Blood Hcy Research Articles

Elevation of pS262-Tau and Demethylated PP2A in Retina Occurs Earlier than in Hippocampus During Hyperhomocysteinemia.

Hyperhomocysteinemia is an independent risk factor of Alzheimer's disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.

Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease.

Homocysteine (Hcy) and hydrogen sulfide (H2S) are important molecules produced during the metabolism of sulfur-containing amino acids. Hcy metabolism is central to the supply of methyl groups that are essential for biological function. Hcy can be either regenerated to methionine or metabolized to cysteine, a precursor for glutathione synthesis. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) play a crucial role in metabolizing Hcy to cysteine through the transsulfuration pathway. These two enzymes are also responsible for H2S generation through desulfuration reactions. H2S, at physiological levels serves as a gaseous mediator and has multifaceted effects. Metabolic imbalance of Hcy and H2S has been implicated in pathological conditions including oxidative stress, inflammation, cardiovascular and cerebral dysfunction, fatty liver disease and ischemiareperfusion injury. Organs such as liver, kidney, gut and pancreas contain all the enzymes that are required for Hcy metabolism. The kidney plays an important role in removing Hcy from the circulation. Hyperhomocysteinemia, a condition of elevated blood Hcy level, is a common clinical finding in patients with chronic kidney disease (CKD) or acute kidney injury (AKI), the latter is often caused by ischemia-reperfusion. This paper reviews exiting literatures regarding (1) the role of kidney in regulating Hcy and H2S metabolism; (2) disruption of sulfur-containing amino acid metabolism during ischemiareperfusion; (3) impact of metabolic imbalance of Hcy and H2S on kidney function. Better understanding of molecular mechanisms that regulate Hcy and H2S metabolism under physiological and pathophysiological conditions will help improve therapeutic strategies for patients with kidney disease or other organ injuries.

Progress of the relationship between homocysteine and kidney disease

Homocysteine(Hcy) is an intermediate product of methionine metabolism.It is considered that Hcy is an independent etiological factor of cardiovascular disease, and blood Hcy level is closely related to many diseases.Patients with kidney disease may have different levels of homocysteine.The study has found that Hcy may not only be related to kidney damage, but also make the risk of cardiovascular disease in patients with kidney disease increased.The relationship between Hcy and kidney disease is briefly introduced in this article in order to provide a new basis for prevention, diagnosis and treatment of kidney disease and complications. Key words: Homocysteine; Hyperhomocysteinemia; Kidney disease; Children

Effect of enalapril maleate and folic acid tablets in the treatment of H type hypertension and its influence on blood homocysteine

Objective To study the clinical effect of enalapril maleate and folic acid tablets in the treatment of H type hypertension, and to observe the blood homocysteine(Hcy), to provide the basis for clinical diagnosis and treatment. Methods 126 patients with H type hypertension were selected. They were divided into study group and control group according to the random number table method, 63 cases in each group. The control group was given enalapril maleate, the study group was given enalapril maleate and folic acid tablets. The clinical efficacy of the two groups was compared. The systolic blood pressure, diastolic blood pressure and Hcy level before and after treatment in two groups were observed. Results The total effective rate of the study group was 90.5%(57/63), which of the control group was 74.6%(47/63), the difference was statistically significant(χ2=15.371, P 0.05). The systolic pressure after treatment of the two groups were (129.3±5.7)mmHg and (137.9±4.9)mmHg, the diastolic blood pressure were (81.5±3.6)mmHg and (89.6±5.1)mmHg, the differences were statistically significant compared with before treatment(t=8.969, 7.851, 7.343, 6.987, all P 0.05), after treatment Hcy levels of the two groups were (8.93±0.63)μmol/L and (15.35±0.57)μmol/L respectively, the differences were statistically significant compared with before treatment(t=8.097, 8.031, all P<0.05), the difference between the two groups was statistically significant(t=7.573, P<0.05). Conclusion Enalapril maleate and folic acid tablets in the treatment of H type hypertension has good clinical effect, can significantly lower blood pressure, improve Hcy level. Key words: Hypertension; Homocysteine; Enalapril maleate and folic acid tablets

The relationship between serum homocysteine and highly sensitive C- reactive protein levels in children on regular hemodialysis.

