Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The study has been designed to investigate the effect of demethylasterroquinone B1 (DAQ B1), an activator of Akt, in diabetes mellitus (DM) and hyperhomocysteinemia (HHcy)-induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of messenger RNA for p22phox and eNOS was assessed by reverse transcription-polymerase chain reaction. Serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion were estimated to assess oxidative stress. DAQ B1 (5 mg kg(-1), p.o.) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. DAQ B1 or atorvastatin markedly improved acetylcholine-induced endothelium-dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of DAQ B1 has been prevented by L-NAME (25 mg kg(-1), i.p.), an inhibitor of eNOS. Therefore, it may be concluded that DAQ B1-induced activation of Akt may activate eNOS and consequently reduce oxidative stress to improve vascular endothelial dysfunction.
Mol Cell Biochem 2007 Jan
PMID:Possible role of Akt to improve vascular endothelial dysfunction in diabetic and hyperhomocysteinemic rats. 1684 Nov 79

Mutations or polymorphisms in the gene of the enzyme methylenetetrahydrofolate (MTHFR) are associated with hyperhomocysteinemia and possibly with an elevated risk for vascular diseases. A study was conducted on 83 individuals with type 2 diabetes in order to determine the allelic and genotypic frequencies of the G1793A mutation and to assess the effect of folic acid supplementation on plasma homocysteine concentrations. The patients were attended by the Diabetes and Hypertension Program--Balneario Camboriu/SC and received daily supplements containing 1 mg of folic acid for 3 months. DNA was previously extracted from leukocytes and the G1793A mutation was detected by PCR-RFLP. Blood samples were collected during the basal period and after supplementation for the determination of homocysteine by HPLC, and of folic acid and vitamin B(12) by RIA. The allele frequency for the G1793A mutation was 3.01% and no homozygous individuals with mutant alleles were detected. Hyperhomocysteinemia was diagnosed in 27.71% of the patients, folic acid deficiency in 15.66%, and vitamin B(12) deficiency in 7.23%. Plasma homocysteine concentrations were inversely correlated with folic acid (r = -0.27, p = 0.01) and vitamin B(12) (r = -0.21; p = 0.05) concentrations. The individuals with a heterozygous genotype for the G1793A mutation showed borderlines or deficient values in folic acid and vitamin B(12) concentrations compared to individuals with a normal genotype. Hyperhomocysteinemia and the vitamin deficiencies presented by type 2 diabetic individuals, included with a heterozygous genotype for the G1793A mutation in the MTHFR gene, reached normal values by daily folic acid supplementation.
Mol Nutr Food Res 2006 Aug
PMID:G1793A polymorphisms in the methylene-tetrahydrofolate gene: effect of folic acid on homocysteine levels. 1686 47

1. The cholinergic system is important in cognition and behavior as well as in the function of the cerebral vasculature. 2. Hyperhomocysteinemia is a risk factor for development of both dementia and cerebrovascular disease. 3. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine, a key process in the regulation of the cholinergic system. 4. It has been hypothesized that the deleterious effects of elevated homocysteine may, in part, be due to its actions on cholinesterases. 5. To further test this hypothesis, homocysteine and a number of its metabolites and analogues were examined for effects on the activity of human cholinesterases. 6. Homocysteine itself did not have any measurable effect on the activity of these enzymes. 7. Homocysteine thiolactone, the cyclic metabolite of homocysteine, slowly and irreversibly inhibited the activity of human AChE. 8. Conversely, this metabolite and some of its analogues significantly enhanced the activity of human BuChE. 9. Structure-activity studies indicated that the unprotonated amino group of homocysteine thiolactone and related compounds represents the essential feature for activation of BuChE, whereas the thioester linkage appears to be responsible for the slow AChE inactivation. 10. It is concluded that hyperhomocysteinemia may exert its adverse effects, in part, through the metabolite of homocysteine, homocysteine thiolactone, which is capable of altering the activity of human cholinesterases, the most pronounced effect being BuChE activation.
Cell Mol Neurobiol 2007 Feb
PMID:Homocysteine thiolactone and human cholinesterases. 1695 66

