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1.
Med Sci Monit ; 25: 5717-5726, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31369520

RESUMO

BACKGROUND Different blood pressure targets should be formulated for different groups of people. This study aimed to assess the effectiveness of intensive blood control in improving the carotid morphology and hemodynamics in Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke. MATERIAL AND METHODS Chinese hypertensive patients with high risk of stroke were randomized to intensive (n=187) and standard (n=192; controls) blood pressure management groups. Systolic blood pressure (SBP) targets were 100< SBP ≤120 and 120< SBP ≤140 mmHg, respectively. All patients received folic acid 0.8 mg/d and atorvastatin 20 mg/d. Calcium antagonist was first used. If blood pressure was still uncontrolled, angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist, ß-receptor blocker, and diuretics were added successively. Follow-up was 12 months. Carotid features, hemodynamics, and adverse events were examined. RESULTS There were no differences in sex, age, body mass index, blood lipids, baseline carotid parameters, and histories of smoking, diabetes, statin use, and stroke between the 2 groups. Carotid plaques after 12 months of treatment were 19.4±2.1 and 23.6±3.1 cm² for the intensive and control groups, respectively (P=0.038). Plaque scores were lower in the intensive group (1.75±0.52 vs. 2.45±0.47, P=0.023). Compared with controls, intensive management resulted in relatively higher Vd and significantly lower Vs/Vd, PI, and RI (all P<0.05). Major adverse events such as hypotension (n=5 (2.7%) vs. 3 (1.6%), P=0.020) and dizziness (n=20 (10.7%) vs. 16 (8.3%), P=0.041) were more frequent in the intensive group. CONCLUSIONS Intensive blood pressure management could be beneficial for Chinese patients with hyperhomocysteinemia-type hypertension and high risk of stroke.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hiper-Homocisteinemia/tratamento farmacológico , Hipertensão/fisiopatologia , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Determinação da Pressão Arterial , Bloqueadores dos Canais de Cálcio/farmacologia , Artérias Carótidas/fisiologia , China , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hiper-Homocisteinemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Acidente Vascular Cerebral/fisiopatologia
2.
Biotechnol Appl Biochem ; 66(5): 715-719, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31314127

RESUMO

Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Creatinina/sangue , Ácido Fólico/farmacologia , Hiper-Homocisteinemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Ácido Úrico/sangue , Humanos , Hiper-Homocisteinemia/sangue , Hipertensão/sangue , Estudos Observacionais como Assunto
3.
Medicine (Baltimore) ; 98(6): e14349, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732165

RESUMO

RATIONALE: Risk factors of cerebral venous sinus thrombosis (CVST) are usually divided into acquired risks (e.g., trauma and pregnancy) and genetic risks (inherited thrombophilia). It is essential but not easy to identify the exact one for each patient. PATIENT CONCERNS: A 14-year-old male patient was admitted in our hospital because of progressively exacerbated severe headache and vomiting for 3 days, accompanied by transient weakness once in his right leg. DIAGNOSIS: CVST due to hyperhomocysteinemia with cystathionine-ß-synthase (CBS) gene mutation. INTERVENTIONS: Persistent oral anticoagulant therapy. OUTCOMES: Follow-ups at 4 months and 1 year showed that the patient's symptoms alleviated and did not recur, accompanied with improved MRV image; however, the cranial MRV image did not display as a completely normal one. LESSONS: We recommend that in case of thrombophilic state, serum homocysteine (Hcy), folic acid, and vitamin B12 levels should be routinely screened; when serum Hcy level is extremely high, congenital diseases caused by gene mutations should be considered. We firstly discovered a new mutation of CBS c.949A>G which had not been reported before.


Assuntos
Cistationina beta-Sintase/genética , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Trombose dos Seios Intracranianos/etiologia , Adolescente , Anticoagulantes/uso terapêutico , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético
4.
J Med Case Rep ; 13(1): 36, 2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30773142

RESUMO

INTRODUCTION: Cerebral venous thrombosis is relatively rare and characterized by a wide spectrum of clinical features. It is more common in young adults with women affected more than men. The diagnosis of cerebral venous thrombosis is easier nowadays due to easy access to advanced neuroimaging techniques. Abnormalities in thrombophilic profile are associated with enhanced risk of cerebral venous thrombosis. It has varied etiologies such as hypercoagulable states, infection, dehydration, pregnancy, and substance abuse. Hyperhomocysteinemia is found to be closely associated with an enhanced risk of cerebral venous thrombosis. CASE PRESENTATION: Here we report a case of cerebral venous thrombosis secondary to hyperhomocysteinemia caused by vitamin B12 deficiency in a 32-year-old Indo-Aryan man. A detailed coagulation workup led us to find the etiology of cerebral venous thrombosis in this patient who followed a strict vegetarian diet and had vitamin B12 deficiency leading to hyperhomocysteinemia. CONCLUSION: There are conflicting reports in the literature about the association of hyperhomocysteinemia, B12 deficiency, and cerebral venous thrombosis but some reports point to a significant association. We conclude that further studies with a large sample size are required to analyze the effect of hyperhomocysteinemia and low vitamin B12 on the risk of cerebral venous thrombosis.