Hyperhomocysteinemia has attracted a lot of attention in renal patients, not only because of its close relationship with renal function but also because it has been implicated as an independent cardiovascular risk factor in these patients. An increased level of C-reactive protein (CRP) has been reported to be a strong predictor of cardiovascular mortality in hemodialysis (HD) patients. The aim of this study was to assess the association between homocysteine (Hcy) and highly sensitive CRP (hsCRP) in cardiovascular risk prediction in children with chronic kidney disease (CKD) on HD. This case-control study was conducted on 40 children with CKD on regular HD and 20 age- and sex-matched healthy children as controls. Their ages ranged from 4 to 18 years, and they were selected from the pediatric nephrology and HD unit at Al-Azhar University Hospital, during the period from May 2015 to April 2016. Complete blood count, serum ferritin, cholesterol, triglycerides, calcium, phosphorus, parathormone (PTH), Hcy, and hsCRP levels were measured in both groups. Measurements of anthropometry and blood pressure (BP) were performed. There was a significant increase in serum Hcy levels in cases than controls; it was 17.22 ± 9.66 pmol/L and 6.32 ± 1.47 pmol/L, respectively (P <0.01). Furthermore, there was a significant increase in hsCRP in patients than controls; 2.73 ± 2.65 and 0.9 ± 0.85, respectively (P <0.01). There was a significant positive correlation between hsCRP and Hcy with BP, cholesterol, triglyceride, PTH, and ferritin levels. Our data highlighted the important correlation between serum Hcy and hsCRP to detect high-risk patients for subsequent cardiovascular disease and utility of preventive strategies that attenuate inflammatory risk.

Cardiovascular Protective Effects of Salvianic Acid A on db/db Mice with Elevated Homocysteine Level.

The onsets of left ventricular hypertrophy (LVH) and endothelial dysfunction (ED) in diabetics, especially in those with elevated homocysteine (Hcy), precede the development of cardiovascular (CV) events. Salvianic acid A (SAA) is a renowned Traditional Chinese Medicine (TCM) that has been applied in the treatment of cardiovascular disease for many decades. In this study, we aimed (1) to investigate the CV protective effects of SAA on ameliorating LVH and ED in db/db mice with elevated blood Hcy level and (2) to decipher whether the observed CV protective effects of SAA are associated with Hcy metabolism by modulating the methylation potential and redox status in the liver of the db/db mice with elevated blood Hcy level. Our results found that the administration of SAA could significantly slow down the build-up of left ventricular mass and ameliorate ED. Immunological assay analysis on the mouse liver tissue also indicated that SAA treatment on db/db mice with elevated Hcy was associated with reduced methylation potential but improved redox status. In conclusion, we revealed that SAA has the potential to protect against the hyperglycemia- and hyperhomocysteinemia-induced oxidative stress on diabetic mice via modulation in Hcy metabolism.

Homocysteine is associated with the progression of non-culprit coronary lesions in elderly acute coronary syndrome patients after percutaneous coronary intervention.

