n-3 Polyunsaturated fatty acid attenuates hyperhomocysteinemia-induced hepatic steatosis by increasing hepatic LXA / 生理学报

Nonalcoholic fatty liver disease (NAFLD) and hyperhomocysteinemia (HHcy) both are major health problems worldwide, whose incidence are closely related with each other. We previously reported the mechanism of HHcy-caused hepatic steatosis, but the role of n-3 polyunsaturated fatty acid (n-3 PUFA) in HHcy-induced hepatic steatosis remains unclear. In this study, 6-week-old C57BL/6 male mice were given a high methionine diet (HMD, 2% methionine diet), and plasma homocysteine levels were measured by ELISA to confirm the establishment of an HHcy model. Meantime, mice were fed HMD with or without n-3 PUFA supplement for 8 weeks to determine the role and mechanism of n-3 PUFA in hepatic steatosis induced by HHcy. Results showed that n-3 PUFA significantly improved hepatic lipid deposition induced by HHcy. qRT-PCR analysis demonstrated that n-3 PUFA inhibited the upregulation of Cd36, a key enzyme of fatty acid uptake, caused by HHcy. Further, the inhibition of hepatic Cd36 expression was associated with the inactivation of aryl hydrocarbon receptor (Ahr) induced by n-3 PUFA. Of note, mass spectrometry revealed that hepatic content of lipoxin A

Effects of isolated vitamin B6 supplementation on oxidative stress and heart function parameters in experimental hyperhomocysteinemia

Introduction: The purpose of this study was to investigate the effects of isolated vitamin B6 (VB6 ) supplementation on experimental hyperhomocysteinemia (Hhe) induced by homocysteine thiolactone (HcyT). Methods: Fifteen male Wistar rats were divided into three groups according to their treatment. Animals received water and food ad libitum and an intragastric probe was used to administer water for 60 days (groups: CB6, HcyT, and HB6 ). On the 30th day of treatment, two groups were supplemented with VB6 in the drinking water (groups: CB6 and HB6 ). After 60 days of treatment, homocysteine (Hcy), cysteine, and hydrogen peroxide concentration, nuclear factor (erythroid-derived 2)-like 2 (NRF2) and glutathione S-transferase (GST) immunocontent, and superoxide dismutase (SOD), catalase (CAT), and GST activities were measured. Results: The HcyT group showed an increase in Hcy concentration (62%) in relation to the CB6 group. Additionally, GST immunocontent was enhanced (51%) in the HB6 group compared to the HcyT group. Also, SOD activity was lower (17%) in the HB6 group compared to the CB6 group, and CAT activity was higher in the HcyT group (53%) compared to the CB6 group. Ejection fraction (EF) was improved in the HB6 group compared to the HcyT group. E/A ratio was enhanced in the HB6 group compared to the CB6 group. Correlations were found between CAT activity with myocardial performance index (MPI) (r = 0.71; P = 0.06) and E/A ratio (r = 0.6; P = 0.01), and between EF and GST activity (r = 0.62; P = 0.02). Conclusions: These findings indicate that isolated VB6 supplementation may lead to the reduction of Hcy concentration and promotes additional benefits to oxidative stress and heart function parameters (AU)

Metabolismo da homocisteína em doenças neurológicas / Homocysteine metabolism in neurologic disorders

OBJETIVO: Realizar uma revisão sobre o metabolismo do aminoácido sulfurado homocisteína, analisando como elevações de seus níveis séricos se correlacionam com a fisiopatologia das mais diversas doenças neurológicas, assim como sobre o tratamento da hiper-homocisteinemia. MÉTODO: Revisão não sistemática de artigos que abordassem o papel da homocisteína associado a doenças neurológicas.Foi priorizada a utilização de artigos que apresentassem no título as palavras-chave "homocisteína" ou "hiper-homocisteinemia",associadas a palavras-chave contendo as enfermidades neurológicas de maior prevalência como acidente vascular cerebral, doença de Alzheimer, doença de Parkinson e outras. Foram utilizadas as bases de dados do PubMed, Lilacs e Google Scholar. RESULTADOS: Foram utilizados 35 artigos em inglês e 2 artigos em português para a confecção desta revisão. CONCLUSÃO: A homocisteína se encontra elevada em associação com as mais diversas doenças neurológicas. Contudo, em muitas delas não está estabelecido se esse aumento é um achado secundário ou se representa um papel da homocisteína na patogênese dessas enfermidades. Mais estudos são necessários para estabelecer o papel da homocisteína em situações neurológicas.O tratamento da hiper-homocisteinemia é fácil, sendo feito com reposição de vitamina B12 e, principalmente, de folatos.