In human reproduction, hyperhomocysteinemia has been reported as a risk factor for early pregnancy loss and congenital birth defects. Hyperhomocysteinemia is also recognized as a cause of maternal obstetric complications such as preeclampsia. The role of plasma hyperhomocysteinemia in female fertility was examined using cystathionine beta synthase knockout (cbs KO) mice. Cbs KO females were infertile, showed alterations in the estrus cycle and an increased progesterone response during pseudo-pregnancy induction. Both cbs KO ovaries and ovulated oocytes showed no major morphological alterations. However, placental and uterine masses were decreased at day 18 of pregnancy and showed morphological abnormalities. In cbs-KO pregnant females, the number of uterine implantation sites was not decreased despite the low number of surviving embryos. Fertility was restored when cbs-deficient ovaries were transplanted to normal ovarectomized recipients. We detected an increased uterine expression of Grp78, a marker of endoplasmic reticulum stress, which was accompanied by the decreased levels of uterine cbs mRNA in both hyperhomocysteinemic heterozygous (fertile) and homozygous (non-fertile) females. Our results indicate that cbs -/- female infertility is a consequence of the uterine failure and demonstrate that uterine endoplasmic reticulum stress and cbs expression are not determinant of infertility, suggesting that uterine dysfunction is a consequence of either hyperhomocysteinemia or other factor(s) in the uterine environment of cbs -/- animals. In summary, these studies demonstrate the potential importance of homocysteine levels for uterine handling of embryos.
Hum Mol Genet 2006 Nov 01
PMID:Cystathionine beta-synthase is essential for female reproductive function. 1698 62

Homocysteine (Hcy) is thought to play an important role in the development of osteoporosis and fracture. Methionine synthase reductase (MTRR) is an enzyme involved in the conversion of Hcy to methionine. We hypothesized that certain genetic polymorphisms of MTRR leading to reduced enzyme activity may cause hyperhomocysteinemia and affect bone metabolism. We therefore examined the associations of the A66G and C524T polymorphisms of the MTRR gene with bone mineral density (BMD) and serum osteocalcin levels in postmenopausal women. Although we did not detect any significant associations between MTRR polymorphisms and BMD or serum osteocalcin levels, we found that the 66G/524C haplotype, which has reduced enzyme activity, was significantly associated with serum osteocalcin levels in a gene-dose dependent manner (P = 0.002). That is, the highest osteocalcin levels (34.5 +/- 16.8 ng/ml) were observed in subjects bearing two copies, intermediate osteocalcin levels (32.6 +/- 14.4 ng/ml) were observed in subjects bearing one copy, and the lowest levels of osteocalcin (28.8 +/- 10.9 ng/ml) were observed in subjects bearing no copies. These results suggest that the 66G/524C haplotype of the MTRR gene affect bone turn over rate.
Exp Mol Med 2006 Oct 31
PMID:Methionine synthase reductase polymorphisms are associated with serum osteocalcin levels in postmenopausal women. 1707 68

Guanidinosuccinic acid is an aberrant metabolite isolated 40 years ago in the blood and urine of uremic subjects and a suspect in the toxicity associated with renal failure. It plays a minor role in the bleeding diathesis of uremia, contributes to the methyl group deficiency of dialysis patients, and is a factor in the premature atherosclerosis of end stage renal disease through the induction of hyperhomocysteinemia. As a major player, however, in the diversity and severity of uremic symptoms, it is a disappointment. Recently its source has been identified. It results from the superoxidation of argininosuccinic acid, which leads, also, to the production of gamma glutamic semialdehyde, an advanced glycation end product (AGE), which normally results from from the Maillard reaction, the non-enzymatic browning of protein. AGEs stimulate cross-linkages in protein that lead ultimately to loss of function, phagocytosis, and removal, and are important elements in the premature aging characteristic of renal disease, and diabetes.
Mol Cell Biochem 2007 Apr
PMID:Premature aging in uremia. 1713 40