BackgroundThe influence of homocysteine (Hcy) on the migration and proliferation of vascular smooth muscle cells has been well established. However, the impact of Hcy levels on the progression of non-culprit coronary lesions (NCCLs) is controversial. This study aims to evaluate whether the plasma level of Hcy is related to the progression of NCCLs after percutaneous coronary stent implantation in elderly patients with acute coronary syndrome (ACS).MethodsA total of 223 elderly patients (≥ 65 years old) with ACS undergoing stent implantation and follow-up coronary angiography were enrolled. Laboratory determination comprised of blood sample evaluation for Hcy was carried out before baseline coronary intervention. The patients were classified into two groups according to the blood Hcy tertiles (≥ 15 mmol/L or < 15 mmol/L). Patients were followed up for 12.2 months. NCCL progression was assessed by three-dimensional quantitative coronary angiography.ResultsA significantly higher ratio of NCCL progression was observed in the group with baseline Hcy concentrations above 15 mmol/L compared to the group with concentrations below 15 mmol/L (41/127, 32.3% vs. 14/96, 14.6%, P = 0.002). Multivariate Cox regression analysis showed that Hcy and diabetes mellitus were independent risk factors for NCCL progression. The crude hazard ratio (HR) of NCCL progression for Hcy level was 1.056 (95% CI: 1.01–1.104, P = 0.015). The adjusted HR of NCCL progression for Hcy level was 1.024 (95% CI: 1.007–1.042, P = 0.007). The adjusted HR of NCCL progression for diabetes mellitus was 1.992 (95% CI: 1.15–3.44, P = 0.013).ConclusionsHcy is an independent risk factor for NCCL progression after 12 months of follow-up in elderly patients with ACS who has undergone percutaneous coronary stenting.

Association of Homocysteine Levels with Subclinical Coronary Atherosclerosis in Asymptomatic Subjects

This article is available from http://www.labmedonline.org 2016, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Progression of atherosclerotic plaques is known to be correlated with elevated circulating homocysteine (Hcy). However, whether the level of Hcy is related with coronary atherosclerosis in the subclinical state is unclear. Therefore, we performed this study to investigate the relationship between blood Hcy levels and subclinical atherosclerosis in asymptomatic self-referred subjects. Methods: We retrospectively enrolled 2,968 self-referred asymptomatic subjects (1,374 men, 1,594 women) who had undergone both coronary CT angiography (CCTA) and coronary artery calcium scoring. The relationships between atherosclerosis, Hcy, and other clinical factors were assessed. Results: Higher levels of Hcy were related with age, male gender, body mass index (BMI), waist circumference, blood pressure, high density lipoprotein (HDL), triglyceride, blood glucose, HbA1c, hsCRP, and coronary artery calcium score (CACS). Coronary plaque was more frequently found in higher Hcy quartile groups (21.3%, 28.8%, 34.4%, and 34.3%, P 50%) was also more frequent in higher Hcy quartile groups (1.8%, 5.4%, 5.0%, and 6.6%, P 400) than the first quartile group. Conclusions: Blood Hcy levels were associated with an increased risk of the presence and extent of subclinical atherosclerosis in asymptomatic subjects.

Homocysteine — is it still an important risk factor for cardiovascular disease?

Copyright © Polskie Towarzystwo Kardiologiczne INTRODUCTION Homocysteine (Hcy) is an aminoacid discovered in 1932, and a relation between high Hcy level and atherosclerosis and thrombosis was suggested by a finding of premature atherosclerosis and thromboembolism in 2 children who died due to a massive stroke [1]. Research on association between Hcy and atherothrombosis was pioneered by McCully [2]. This was followed by observational studies, both retrospective and prospective, which suggested a causal relations [3]. Blood Hcy level is reduced by supplementation with folic acid, vitamin B12, and vitamin B6, as these vitamins participate in the metabolism of this toxic aminoacid [4, 5]. A negative correlation was found between folic acid and Hcy levels [6]. However, previous clinical trials of supplementation of these vitamins yielded negative results, i.e. showed no reduction in cardiovascular (CV) events. Recently, these studies were critically reviewed by Ntaios et al. [5] and Debreceni and Debreceni [7, 8]. These intriguing findings continue to puzzle researchers who attempt to clarify this issue. Thus, we also would like to review this interesting topic for our readers.

Methylation reactions, the redox balance and atherothrombosis: the search for a link with hydrogen sulfide.