Assuntos
Hiper-Homocisteinemia/etiologia , Trombose Intracraniana/etiologia , Deficiência de Vitamina B 12/complicações , Adulto , Anticoagulantes/uso terapêutico , Anticonvulsivantes/uso terapêutico , Encéfalo/diagnóstico por imagem , Diuréticos Osmóticos/uso terapêutico , Glicerol/uso terapêutico , Heparina/uso terapêutico , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/tratamento farmacológico , Imagem por Ressonância Magnética , Masculino , Manitol/uso terapêutico , Convulsões/complicações , Convulsões/tratamento farmacológico , Ácido Valproico/uso terapêutico , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/tratamento farmacológico , Complexo Vitamínico B/uso terapêutico , Varfarina/uso terapêutico
5.
Neurosci Bull ; 35(4): 724-734, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30632006

RESUMO

Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD), and insulin-resistance is commonly seen in patients with Hhcy. Liraglutide (Lir), a glucagon-like peptide that increases the secretion and sensitivity of insulin, has a neurotrophic or neuroprotective effect. However, it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy. By vena caudalis injection of homocysteine to produce the Hhcy model in rats, we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit, along with increased density of dendritic spines and up-regulation of synaptic proteins. Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aß overproduction, and the molecular mechanisms involved the restoration of protein phosphatase-2A activity and inhibition of ß- and γ-secretases. Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir. Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulin-resistance and the pathways generating abnormal tau and Aß.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Hiper-Homocisteinemia/tratamento farmacológico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hiper-Homocisteinemia/induzido quimicamente , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Resistência à Insulina , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/tratamento farmacológico , Plasticidade Neuronal , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores , Proteínas tau/metabolismo
6.
Curr Med Chem ; 26(16): 2948-2961, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29532755

RESUMO

Homocysteine (Hcy) is a thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria is connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer's disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine ß-synthase (CßS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent, deficiency in B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders.


Assuntos
Homocisteína/metabolismo , Hiper-Homocisteinemia/etiologia , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/deficiência , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Animais , Deficiência de Vitaminas , Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Ácido Fólico/uso terapêutico , Humanos , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitamina B 12/uso terapêutico , Vitamina B 6/uso terapêutico
7.
Mol Cell Biochem ; 452(1-2): 199-217, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30120639

RESUMO

The aim of this study was to evaluate the effects of atorvastatin and simvastatin on behavioral manifestations that followed hyperhomocysteinemia induced by special dietary protocols enriched in methionine and deficient in B vitamins (B6, B9, B12) by means of alterations in anxiety levels in rats. Simultaneously, we investigated the alterations of oxidative stress markers in rat hippocampus induced by applied dietary protocols. Furthermore, considering the well-known antioxidant properties of statins, we attempted to assess their impact on major markers of oxidative stress and their possible beneficial role on anxiety-like behavior effect in rats. The 4-week-old male Wistar albino rats were divided (eight per group) according to basic dietary protocols: standard chow, methionine-enriched, and methionine-enriched vitamins B (B6, B9, B12) deficient. Each dietary protocol (30 days) included groups with atorvastatin (3 mg/kg/day i.p.) and simvastatin (5 mg/kg/day i.p.). The behavioral testing was performed in the open field and elevated plus maze tests. Parameters of oxidative stress (index of lipid peroxidation, superoxide dismutase, catalase activity, glutathione) were determined in hippocampal tissue samples following decapitation after anesthesia. Methionine-load dietary protocols induced increased oxidative stress in rat hippocampus, which was accompanied by anxiogenic behavioral manifestations. The methionine-enriched diet with restricted vitamins B intake induced more pronounced anxiogenic effect, as well as increased oxidative stress compared to the methionine-load diet with normal vitamins B content. Simultaneous administration of statins showed beneficial effects by means of both decreased parameters of oxidative stress and attenuation of anxiety. The results obtained with simvastatin were more convincible compared to atorvastatin.