OBJECTIVE: Review the metabolism of sulfur amino acid homocysteineand how elevation of its serum levels is correlated with the pathophysiologyof several neurological diseases, as well as the treatment of hyperhomocysteinemia. METHOD: A non-systematic review of articles discussing the role of homocysteine associated with neurological diseases was performed. The use of articles that presented in the title the keywords "homocysteine" or "hyperhomocysteinemia" associated with keywords containing the most prevalent neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease and others were preferred. The search was underdone through PubMed, Google Scholar and Lilacs databases. RESULTS: There were selected 35 articles in English and 2 articles in Portuguese in this this review. CONCLUSION: High levels of homocysteine are associated with various neurological disorders. However, in many of these are not established whether this increase is a consequence of these disorders or if homocysteine plays a role in the pathogenesis of these diseases. More studies are needed to establish the participation ofhomocysteine in neurological disorders. The treatment of hyperhomocysteinemia is easy, being done with replacement of vitamin B12and especially folate.

Genetics of homocysteine metabolism and associated disorders

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5 percent of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

Cortical venous thrombosis due to acquired hyperhomocysteinaemia.

A 20-year-old student presented with generalized tonic– clonic seizures and was diagnosed to have cortical venous thrombosis. Her dietary history and the clinical signs of vitamin deficiency prompted further investigations, which detected hyperhomocysteinaemia secondary to vitamin B12 deficiency as a factor contributing to the hypercoagulable state. This case highlights the importance of a balanced diet, as well as the necessity for primordial prevention.

Hiper-homocisteinemia e risco cardiometabólico: [revisão] / Hyperhomocysteinemia and cardiometabolic risk: [review]

A hiper-homocisteinemia, quando considerada como fator causal de doenças vasculares, tem suscitado muitas discussões. Estudos caso-controle, retrospectivos e prospectivos têm identificado relação entre concentrações plasmáticas elevadas de homocisteína e doenças vasculares. Na presente revisão, objetivou-se compreender melhor a inter-relação entre as concentrações plasmáticas de homocisteína e doenças vasculares, além do envolvimento de fatores de risco clássicos para a doença: os genéticos, como as mutações em genes que codificam as enzimas envolvidas no metabolismo da homocisteína, e os nutricionais, como a deficiência de vitaminas do complexo B. Foram consultadas as publicações das principais bases de dados em saúde, no período de 1962 a 2009. O mecanismo pelo qual a hiper-homocisteinemia atua como fator de risco para doenças vasculares ainda não está totalmente esclarecido; entretanto, sugere-se o envolvimento da disfunção endotelial e da peroxidação lipídica. O tratamento da hiper-homocisteinemia fundamenta-se na suplementação alimentar e medicamentosa, com ácido fólico e vitaminas B6 e B12.

Hyperhomocysteinemia, when considered as a causal factor of vascular diseases, has been subject of much discussion. Case-control, retrospective and prospective studies have identified a relationship between high plasma concentrations of homocysteine and vascular disease. The aim of the present review was to better understand the interrelation between plasma concentrations of homocysteine and vascular diseases, as well as the involvement of classical risk factors for the disease: genetic factors, such as mutations in the genes that codify the enzymes involved in the metabolism of homocysteine, and nutritional factors, such as complex B vitamin deficiency. The publications of the main databases in health were consulted for the period 1962 to 2009. The mechanism by which hyperhomocysteinemia acts as a risk factor for vascular diseases still has not been fully clarified, but involvement of endothelial dysfunction and lipid peroxidation is suggested. The treatment of hyperhomocysteinemia is based on food supplements and medication, with folic acid and vitamins B6 and B12.

Influence of folic acid on plasma homocysteine levels & arterial endothelial function in patients with unstable angina.