It is now clear that homocysteine (Hcy) is irreversibly degraded to hydrogen sulfide (H(2)S), an endogenous gasotransmitter that causes in vivo platelet activation via upregulation of phospholipase A2 and downstream boost of the arachidonate cascade. This mechanism involves a transsulfuration pathway. Based on these new data, clinical and experimental models on the relationships between Hcy and folate pathways in vascular disease and information on the Hcy controversy have been reanalyzed in the present review. Most interventional trials focused on Hcy lowering by folate administration did not exclude patients routinely taking the arachidonate inhibitor aspirin. This may have influenced the results of some of these trials. It is also clear that nutritional intake of folate affects several enzymatic reactions of the methionine-Hcy cycle and associated one-carbon metabolism and, thereby, both methylation reactions and redox balance. Hence, it is conceivable that the abnormally high Hcy levels seen in pathologic states reflect a poorly elucidated perturbation of such reactions and of such balance. While it is unknown whether there is an interplay between H2S, methylation reactions, and redox balance, measuring the sole reduction of blood Hcy that follows folate administration may well be an oversimplified approach to a complex biologic perturbation. The need to investigate this complex framework is thoroughly discussed in this article.

Associations between Alzheimer's disease and blood homocysteine, vitamin B12, and folate: a case-control study.

There is a growing focus on nutritional therapy for Alzheimer's disease (AD), and controversy exists regarding the association between AD and homocysteine (Hcy), vitamin B12, and folate levels. The present study evaluated the association between AD and the combined levels of Hcy, vitamin B12, and folate. This case-control study consisted of 115 patients with AD and 115 matched controls. Serum folate and vitamin B12 were measured using an automated immunoassay analyzer. Plasma Hcy was measured using high-performance liquid chromatography. The association between AD and Hcy, vitamin B12, and folate was analyzed using binary logistic regression, adjusted for age and sex. With the combination of normal blood Hcy, vitamin B12, and folate levels as the reference category, low vitamin B12 in subjects with normal Hcy and folate was associated with AD (adjusted odds ratio [OR], 4.6; 95% confidence interval [CI]: 1.6-13.2). The combination of low vitamin B12 and folate in subjects with normal Hcy was associated with AD (adjusted OR, 4.3; 95% CI: 1.3-14.6). The combination of high Hcy and low folate levels in patients with normal vitamin B12 was associated with AD (adjusted OR, 17.0; 95% CI: 5.4- 53.4). The combination of high Hcy, low vitamin B12, and any folate level was associated with AD (adjusted OR, 30.5; 95% CI: 9.7-95.9). Vitamin B12 was directly associated with AD. The combination of high Hcy, low vitamin B12, and any folate level represented the poorest association with AD.

The clinical effects of cowpox vaccination in inflammatory skin extract in the treatment ofdiabetic peripheral neuropathy

Objective To study the effectiveness of vaccinia vaccination rabbit inflammatory skin extracts on blood homocysteine（Hcy） and insulin-like growth factor-1（IGF-1） in patients with diabetic peripheral neuropathy. Methods 100 patients with diabetic peripheral neuropathy were randomly divided into the two groups,the observa-tion group（n=50 cases） and the control group（n=50 cases）.The observation group was treated through vaccinia vaccination rabbit inflammatory skin extracts, while the control group was treated through mecobalamin.They were treated for 15 days.Median nerve,peroneal motor nerve conduction velocity （MCV） and sensory nerve conduction velocity （ SCV） were determined before and after treatment.Blood IGF-1 and Hcy were detected.Results TSS were significantly lowered after treatment （t=9.772,13.624,all P〈0.01）.Compared with the control group,the observa-tion group was significantly decreased （t=3.925,P〈0.05）.After treatment,the median nerve,peroneal nerve MCV and SCV were significantly increased （t=5.103,3.019,4.998,2.928,5.128,3.112,5.286,3.118,all P〈0.05）. Compared with the control group,theobservation group was observed to increase more significantly（t=2.826,2.743, 3.268,3.096,all P〈0.05）.After treatment,serum IGF-1 were significantly elevated,and compared with the control group after treatment,post-treatment observation group increased more significantly（t=4.179,P〈0.05）.After treat-ment plasma Hcy were significantly lower than that of the control group after treatment,the observation group after treatment significantly decreased（t=3.165,P〈0.05）.Conclusion Vaccinia vaccination rabbit inflammatory skin extracts can improve blood Hcy and IGF-1 in patients with diabetic peripheral neuropathy. Key words: Diabetic neuropathies; Viral vaccines; Tissue extracts; Cysteine

Relationship between homocysteine level and diabetic retinopathy: a systematic review and meta-analysis.