Assuntos
Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Atorvastatina/farmacologia , Dieta/efeitos adversos , Homocisteína/metabolismo , Hiper-Homocisteinemia/tratamento farmacológico , Sinvastatina/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Transtornos de Ansiedade/etiologia , Comportamento Animal/efeitos dos fármacos , Hiper-Homocisteinemia/etiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
8.
J Cell Physiol ; 234(3): 3007-3019, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30206943

RESUMO

An elevated level of homocysteine (Hcy) leads to hyperhomocysteinemia (HHcy), which results in vascular dysfunction and pathological conditions identical to stroke symptoms. Hcy increases oxidative stress and leads to increase in blood-brain barrier permeability and leakage. Hydrogen sulfide (H2 S) production during the metabolism of Hcy has a cerebroprotective effect, although its effectiveness in Hcy-induced neurodegeneration and neurovascular permeability is less explored. Therefore, the current study was designed to perceive the neuroprotective effect of exogenous H 2 S against HHcy, a cause of neurodegeneration. To test this hypothesis, we used four groups of mice: control, Hcy, control + sodium hydrosulfide hydrate (NaHS), and Hcy + NaHS, and an HHcy mice model in Swiss albino mice by giving a dose of 1.8 g of dl-Hcy/L in drinking for 8-10 weeks. Mice that have 30 µmol/L Hcy were taken for the study, and a H 2 S supplementation of 20 µmol/L was given for 8 weeks to all groups of mice. HHcy results in the rise of the levels of superoxide and nitrite, although a concomitant decrease in the level of superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, and arginase in oxidative stress and a concomitant decrease in the endogenous level of H 2 S. Although H 2 S supplementation ameliorated, the effect of HHcy and the levels of H 2 S returned to the average level in HHcy animals supplemented with H 2 S. Interestingly, H 2 S supplementation ameliorated neurovascular remodeling and neurodegeneration. Thus, our study suggested that H 2 S could be a beneficial therapeutic candidate for the treatment of Hcy-associated neurodegeneration, such as stroke and neurovascular disorders.


Assuntos
Transtornos Cerebrovasculares/tratamento farmacológico , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/tratamento farmacológico , Degeneração Neural/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Transtornos Cerebrovasculares/induzido quimicamente , Transtornos Cerebrovasculares/metabolismo , Transtornos Cerebrovasculares/patologia , Modelos Animais de Doenças , Homocisteína/toxicidade , Humanos , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Metaloproteinase 9 da Matriz/genética , Camundongos , Degeneração Neural/induzido quimicamente , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
9.
Int J Neuropsychopharmacol ; 22(1): 57-70, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407508

RESUMO

Background: Hyperhomocysteinemia is an independent risk factor for dementia, including Alzheimer's disease. Lowering homocysteine levels with folic acid treatment with or without vitamin B12 has shown few clinical benefits on cognition. Methods: To verify the effect of emodin, a naturally active compound from Rheum officinale, on hyperhomocysteinemia-induced dementia, rats were treated with homocysteine injection (HCY, 400 µg/kg/d, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations for 2 weeks: 0 (HCY-E0), 20 (HCY-E20), 40 (HCY-E40), and 80 mg/kg/d (HCY-E80). Results: ß-Amyloid overproduction, tau hyperphosphorylation, and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioral performance. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/d) reduced the levels of ß-amyloid and tau phosphorylation, decreased the levels of ß-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins, and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased. In addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6, and tumor necrosis factor α were also observed. Lastly, hyperhomocysteinemia-induced microangiopathic alterations, oxidative stress, and elevated DNA methyltransferases 1 and 3ß were rescued by emodin. Conclusions: Emodin represents a novel potential candidate agent for hyperhomocysteinemia-induced dementia and Alzheimer's disease-like features.


Assuntos
Demência/tratamento farmacológico , Demência/etiologia , Emodina/farmacologia , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/tratamento farmacológico , Nootrópicos/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/fisiologia , Demência/metabolismo , Demência/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/patologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Proteínas tau/metabolismo
10.
Fundam Clin Pharmacol ; 33(4): 428-440, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30506745