Background & objectives: High plasma homocysteine (Hcy) levels are known to be associated with coronary artery disease, but the precise level associated with an increased risk is yet controversial. Whether the beneficial effects of folic acid on arterial endothelial function persist over longer periods is not known. This study was carried out to assess whether folic acid supplementation could produce improvements in Hcy levels and arterial endothelial function in the patients with unstable angina (UA) and hyperhomocysteinaemia. Methods: The plasma Hcy levels of 52 cases with UA and 30 control subjects were measured by using high-performance liquid chromatography (HPLC) with fluorescence detection, plasma folic acid and vitamin B12 levels were also measured. The patients with hyperhomocysteinaemia were treated with 5 mg of folic acid for 8 wk, and then rechecked the plasma levels of Hcy, folic acid and vitamin B12 at the end of 4th and 8th wk. Arterial endothelial function was measured as flow-mediated dilation of the brachial artery using high-resolution B-mode ultrasound in 22 cases with UA and hyperhomocysteinaemia before and after folic acid treatment. Results: The plasma Hcy level was significant higher in the patients with UA than in the controls (19.2 ± 4.9 vs 10.7 ± 5.3 μmol/l, P<0.01). The plasma levels of folic acid and vitamin B12 were significant lower in the patients with UA than in the controls. There were 22(42.3%) patients with hyperhomocysteinaemia in UA group. After 4 and 8 wk of administration of folic acid, the Hcy level reduced by 20.3 and 55.3 per cent in the UA patients with hyperhomocysteinaemia, respectively. Flow-mediated dilation also improved significantly, from 6.4 ± 1.9 to 9.0 ± 1.2 per cent (P<0.05) after 8 wk treatment with folic acid. Interpretation & conclusions: Plasma Hcy level was elevated in patients with UA. Folic acid can reduce the plasma Hcy levels and improve arterial endothelial function in the UA patients with hyperhomocysteinaemia.

Different doses of oral folic acid for homocysteine-lowering therapy in patients on hemodialysis a randomized controlled trial

We compared the effect of higher and lower doses of folic acid compared to our routine daily dose on plasma homocysteine levels, in our hemodialysis patients. Eighty patients on hemodialysis receiving oral folic acid, 10 mg/d, were randomized to receive folic acid at either doses of 5 mg/d [group 1] or 15 mg/d [group 2] for 2 months. Plasma levels of total homocysteine were measured before and after the study period. Hyperhomocysteinemia was seen in 75 patients [93.8%] before, and in 37 patients of group 1 [92.5%] and 39 of group 2 [97.5%] after the study period. In group 1, a nonsignificant decrease occurred in plasma homocysteine level [29.67 +/- 12.26 micro mol/L to 27.78 +/- 9.94 micro mol/L, P = .30], while in group 2, there was a significant decrease in homocysteine level [32.40 +/- 9.76 micro mol/L to 29.58 +/- 9.62 micro mol/L, P = .01]. Changes in homocysteine level correlated with its baseline level [r = -0.42, P < .001]. In both groups, significant reductions in homocysteine level were seen mostly in those patients with high baseline homocysteines. Routine folic acid supplementation of 10 mg/d could not normalize plasma homocysteine levels in most of our patients. Increasing folic acid dose made a statistically significant but clinically trivial decrease in homocysteine levels, and could not normalize homocysteine level in most patients. Patients with a higher baseline homocysteine level achieved a greater reduction, which may be explained by primary noncompliance of some patient. Further investigation of folic acid dosage is suggested

Obstrução arterial retiniana periférica associada com hiper-homocisteinemia: relato de caso / Peripheral retinal arterial obstruction associated with hyperhomocysteinemia: case report

A hiperhomocisteinemia é fator de risco para fenômenos trombo-embólicos retinianos associados a quadro de oclusão vascular venosa e arterial. Descrevemos um paciente com obstrução arterial retiniana periférica, sem sinais de vasculite ativa, associada a proliferação de neovasos com tração vítreo-retiniana e hemorragia vítrea recidivante. O alto nível sérico de homocisteína decorrente de deficiência de vitamina B12 e ácido fólico, sem outras alterações na cascata da coagulação, inclusive com a pesquisa do fator V de Leiden, sugere que a hiper-homocisteinemia esteja diretamente ligada como fator causal deste quadro clínico. Embora apresentasse PPD elevado, o diagnóstico diferencial mais importante de doença de Eales foi menos considerado por ser diagnóstico de exclusão. O controle do quadro clínico foi feito com suplemento de vitaminas (B12 e ácido fólico) e fotocoagulação retiniana periférica. A homocisteína plasmática total deve ser dosada em pacientes com obstrução vascular retiniana, já que a hiper-homocisteinemia é fator de risco modificável e de fácil tratamento por meio de dieta ou suplementação vitamínica.

