1.3, followed by LA with a fold increase of 1.2. The results from the present study showed that sulforaphane, followed by lipoic acid, resveratrol and Polygonum multiflorum were all identified as potent "GSH and Cys-Gly boosters". PMID:24191238

  7. Effects of bromocriptine mesylate on homocysteine and high-sensitivity C-reactive protein levels in patients with type-2 diabetes mellitus

    PubMed Central

    Niafar, Mitra; Pourafkari, Leili; Shahsavarinia, Kavus; Milanchian, Nushin; Niafar, Farhad; Nader, Nader D.

    2016-01-01

    Introduction: Quick release bromocriptine (BROM-QR), currently approved for glycemic control, reduces the risk of cardiovascular events in adults with type-2 diabetes mellitus (T2DM). This study evaluates the effect of BROM-QR on homocysteine (HOMC) and high sensitive C-reactive protein (hs-CRP), the biochemical markers of coronary atherosclerosis/inflammation, in patients with uncontrolled T2DM. Methods: In this non-randomized, before-and-after clinical trial, patients with uncontrolled T2DM on stable doses of two oral hypoglycemic agents received BROM-QR for 6 months. The change in serum concentrations of HOMC was the primary endpoint. Anthropometric measurements such as body mass index (BMI) and waist circumference were measured at the baseline and at the completion of treatment along with fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, creatinine and hs-CRP. Multivariate regression analysis was performed to identify factors associated with changes in the levels of HOMC. Results: In 64 patients (46 completed 6 months of treatment), age was 55±7 years and the duration of T2DM was 8.0 ± 4.4 years. On enrollment, mean HbA1c, FPG, hs-CRP and HOMC levels were 9.0± 1.3 percent, 184 ± 42 mg/dL, 3.8± 3.4 mg/dl and 10.8 ± 6.2 micromole/L; respectively. Mean decrease of 0.7 ± 1.1 percent for HbA1c (P = 0.001) and 22 ± 44 mg/dL for FPG was observed (P = 0.002). HOMC levels decreased to 8.5 ± 5.2 micromole/L (P = 0.011) while hs-CRP levels remained unchanged at 3.7 ± 2.9 mg/dL (P = 0.835). Conclusion: While HOMC and HbA1c levels decreased significantly after 6 months of treatment with BROM-QR in patients with T2DM, serum levels of hs-CRP, total cholesterol and triglyceride did not significantly change. PMID:27069561

  8. Transforming a Blue Copper into a Red Copper Protein: Engineering Cysteine and Homocysteine into the Axial Position of Azurin using Site-Directed Mutagenesis and Expressed Protein Ligation

    PubMed Central

    Clark, Kevin M.; Yu, Yang; Marshall, Nicholas M.; Sieracki, Nathan A.; Nilges, Mark J.; Blackburn, Ninian J.; van der Donk, Wilfred; Lu, Yi

    2010-01-01

    The interactions of the axial ligands with copper are known to be important in tuning spectroscopic and redox properties of cupredoxins. While conversion of blue copper sites with a weak axial ligand to green copper sites containing a medium strength axial ligand has been demonstrated in cupredoxins, converting blue copper sites to a red copper site with a strong axial ligand has not been reported. Here we show that replacing Met121 in azurin from Pseudomonas aeruginosa with Cys caused an increased ratio (RL) of absorption at 447 nm over that at 621 nm. While no axial Cu-S(Cys121) interaction in Met121Cys was detectable by the extended x-ray absorption fine structure (EXAFS) at pH 5, similar to what was observed in WT azurin with Met121 as the axial ligand, the Cu-S(Cys121) interaction at 2.74 Å is clearly visible at higher pH. Despite the higher RL and stronger axial Cys121 interaction with Cu(II) ion, the Met121Cys variant remains largely a type 1 copper protein at low pH (with hyperfine coupling constant A|| = 54 × 10−4 cm−1 at pH 4 and 5), or distorted type 1 or green copper protein at high pH (A|| = 87 × 10−4 cm−1 at pH 8 and 9), attributable to the relatively long distance between the axial ligand and copper and the constraint placed by the protein scaffold. To shorten the distance between axial ligand and copper, we replaced Met121 with the nonproteinogenic amino acid homocysteine that contains an extra methylene group, resulting in a variant whose spectra (RL= 1.5, and A|| = 180 × 10−4 cm−1) and Cu-S(Cys) distance (2.22 Å) are very similar to those of the red copper protein nitrosocyanin. Replacing Met121 with Cys resulted in lowering of the reduction potential from 222 mV in the native azurin to 95 ± 3 mV for Met121Cys azurin and 113 ± 6 mV for Met121Hcy at pH 7. The results strongly support the “coupled distortion” model that helps explain axial ligand tuning of spectroscopic properties in cupredoxins, and demonstrate the power of