RESUMO

The incidence of cardiovascular diseases in vegetarian individuals is lower than that in the general population. Nevertheless, individuals who adhere to vegan diets have a higher prevalence of hyperhomocysteinemia with eventual adverse effects on vascular reactivity. Creatine supplementation (CrS) reduces plasma homocysteine levels and enhances vascular reactivity in the microcirculation. Thus, we investigated the effects of CrS on systemic microcirculation and homocysteine blood levels in strict vegan subjects. Forty-nine strict vegan subjects were allocated to the oral CrS (5 g micronized creatine monohydrate daily for three weeks; n = 31) and placebo (n = 18) groups. Laser speckle contrast imaging coupled with acetylcholine skin iontophoresis was used to evaluate cutaneous microvascular reactivity, and intravital video-microscopy was used to evaluate skin capillary density and reactivity before and after CrS. We demonstrated that CrS reduces the plasma levels of homocysteine and increases those of folic acid. After the CrS period, the homocysteine levels of all of the vegan subjects normalized. CrS also induced increases in baseline skin functional capillary density and endothelium-dependent capillary recruitment in both normo- (N-Hcy) and hyperhomocysteinemic (H-Hcy) individuals. CrS increased endothelium-dependent skin microvascular vasodilation in the H-Hcy vegan subjects but not in the N-Hcy vegan subjects. In conclusion, three weeks of oral CrS was sufficient to increase skin capillary density and recruitment and endothelium-dependent microvascular reactivity. CrS also resulted in plasma increases in folic acid levels and reductions in homocysteine levels among only the H-Hcy individuals.


Assuntos
Creatina/farmacologia , Creatina/uso terapêutico , Dieta Vegana , Endotélio Vascular/efeitos dos fármacos , Hiper-Homocisteinemia/tratamento farmacológico , Adulto , Pesos e Medidas Corporais , Creatina/administração & dosagem , Suplementos Nutricionais , Feminino , Ácido Fólico , Humanos , Iontoforese , Fluxometria por Laser-Doppler , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional/efeitos dos fármacos
11.
Oxid Med Cell Longev ; 2018: 2746873, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581528

RESUMO

Maternal high levels of the redox active amino acid homocysteine-called hyperhomocysteinemia (hHCY)-can affect the health state of the progeny. The effects of hydrogen sulfide (H2S) treatment on rats with maternal hHCY remain unknown. In the present study, we characterized the physical development, reflex ontogeny, locomotion and exploratory activity, muscle strength, motor coordination, and brain redox state of pups with maternal hHCY and tested potential beneficial action of the H2S donor-sodium hydrosulfide (NaHS)-on these parameters. Our results indicate a significant decrease in litter size and body weight of pups from dams fed with methionine-rich diet. In hHCY pups, a delay in the formation of sensory-motor reflexes was observed. Locomotor activity tested in the open field by head rearings, crossed squares, and rearings of hHCY pups at all studied ages (P8, P16, and P26) was diminished. Exploratory activity was decreased, and emotionality was higher in rats with hHCY. Prenatal hHCY resulted in reduced muscle strength and motor coordination assessed by the paw grip endurance test and rotarod test. Remarkably, administration of NaHS to pregnant rats with hHCY prevented the observed deleterious effects of high homocysteine on fetus development. In rats with prenatal hHCY, the endogenous generation of H2S brain tissues was lower compared to control and NaHS administration restored the H2S level to control values. Moreover, using redox signaling assays, we found an increased level of malondialdehyde (MDA), the end product of lipid peroxidation, and decreased activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the brain tissues of rats of the hHCY group. Notably, NaHS treatment restored the level of MDA and the activity of SOD and GPx. Our data suggest that H2S has neuroprotective/antioxidant effects against homocysteine-induced neurotoxicity providing a potential strategy for the prevention of developmental impairments in newborns.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Feminino , Glutationa Peroxidase/metabolismo , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Peroxidação de Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Malondialdeído/sangue , Gravidez , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfetos/uso terapêutico , Superóxido Dismutase/metabolismo
12.
BMC Ophthalmol ; 18(Suppl 1): 220, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30255822

RESUMO

BACKGROUND: Retinal vascular occlusions are uncommon in young people and require more in-depth investigation into the cause. Studies have revealed that a high level of circulating homocysteine poses a risk for retinal vaso-occlusive events across a wide age range. This case report reflects on how the interplay of genetic mutation and vitamin deficiency can cause a pathological level of homocysteine with resultant branch retinal artery occlusion in a young patient. CASE PRESENTATION: A 16-year-old boy presented to eye casualty with acute inferior visual field loss in the left eye. Visual acuity remained normal at 6/6 each eye and the event was painless. Initial assessment, and retinal photography revealed a left superior hemi-field branch retinal artery occlusion with macular sparing. Given the patient's age, extensive investigation into the cause was carried out. Positive findings were of an elevated level of homocysteine as a result of vitamin B12 and folic acid deficiency as well as a genetic mutation in the MTHFR gene (encoding MTHFR enzyme which is vital in normal homocysteine metabolism). Vitamin B12 and folic acid were replaced which in turn normalized the patient's homocysteine levels. At two months, the patient's visual fields had also improved, and no further vascular event had occurred. CONCLUSIONS: This case report has highlighted the link between hyperhomocysteinaemia and retinal artery occlusion. However, despite vitamin replacement being shown to normalize homocysteine levels, no evidence exists to date as to whether this will reduce the risk of further retinal vascular occlusion.