Hyperhomocysteinemia is a risk factor for thromboembolic events of the retina associated with vascular venous or arterial occlusion. We describe a patient with occlusion of the peripheral arteriolar network without active vasculitis, associated with neovascular proliferation, peripheral vitreous-retinal traction and relapsing vitreous hemorrhage. The high serum homocysteine level resulting from vitamin B12 and folic acid deficiency, without further changes in the coagulation cascade including the test for Leiden's Factor V, indicates hyperhomocysteinemia as a direct causal factor in this clinical condition. Despite a high PPD, Eales Disease, a major differential diagnosis, was not fully considered, since it is established by exclusion. The patient was treated with photocoagulation and vitamin supplements and the condition was successfully controlled. Patients with retinal vascular obstruction should have their total plasma homocysteine levels measured, since this modifiable risk factor can be easily treated with dietary approaches including vitamin supplementation.

Young man presenting with chest pain

This is a case report of a young man, who had an acute coronary event followed by angioplasty. On further workup he was found out to have hyper-homocysteinemia

Homocisteína e transtornos psiquiátricos / Homocysteine and neuropsychiatric disorders

O autor apresenta uma visão geral da literatura atual sobre homocisteína como um fator de risco para os transtornos neuropsiquiátricos. Foram pesquisados os bancos de dados MEDLINE, Current Contents e EMBASE (entre 1966 e 2002) para publicações em língua inglesa utilizando as palavras-chave Homocisteína e AVC; Doença de Alzheimer; Déficit Cognitivo, Epilepsia, Depressão ou Doença de Parkinson. Artigos individuais foram pesquisados para referências cruzadas relevantes. É biologicamente plausível que altos níveis de homocisteína possam causar lesão cerebral e transtornos neuropsiquiátricos. A homocisteína é pró-aterogênica e pró-trombótica. Dessa forma, aumenta o risco de acidente vascular cerebral, podendo ter um efeito neurotóxico direto. Evidências de que a homocisteína seja um fator de risco para doença microvascular cerebral são conflitantes, mas justificam maiores estudos. Estudos transversais e alguns longitudinais suportam a crescente prevalência de acidente vascular cerebral e demência vascular em indivíduos com hiper-homocisteinemia. As evidências de crescente neurodegeneração estão se acumulando. A relação com a depressão ainda é experimental, da mesma forma como com a epilepsia. Atualmente, estudos sobre tratamentos são necessários para colocar as evidências sobre bases mais sólidas. Os pacientes de alto risco também devem ser pesquisados para hiper-homocisteínemia, cujo tratamento deve ser feito com ácido fólico. Mais evidências são necessárias antes que pesquisas populacionais possam ser recomendadas.

Role of nutritional supplementation in reducing the levels of homocysteine.

Elevated plasma homocysteine level is a risk factor for atherosclerotic disease. Plasma homocysteine levels are influenced by genetic, physiological and lifestyle factors. Among the lifestyle factors, diet plays a significant role. Dietary intakes of folate, vitamins B12, B6 and B2 have been reported to be inversely related to plasma homocysteine concentration. Prevalence of subclinical deficiencies of these vitamins is high in Indian population. Folate status is the major determinant of plasma homocysteine level and there is a strong inverse correlationship between plasma homocysteine level and serum or erythrocyte folate levels. A combination therapy with B vitamins--folate, vitamins B12 and B6 is an effective means to reduce elevated homocysteine levels in general people and in patients with myocardial infarction. To maintain low plasma homocysteine concentration, people should be advised to increase their consumption of pulses, eggs, green leafy vegetables and fruits which are rich in B vitamins.