BackgroundThe relationship between homocysteine (Hcy) and diabetic retinopathy (DR) remains unclear to date. Therefore, a systematic review and meta-analysis was performed on the relationship between Hcy level and DR.MethodsStudies were identified by searching PubMed, Embase, and Web of Science databases until 5 May, 2014.ResultsA total of 31 studies involving 6,394 participants were included in the meta-analysis. After pooling the data from each included study, the blood Hcy concentration in the DR group was observed to be higher than that in the control group [WMD = 2.55; 95% confidence interval (CI), 1.70–3.40], and diabetes mellitus (DM) patients with hyperhomocysteinemia were at a risk for DR [odds ratio (OR) = 1.93; 95% CI, 1.46–2.53]. Considering the different DM types, hyperhomocysteinemia in T1DM (OR = 1.83, 95% CI, 1.28–2.62) was associated with DR rather than in T2DM (OR = 1.59, 95% CI, 0.72–3.51). Considerable statistical heterogeneity in the overall summary estimates was partly explained by the geographical differences.ConclusionsResults from this current meta-analysis indicate that hyperhomocysteinemia is a risk factor for DR, especially proliferative DR. Differences between geographical regions were observed in the relationship between hyperhomocysteinemia with T1DM risk. Given the heterogeneous results, the relationship between high Hcy and DR needs further investigation.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_167

Evaluation of the association between blood homocysteine concentration and the degree of behavioral symptoms in the 6-hydroxydopamine-induced Parkinsonism in rat

Growing evidence indicates that homocysteine (Hcy) may be involved in the pathophysiology of several neurological disorders including Parkinson's disease. In the present study, the association between blood Hcy concentration and the degree of behavioral symptoms in the 6-hydroxydopamine (6-OHDA)-induced Parkinsonism in rat was evaluated. Total serum Hcy (tHcy) was measured before and 6weeks after the intracerebral injection of 6-OHDA. Apomorphine-induced rotational test was performed at second, third and sixth weeks after 6-OHDA injection. Subsequently, cell replacement therapy was performed on rats with good rotation score. No correlation between tHcy in before 6-OHDA injection and severity of the rotations after 6-OHDA injection was observed. On the other hand, 6-OHDA treatment significantly decreased tHcy level. However, this reduction was only observed in animals with low degree of rotations and in rats with high number of rotations; tHcy did not change significantly. Furthermore, 10weeks after cell transplantation, tHcy was significantly lower than that found before therapy if the rats showed good improvement in the degree of rotations. We also examined the effect of different supplements of B vitamins on tHcy before and after 6-OHDA injection. In healthy rats, all kinds of B vitamins and also supplement B6 or B12 alone reduced tHcy. Following 6-OHDA injection, B vitamin supplementation failed to cause remarkable effect. Considering the direct correlation between the severity of rotational behavior and the degree of lesion in the substantia nigra (SN), our data indicate that higher tHcy values can predict higher SN dopaminergic neurodegeneration.