Assuntos
Deficiência de Ácido Fólico/diagnóstico , Hiper-Homocisteinemia/complicações , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Oclusão da Artéria Retiniana/etiologia , Deficiência de Vitamina B 12/diagnóstico , Adolescente , Ácido Fólico/uso terapêutico , Predisposição Genética para Doença/genética , Genótipo , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/tratamento farmacológico , Masculino , Desnutrição/diagnóstico , Oclusão da Artéria Retiniana/sangue , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/tratamento farmacológico , Transtornos da Visão/diagnóstico , Transtornos da Visão/etiologia , Acuidade Visual/fisiologia , Testes de Campo Visual , Campos Visuais , Vitamina B 12/uso terapêutico
13.
Am J Physiol Cell Physiol ; 315(5): C609-C622, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30110564

RESUMO

Although hyperhomocysteinemia (HHcy) occurs because of the deficiency in cystathionine-ß-synthase (CBS) causing skeletal muscle dysfunction, it is still unclear whether this effect is mediated through oxidative stress, endoplasmic reticulum (ER) stress, or both. Nevertheless, there is no treatment option available to improve HHcy-mediated muscle injury. Hydrogen sulfide (H2S) is an antioxidant compound, and patients with CBS mutation do not produce H2S. In this study, we hypothesized that H2S mitigates HHcy-induced redox imbalance/ER stress during skeletal muscle atrophy via JNK phosphorylation. We used CBS+/- mice to study HHcy-mediated muscle atrophy, and treated them with sodium hydrogen sulfide (NaHS; an H2S donor). Proteins and mRNAs were examined by Western blots and quantitative PCR. Proinflammatory cytokines were also measured. Muscle mass and strength were studied via fatigue susceptibility test. Our data revealed that HHcy was detrimental to skeletal mass, particularly gastrocnemius and quadriceps muscle weight. We noticed that oxidative stress was reversed by NaHS in homocysteine (Hcy)-treated C2C12 cells. Interestingly, ER stress markers (GRP78, ATF6, pIRE1α, and pJNK) were elevated in vivo and in vitro, and NaHS mitigated these effects. Additionally, we observed that JNK phosphorylation was upregulated in C2C12 after Hcy treatment, but NaHS could not reduce this effect. Furthermore, inflammatory cytokines IL-6 and TNF-α were higher in plasma from CBS as compared with wild-type mice. FOXO1-mediated Atrogin-1 and MuRF-1 upregulation were attenuated by NaHS. Functional studies revealed that NaHS administration improved muscle fatigability in CBS+/- mice. In conclusion, our work provides evidence that NaHS is beneficial in mitigating HHcy-mediated skeletal injury incited by oxidative/ER stress responses.


Assuntos
Cistationina beta-Sintase/genética , Hiper-Homocisteinemia/tratamento farmacológico , Atrofia Muscular/tratamento farmacológico , Sulfitos/administração & dosagem , Fator 6 Ativador da Transcrição/genética , Animais , Antioxidantes/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/genética , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Interleucina-6/sangue , MAP Quinase Quinase 4/genética , Camundongos , Proteínas Musculares/genética , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/sangue , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Ligases SKP Culina F-Box/genética , Proteínas com Motivo Tripartido/genética , Fator de Necrose Tumoral alfa/sangue , Ubiquitina-Proteína Ligases/genética
14.
Neuromolecular Med ; 20(4): 475-490, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30105650

RESUMO

Homocysteine (Hcy) is a sulfur-containing amino acid derived from methionine metabolism. Elevated plasma Hcy levels (> 15 µM) result in a condition called hyperhomocysteinemia (HHcy), which is an independent risk factor in the development of various neurodegenerative disorders. Reactive oxygen species (ROS) produced by auto-oxidation of Hcy have been implicated in HHcy-associated neurological conditions. Hydrogen sulfide (H2S) is emerging as a potent neuroprotective and neuromodulator molecule. The present study was aimed to evaluate the ability of NaHS (a source of H2S) to attenuate Hcy-induced oxidative stress and altered antioxidant status in animals subjected to HHcy. Impaired cognitive functions assessed by Y-maze and elevated plus maze in Hcy-treated animals were reversed on NaHS administration. Increased levels of ROS, lipid peroxidation, protein carbonyls, and 4-hydroxynonenal (4-HNE)-modified proteins were observed in the cortex and hippocampus of Hcy-treated animals suggesting accentuated oxidative stress. This increase in Hcy-induced oxidative stress was reversed following NaHS supplementation. GSH/GSSG ratio, activity of antioxidant enzymes viz; superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase were decreased in Hcy-treated animals. NaHS supplementation, on the otherhand, restored redox ratio and activity of antioxidant enzymes in the brains of animals with HHcy. Further, NaHS administration normalized nuclear factor erythroid 2-related factor 2 expression and acetylcholinesterase (AChE) activity in the brain of Hcy-treated animals. Histopathological studies using cresyl violet indicated higher number of pyknotic neurons in the cortex and hippocampus of HHcy animals, which were reversed by NaHS administration. The results clearly demonstrate that NaHS treatment significantly ameliorates Hcy-induced cognitive impairment by attenuating oxidative stress, improving antioxidant status, and modulating AChE activity thereby suggesting potential of H2S as a therapeutic molecule.