Cystathionine beta synthase (CBS) is a crucial regulator of plasma concentrations of homocysteine. Severe hyperhomocysteinemia due to CBS deficiency confers diverse clinical manifestations, notably pulmonary thrombotic disease. However, the association between hyperhomocysteinemia and chronic obstructive pulmonary disease is not well understood. To investigate the role of hyperhomocysteinemia in lung injury and pulmonary fibrosis, we analyzed the lung of CBS-deficient mice, a murine model of severe hyperhomocysteinemia. The degree of lung injury was assessed by histologic examination. Analysis of profibrogenic factors was performed by real-time quantitative reverse transcription-polymerase chain reaction. CBS-deficient mice develop fibrosis and air space enlargement in the lung, concomitant with an enhanced expression of heme oxygenase-1, pro(alpha)1 collagen type I, transforming growth factor-beta1 and alpha-smooth muscle actin. However, lung fibrosis was found in the absence of increased inflammatory cell infiltrates as determined by histology, without changes in gene expression of proinflammatory cytokines TNFalpha and interleukin 6. The increased expression of alpha-smooth muscle actin and transforming growth factor-beta1 emphasizes the role of myofibroblasts differentiation in case of lung fibrosis due to CBS deficiency in mice.
Exp Mol Pathol 2007 Oct
PMID:Mice lacking cystathionine beta synthase have lung fibrosis and air space enlargement. 1754 41

Cystathionine beta synthase (CBS) deficiency is a metabolic disorder that is biochemically characterized by severe hyperhomocysteinemia. In order to show the effects of CBS deficiency onto the activity of the enzymes involved in the remethylation pathway, we used the well characterized genetic model of severe hyperhomocysteinemia in mice. We showed that CBS deficiency in mice reduced hepatic methionine synthase and betaine-homocysteine methyltransferase activities, whereas 5,10-methylene tetrahydrofolate reductase activity was increased.
Mol Genet Metab 2007 Aug
PMID:Mice deficient in cystathionine beta synthase display altered homocysteine remethylation pathway. 1756 77

Hyperhomocysteinemia has been documented in chronic renal failure (CRF). Premature as well as progressive occlusive vascular disease is common. Mutations or polymorphisms in the gene of the enzyme methylenetetrahydrofolate reductase (MTHFR), as C677T, A1298C and G1793A, are associated with hyperhomocysteinemia and possibly with elevated risk for vascular diseases. This study was conducted on 89 individuals with renal failure on dialysis to determine the allelic and genotypic frequencies of the mutations in the MTHFR gene and hyperhomocysteinemia. Blood samples were colleted for determination of homocysteine and DNA. The C677T, A1298C and G1793A mutations were detected. This study confirmed the high prevalence of hyperhomocysteinemia in patients on dialysis, which was diagnosed in 76 patients (85.39%) and high incidence of the C677T and A1298C mutation, 42 (47.19%) and 29 (32.58%) patients, respectively. Five patients (5.62%) presented the G1793A mutation and hyperhomocysteinemia. The authors concluded that there was no influence of the polymorphisms on homocysteine levels in these patients.
Mol Nutr Food Res 2007 Nov
PMID:Hyperhomocysteinemia and polymorphisms of the methylenetetrahydrofolate gene in hemodialysis and peritoneal dialysis patients. 1796 40

Type 2 diabetes mellitus induces a characteristic platelet hyperactivity that might be due to several factors including oxidative stress and abnormal intracellular Ca2+ homeostasis. Hyperhomocysteinaemia is considered a risk factor in the development of thrombosis although its effect on platelet function and the mechanisms involved are still poorly understood. Here we show that homocysteine (Hcy) induce a concentration-dependent increase in endogenous production of reactive oxygen species (ROS), which was significantly greater in platelets from diabetic patients than in controls. Platelet treatment with Hcy resulted in Ca2+ release from the dense tubular system and the acidic stores. Ca2+ mobilisation-induced by Hcy consisted in two components, an initial slow increase in intracellular free Ca2+ concentration ([Ca2+]i) and a rapid and marked increase in [Ca2+]i, the second leading to the activation of platelet aggregation. As well as ROS generation, Ca2+ mobilization and platelet aggregation were significantly greater in platelets from diabetic donors than in controls, which indicate that platelets from diabetic donors are more sensitive to Hcy. These findings, together with the hyperhomocysteinaemia reported in diabetic patients, strongly suggest that Hcy might be considered a risk factor in the development of cardiovascular complications associated to type 2 diabetes mellitus.
J Cell Mol Med 2008 Dec
PMID:Effect of homocysteine on calcium mobilization and platelet function in type 2 diabetes mellitus. 1808 91


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