Relationships of levels of homocysteine, placental growth factor, folic acid and vitamin B12 in maternal blood and umbilical cord blood and their correlations with fetal growth restriction

Objective To observe the levels of the placenta growth factor(PLGF), the homocysteine(Hcy), the folic acid(Fa) and the Vitamin B12(Vit B12) in the maternal blood and the umbilical cord blood, and study the correlation and the mutual influence on the level of the fetal growth restriction(FGR). Methods The 44 inpatient delivery mothers and their babies were selected from Feb.to Nov.2010 in the Third Affiliated Hospital of Inner Mongolia Medical University, according to the womb age with birth weight percentile, and they were divided into 3 groups: the FGR group, appropriate for gestational age(AGA) group, large for gestational age(LGA) group.The fetal birth weight, height, head circumference, abdominal circumference, placenta weight were measured, and body mass index(BMI) was calculated, neonatal growth status was evaluated, and the delivery method and gender were recorded, and the Hcy, Fa, Vit B12 levels in the maternal blood and the umbilical cord blood were detected by enzyme-linked immunosorbent assay, respectively. Results 1.The Fa, Vit B12 levels in the maternal blood, umbilical cord blood in FGR group were obviously lower than those in the LGA group and AGA group(all P<0.05, 0.01). The Hcy levels in the maternal blood, umbilical cord blood in FGR group were obviously higher than those in the LGA group, AGA group(all P<0.05). The PLGF levels in the maternal blood, umbilical cord blood of FGR group were remarkably lower than those in the LGA group and AGA group(P<0.05, 0.01). In the maternal blood and umbilical cord blood, the Fa, Vit B12 levels, were positively correlated with PLGF(all P<0.001).2.The Hcy level in the maternal blood and umbilical cord blood, were negatively correlated with fetal birth weight, height, head circumference, abdominal circumference, placenta weight, BMI(all P<0.05). In the pregnant women blood Fa level, compared with fetal birth weight, head circumference, abdominal circumference, placenta weight, and BMI, were positively correlated(all P<0.05). In the maternal blood Vit B12 level, compared with fetal birth head circumference, abdominal circumference, and BMI, were positively correlated(all P<0.05). In the maternal blood PLGF level, compared with fetal birth weight, head circumference, abdominal circumfe-rence, BMI, was positively correlated(all P<0.05). By the stepwise multiple regression analysis, screening out the maternal blood Fa, Hcy, the umbilical cord blood Hcy influenced the fetal birth weight obviously, the most influent factor for the placenta weight was the maternal blood Hcy.3.The placenta weight in FGR group was lower than that of the LGA group and AGA group(P<0.001), and in the LGA group, AGA group, fetal birth weight, height, head circumfe-rence, abdominal circumference, BMI, compared with the placenta weight, were positively correlated(all P<0.001). Conclusions 1.Hyperhomocysteinemia may happen during pregnancy for the lack of the Fa and Vit B12, and FGR attacks may be related to the rise of Hcy level.2.In the later period of the pregnant women, the Fa, Vit B12, Hcy levels have the severe influence on the fetal physical condition.3.Placenta weight plays an important role in the fetal growth and development.4.The PLGF hyposecretion of the placenta may be the one of the key links to the pathogenesis of the FGR. Key words: Fetal growth restriction; Homocysteine; Folic acid; Vitamin B12; Placenta growth factor

C677T Methylenetetrahydrofolate Reductase and Plasma Homocysteine Levels among Thai Vegans and Omnivores

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.

Homocysteine Lowering in End-Stage Renal Disease

In 1969, McCully reported an association between homocystinuria, a rare metabolic disorder characterized by high blood levels (>100 μmol/L) of the amino acid homocysteine (Hcy), and severe atherosclerosis among postmortem subjects.1 His report is widely recognized as the basis for the “homocysteine hypothesis,” namely, that elevated blood Hcy is a risk factor for cardiovascular disease (CVD). Since then, a wealth of supporting observational epidemiological evidence has accumulated. In a 2002 meta-analysis of 11 prospective cohort studies of individuals without a history of CVD, a 25% (3 μmol/L) reduction in Hcy was associated with an 11% lower risk of coronary heart disease events and a 19% lower risk of stroke after adjustment for smoking, blood pressure, total cholesterol, and regression dilution.2 Surprisingly, these findings were not confirmed in randomized controlled trials (RCTs). Two meta-analyses of RCTs that used folic acid and B vitamins to lower blood Hcy found almost no effects on fatal and nonfatal CVD events.3,4 Thus, many have concluded that the relationship between Hcy and CVD events is simply due to confounding in the observational studies. One potentially important confounder is chronic kidney disease. Hcy levels are inversely associated with glomerular filtration rate, which is itself inversely associated with CVD and its related phenotypes (eg, carotid intimal medial thickness).5,6 Therefore, the relationship between Hcy and CVD events among observational studies could have been due in part to unmeasured chronic kidney disease. Nevertheless, the question of whether Hcy is a CVD risk factor persists for several reasons. Article see p 1432 First, laboratory investigations point to the role of Hcy in activating pathways attributed to atherogenesis and thrombosis, such as endothelial …