Assuntos
Antioxidantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Transtornos Cognitivos/prevenção & controle , Hipocampo/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/tratamento farmacológico , Fator 2 Relacionado a NF-E2/fisiologia , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Animais , Córtex Cerebral/metabolismo , Transtornos Cognitivos/etiologia , Hipocampo/metabolismo , Homocisteína/toxicidade , Sulfeto de Hidrogênio/uso terapêutico , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/psicologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Oxirredução , Estresse Oxidativo , Oxirredutases/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
15.
Exp Cell Res ; 370(2): 434-443, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29981342

RESUMO

Hydrogen sulfide (H2S) prevents endothelial cells damage and P-selectin of platelets promotes neutrophils extracellular traps (NETs) formation. However, how sodium hydrosulfide (NaHS), a donor that produces H2S regulates the activation of platelets and whether H2S inhibits the formation of neutrophils extracellular traps in hyperhomocysteinemia rats have not been previously investigated. The morphological and ultrastructural alterations of endothelial cells (ECs) and platelets were tested by transmission electron microscopy. The expressions of P-selectin of platelets were determined by flow cytometry. Additionally, the cellular ROS and the H2S level were detected by DCFH-DA staining and H2S probe, the expressions of Bax and Bcl-2 in arteries and cultured ECs from rat thoracic aortas and the phosphor-p38 mitogen-activated protein kinase (MAPK), CSE and CBS of platelets were measured by western blotting. The NETs formations, the concentration of DNA in serum and supernatant of cultured neutrophils stimulated with platelet-rich plasma (PRP) were tested by Sytox Green and PicoGreen commercial Kits. The vascular ECs damaged, the expression of P-selectin of platelets and NETs formation increased; the concentration of DNA in serum and supernatant of cultured neutrophils stimulated with PRP also increased; the expression of Bax increased while Bcl-2 decreased in arteries, the phosphor-p38 MAPK of platelets increased while CSE and CBS have no statistically significant changes in the HHcy group compared to the control group. In the cultured ECs, the ROS level increased while the H2S level decreased after 48 and 72 h treatment by HHcy; the expression of Bcl-2 decreased while Bax increased after 72 h treatment by HHcy. NaHS significantly inhibited the ECs injured, cellular ROS production, platelet activation and NETs formation, reversed the expressions of Bax, Bcl-2, phosphor-p38 MAPK, P-selectin and the increased concentration of DNA in serum and supernatant of cultured neutrophils which caused by high homocysteine. Our results demonstrate that the donor of H2S inhibits the platelets activation and NETs formation, which concerts the protection of ECs in hyperhomocysteinemia.


Assuntos
Plaquetas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/metabolismo , Neutrófilos/efeitos dos fármacos , Animais , Células Cultivadas/efeitos dos fármacos , Células Endoteliais/metabolismo , Armadilhas Extracelulares/efeitos dos fármacos , Hiper-Homocisteinemia/tratamento farmacológico , Masculino , Neutrófilos/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
16.
Dig Dis Sci ; 63(12): 3339-3347, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29974377