Folic acid supplementation inhibits homocysteine‐induced superoxide anion production and chemokine expression in the kidney

Hyperhomocysteinemia (HHcy), a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. Kidney dysfunction is a common risk factor causing HHcy. Recent studies indicate that HHcy also lead to renal injury by inducing oxidative stress and expression of inflammatory markers. Monocyte chemoattractant protein‐1 (MCP‐1) is a potent chemokine that stimulates monocyte/macrophage accumulation in the kidney. Upregulation of this chemokine is associated with inflammatory injury. Although folic acid supplementation can reduce blood Hcy levels, its effect on the kidney is not clear. The aim of this study was to investigate the effect of folic acid on Hcy‐induced superoxide generation and chemokine expression in the kidney. HHcy was induced in Sprague Dawley rats fed a high‐methionine diet. The NADPH oxidase‐mediated superoxide production and MCP‐1 mRNA expression were significantly increased in HHcy rat kidneys. Folic acid supplementation effectively abolished HHcy‐induced oxidative stress by inhibition of NADPH oxidase activation. This, in turn, prevented HHcy‐induced chemokine expression in the kidney. Such a beneficial effect of folic acid is not directly related to Hcy reduction. Our results suggest that folic acid supplementation may offer a renal protective effect by antagonizing oxidative stress‐mediated inflammatory response.(This study was supported by NSERC and CIHR)

Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson´s disease

In the present work we measured blood levels of total homocysteine ((t)Hcy), vitamin B(12) and folic acid in patients with Parkinson s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma (t)Hcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of (t)Hcy in PD patients was folic acid deficiency, whereas in controls (t)Hcy levels were mainly determined by plasma vitamin B(12) concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma (t)Hcy, folic acid and vitamin B(12) levels in parkinsonians. Furthermore, disease duration was positively associated with (t)Hcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder.

Homocysteine stimulates monocyte chemoattractant protein-1 expression in the kidney via nuclear factor-κB activation

Hyperhomocysteinemia, or an elevation of blood homocysteine (Hcy) levels, is associated with cardiovascular disorders. Although kidney dysfunction is an important risk factor causing hyperhomocysteinemia, the direct effect of Hcy on the kidney is not well documented. There is a positive association between an elevation of blood Hcy levels and the development of chronic kidney disease. Inflammatory response such as increased chemokine expression has been implicated as one of the mechanisms for renal disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in renal disease. Nuclear factor-kappaB (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism underlining such an effect in rat kidneys as well as in proximal tubular cells. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 12 wk. The MCP-1 mRNA expression and MCP-1 protein levels were significantly increased in kidneys isolated from hyperhomocysteinemic rats. The NF-kappaB activity was significantly increased in the same kidneys. Pretreatment of hyperhomocysteinemic rats with a NF-kappaB inhibitor abolished hyperhomocysteinemia-induced MCP-1 expression in the kidney. To confirm the causative role of NF-kappaB activation in MCP-1 expression, human kidney proximal tubular cells were transfected with decoy NF-kappaB oligodeoxynucleotide to inhibit NF-kappaB activation. Such a treatment prevented Hcy-induced MCP-1 mRNA expression in tubular cells. Our results suggest that hyperhomocysteinemia stimulates MCP-1 expression in the kidney via NF-kappaB activation. Such an inflammatory response may contribute to renal injury associated with hyperhomocysteinemia.