RESUMO

BACKGROUND: The hyperhomocysteinaemia (Hhcy) is a common phenomenon observed in patients with inflammatory bowel disease (IBD). Our previous study showed that Hhcy aggravated intestinal inflammation in an animal model of colitis. Increased levels of IL-17 and RORγt were also observed in this animal model of colitis with Hhcy. However, the direct effect of homocysteine on the differentiation of Th17 cells has never been studied. The aim of this study was to investigate the direct effect of Hhcy on the differentiation of CD4+ T cells into Th17 cells. METHOD: Lamina propria lymphocytes (LPLs) in colonic mucosa of Wistar rats were isolated and cultured under Th17-inducing (iTH17) environments. Different concentrations of the Hcy (0-100 µmol/ml) were added alone or combined with IL-23 (100 ng/ml) or folate (5 µmol/ml). The LPLs were divided into eight groups as follows: (1) Control group; (2) 10 µmol/ml Hcy group; (3) 25 µmol/ml Hcy group; (4) 50 µmol/ml Hcy group; (5) 100 µmol/ml Hcy group; (6) 100 ng/ml IL-23 group; (7) 50 µmol/ml Hcy + 100 ng/ml IL-23 group and (8) 50 µmol/ml Hcy + 100 ng/ml IL-23 + 5 µmol/ml folate group. The protein expression levels of IL-17, retinoid-related orphan nuclear receptor-γt (RORγt), p38 MAPK, phosphorylated p38 MAPK, cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 and cyclooxygenase 2 (COX2) were detected by immunoblot analysis. The protein level of prostaglandin E2 (PGE2) and IL-17 was detected by ELISA, and IL-17 and RORγt-positive CD4+ T cells were stained and analyzed by flow cytometry. RESULTS: Hcy increased the protein levels of IL-17, RORγt, the ratio of phosphorylated p38 MAPK to p38 MAPK (p-p38/p38), the ratio of phosphorylated cPLA2 to cPLA2 (p-cPLA2/cPLA2) and COX2. The effect was concentration dependent to a certain degree; Hcy of 50 µmol/ml was the optimal concentration to increase the protein levels of those molecules. The level of IL-17 and PGE2 in the cell culture supernatants and the expression of IL-17 and RORγt in positive CD4+ T cells were also increased in the group of Hhcy. IL-23 showed a cooperative effect with Hcy on the differentiation of CD4+ Th cells into Th17 cells, whereas folate supplementation showed an inhibition action. CONCLUSIONS: Homocysteine promoted the differentiation of CD4+ T cells into Th17 cells in a dose-dependant manner. This effect could be inhibited by folate.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular , Ácido Fólico/farmacologia , Homocisteína/metabolismo , Hiper-Homocisteinemia , Doenças Inflamatórias Intestinais , Células Th17/fisiologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Colo/metabolismo , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Fosfolipases A2 do Grupo IV/metabolismo , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/metabolismo , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ratos , Ratos Wistar , Resultado do Tratamento , Complexo Vitamínico B/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Med Sci Monit ; 24: 3744-3751, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29863106

RESUMO

BACKGROUND At present, a constant progress in pathophysiology understanding and treatment of the chronic heart failure (CHF) is arising. Meanwhile, hyperhomocysteinemia (HHcy) has been linked to impaired left ventricular function and clinical class in patients with CHF. Atorvastatin therapy can reduce the incidence of sudden cardiac death in patients with advanced CHF. Folic acid could enhance endothelial function in vascular disease states. The present study aims to investigate the effect of atorvastatin and folic acid combined on the cardiac function and ventricular remodeling in CHF patients with HHcy. MATERIAL AND METHODS Elderly CHF patients with HHcy were divided into four groups: routine, routine + atorvastatin, routine + folic acid, and routine + atorvastatin + folic acid groups. Serum homocysteine (Hcy) level was detected using enzymatic cycling methods, and N-terminal pro brain natriuretic peptide (NT-proBNP) level by ELISA. The cardiac function indexes and left ventricular early diastolic peak flow velocity/atrial systolic peak flow velocity (E/A) ratio were evaluated. The six-minute walk test was performed to measure the six-minute walk distance (6MWD). RESULTS 6MWD increased, the serum Hcy and NT-proBNP levels decreased, and cardiac function was improved compared with before treatment, which was the most significant in the routine + atorvastatin + folic acid group, followed by the routine + atorvastatin group, then the routine + folic acid group, and lastly, the routine group. CONCLUSIONS The results indicated that the combination of atorvastatin and folic acid improved the cardiac function and inhibited ventricular remodeling of elderly CHF patients with HHcy.


Assuntos
Atorvastatina/uso terapêutico , Ácido Fólico/uso terapêutico , Hiper-Homocisteinemia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Atorvastatina/metabolismo , Atorvastatina/farmacologia , China , Doença Crônica , Feminino , Ácido Fólico/metabolismo , Ácido Fólico/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Remodelação Ventricular/efeitos dos fármacos
18.
Bone ; 114: 90-108, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29908298

RESUMO

Hydrogen sulfide (H2S) is a novel gasotransmitter produced endogenously in mammalian cells, which works by mediating diverse physiological functions. An imbalance in H2S metabolism is associated with defective bone homeostasis. However, it is unknown whether H2S plays any epigenetic role in bone loss induced by hyperhomocysteinemia (HHcy). We demonstrate that diet-induced HHcy, a mouse model of metabolite induced osteoporosis, alters homocysteine metabolism by decreasing plasma levels of H2S. Treatment with NaHS (H2S donor), normalizes the plasma level of H2S and further alleviates HHcy induced trabecular bone loss and mechanical strength. Mechanistic studies have shown that DNMT1 expression is higher in the HHcy condition. The data show that activated phospho-JNK binds to the DNMT1 promoter and causes epigenetic DNA hyper-methylation of the OPG gene. This leads to activation of RANKL expression and mediates osteoclastogenesis. However, administration of NaHS could prevent HHcy induced bone loss. Therefore, H2S could be used as a novel therapy for HHcy mediated bone loss.


Assuntos
Doenças Ósseas Metabólicas/metabolismo , Epigenômica/métodos , Sulfeto de Hidrogênio/uso terapêutico , Hiper-Homocisteinemia/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Animais , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/genética , Feminino , Sulfeto de Hidrogênio/farmacologia , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/genética , Camundongos , Camundongos Endogâmicos C57BL , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Osteoprotegerina/genética , Ligante RANK/genética
19.
Cardiovasc Drugs Ther ; 32(2): 233-240, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29679304

RESUMO

Homocysteine is an intermediary metabolite in the methionine cycle. Accumulation of homocysteine is caused either by mutation of relevant genes or by nutritional depletion of related vitamin(s). This review covers the historical background of hyperhomocysteinemia in which indispensable subjects in relation to underlying pathophysiological processes are discussed with the view of metabolism and genetics of folate and methionine cycles. This review emphasizes the unique role of homocysteine that is clearly distinct from other risk factors, particularly cholesterol in the development of vascular disease. The critical issue in understanding the role of homocysteine is the relation with plasma folic acid. The majority of subjects with homocysteine > 15 µmol/L exhibit plasma folate < 9 nmol/ L, indicating that depletion of folate is the main cause of hyperhomocysteinemia irrespective of the presence or absence of vascular disease. Furthermore, only the group of subjects with homocysteine levels > 15 µmol/L demonstrated a higher prevalence of vascular disease. Analytic approaches to treat hyperhomocysteinemia are discussed in which stepwise administration with nutritional doses of folic acid, 5-methyitetrahydrofolate (5-MTHF), and betaine is provided singly or by combined manner based on clinical and laboratory evaluations. Whether correction of hyperhomocysteinemia is able to prevent the development of homocysteine-associated vascular disease remains an unresolved issue. The review discussed a biochemical and mechanistic approach to resolve questions involved in the relation between homocysteine and the development of atherosclerotic vascular disease.


Assuntos
Betaína/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Ácido Fólico/uso terapêutico , Homocisteína/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Tetra-Hidrofolatos/uso terapêutico , Animais , Betaína/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Ácido Fólico/efeitos adversos , Predisposição Genética para Doença , Humanos , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/genética , Fenótipo , Fatores de Risco , Tetra-Hidrofolatos/efeitos adversos , Resultado do Tratamento
20.
Br J Nutr ; 119(8): 887-895, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29644956

RESUMO

The aim of this study is to analyse the efficacy rate of folate for the treatment of hyperhomocysteinaemia (HHcy) and to explore how folate metabolism-related gene polymorphisms change its efficacy. This study also explored the effects of gene-gene and gene-environment interactions on the efficacy of folate. A prospective cohort study enrolling HHcy patients was performed. The subjects were treated with oral folate (5 mg/d) for 90 d. We analysed the efficacy rate of folate for the treatment of HHcy by measuring homocysteine (Hcy) levels after treatment. Unconditioned logistic regression was conducted to analyse the association between SNP and the efficacy of folic acid therapy for HHcy. The efficacy rate of folate therapy for HHcy was 56·41 %. The MTHFR rs1801133 CT genotype, TT genotype and T allele; the MTHFR rs1801131 AC genotype, CC genotype and C allele; the MTRR rs1801394 GA genotype, GG genotype and G allele; and the MTRR rs162036 AG genotype and AG+GG genotypes were associated with the efficacy of folic acid therapy for HHcy (P<0·05). No association was seen between other SNP and the efficacy of folic acid. The optimal model of gene-gene interactions was a two-factor interaction model including rs1801133 and rs1801394. The optimal model of gene-environment interaction was a three-factor interaction model including history of hypertension, history of CHD and rs1801133. Folate supplementation can effectively decrease Hcy level. However, almost half of HHcy patients failed to reach the normal range. The efficacy of folate therapy may be genetically regulated.


Assuntos
Ácido Fólico/metabolismo , Ácido Fólico/uso terapêutico , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/genética , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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