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1.
Turk J Med Sci ; 49(5): 1444-1449, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651110

RESUMO

Background/aim: Raynaud's phenomenon (RP) is not a rare health problem; global prevalence is about 3%­20%. Etiology and pathophysiology of this pathology has not been clarified. There are many precipitating factors resulting in RP. Hyperhomocysteinemia resulting from methylenetetrahydrofolate reductase (MTHFR) gene mutationmay have a role in its etiology. The aim of this study was to observe the frequency of RP in patients with MTFHR gene mutation and hyperhomocysteinemia. Possible relationships among vitamin B12, folic acid, complete blood count (leukocytes and platelets), and c-reactive protein levels and RP were also analyzed. Materials and methods: A total of 388 patients admitted to the internal medicine, hematology, and obstetric clinics of a university hospital between January 2012 and April 2013 ranging in age from 21 to 83 (mean age 38.16 ± 13.1) were enrolled in the study. Eighty-five (21.9%) of the patients were male and 303 (78.1%) were female. MTHFR gene mutation was analyzed in 388 patients; 52 (13.4%) were homozygous, 275 (70.9%) were heterozygous, and 61 (15.7%) were found to be negative for the MTHFR gene mutation and accepted as a control group. Vitamin B12, folic acid, complete blood count (leukocytes and platelets), and c-reactive protein levels were also analyzed. Results: Homocysteine levels were higher in both heterozygous and homozygous groups (P < 0.05). RP was more frequently observed in patients with elevated homocysteine levels (P < 0.05; X2 = 14.51). There was no significant relationship in other parameters studied. Conclusion: RP was more frequently observed in the groups with the MTHFR mutation and hyperhomocysteinemia. Serum homocysteine levels in patients with RP may be helpful for diagnosis.


Assuntos
Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Doença de Raynaud/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença de Raynaud/epidemiologia , Adulto Jovem
2.
J Hum Genet ; 64(12): 1227-1235, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31558761

RESUMO

Both betaine homocysteine methyltransferase (BHMT) and cystathionine ß-synthase (CBS) are major enzymes in the metabolism of plasma homocysteine (Hcy). Abnormal methylation levels of BHMT and CBS are positively associated with Hcy levels. The present study is performed to explore the association between the methylation levels in the promoter regions of the BHMT and CBS genes and the efficacy of folic acid therapy in patient with hyperhomocysteinemia (HHcy). A prospective cohort study recruiting HHcy (Hcy ≥ 15 µmol/L) patients was performed. The subjects were treated with oral folic acid (5 mg/d) for 90 days, and the patients were divided into the success group (Hcy < 15 µmol/L) and the failure group (Hcy ≥ 15 µmol/L) according to their Hcy levels after treatment. In the logistic regression model with adjusted covariates, the patients with lower total methylation levels in the BHMT and CBS promoter regions exhibited 1.627-fold and 1.671-fold increased risk of treatment failure compared with higher methylation individuals, respectively. Similarly, subjects who had lower methylation levels (

Assuntos
Betaína-Homocisteína S-Metiltransferase/genética , Cistationina beta-Sintase/genética , Ácido Fólico/uso terapêutico , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/genética , Regiões Promotoras Genéticas/genética , Idoso , Feminino , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Estudos Prospectivos
3.
Bull Exp Biol Med ; 167(4): 533-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31502125

RESUMO

A model of moderate hyperhomocysteinemia associated with mechanical injury of the musculoskeletal system was developed and experimentally substantiated. The adequacy of this model for studies of morphological and functional regularities is verified. This model can be used for the development of a new concept of evaluation of thrombotic complications of mechanical injury.


Assuntos
Hiper-Homocisteinemia/patologia , Hiper-Homocisteinemia/fisiopatologia , Microcirculação/fisiologia , Animais , Modelos Animais de Doenças , Genótipo , Hiper-Homocisteinemia/genética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ratos , Trombose/genética , Trombose/fisiopatologia
4.
Arterioscler Thromb Vasc Biol ; 39(10): 2097-2119, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31366217

RESUMO

OBJECTIVE: Hyperhomocysteinemia (HHcy) is a potent risk factor for diabetic cardiovascular diseases. We have previously reported that hyperhomocysteinemia potentiates type 1 diabetes mellitus-induced inflammatory monocyte differentiation, vascular dysfunction, and atherosclerosis. However, the effects of hyperhomocysteinemia on vascular inflammation in type 2 diabetes mellitus (T2DM) and the underlying mechanism are unknown. Approach and Results: Here, we demonstrate that hyperhomocysteinemia was induced by a high methionine diet in control mice (homocysteine 129 µmol/L), which was further worsened in T2DM db/db mice (homocysteine 180 µmol/L) with aggravated insulin intolerance. Hyperhomocysteinemia potentiated T2DM-induced mononuclear cell, monocyte, inflammatory monocyte (CD11b+Ly6C+), and M1 macrophage differentiation in periphery and aorta, which were rescued by folic acid-based homocysteine-lowering therapy. Moreover, hyperhomocysteinemia exacerbated T2DM-impaired endothelial-dependent aortic relaxation to acetylcholine. Finally, transfusion of bone marrow cells depleted for Ly6C by Ly6c shRNA transduction improved insulin intolerance and endothelial-dependent aortic relaxation in hyperhomocysteinemia+T2DM mice. CONCLUSIONS: Hyperhomocysteinemia potentiated systemic and vessel wall inflammation and vascular dysfunction partially via inflammatory monocyte subset induction in T2DM. Inflammatory monocyte may be a novel therapeutic target for insulin resistance, inflammation, and cardiovascular complications in hyperhomocysteinemia+T2DM.


Assuntos
Antígenos Ly/genética , Aterosclerose/complicações , Diabetes Mellitus Tipo 2/genética , Hiper-Homocisteinemia/complicações , Monócitos/metabolismo , Doenças Vasculares/etiologia , Animais , Diferenciação Celular/genética , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Feminino , Hiper-Homocisteinemia/genética , Insulina/uso terapêutico , Resistência à Insulina , Macrófagos/metabolismo , Camundongos , Distribuição Aleatória , Fatores de Risco , Sensibilidade e Especificidade , Doenças Vasculares/fisiopatologia
5.
Int J Low Extrem Wounds ; 18(3): 339-341, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31409160

RESUMO

Leg ulcers may occur due to many autoimmune, hereditary, inflammatory, and infectious causes including venous, arterial, and neuropathic ulcers. Hyperhomocysteinemia is a metabolic disorder caused by various enzyme defects in methionine metabolism. The most common cause is methylenetetrahydrofolatreductase (MTHFR) enzyme gene mutations. Hyperhomocysteinemia is an independent risk factor for deep vein thrombosis and peripheral arterial disease. The effects of endothelial cell damage on smooth muscle hypertrophy, platelet aggregation, coagulation, and fibrinolysis cause atherogenesis and thrombosis, leading to venous and arterial lower extremity ulcers. In this article, we report the case of a 47-year-old male patient who was admitted to our clinic due to painful leg ulcers that started 1 year ago. He had a history of vena cava inferior thrombosis, deep vein thrombosis, and 40 pack-year smoking. Histopathological examination of punch biopsy taken from ulcerative lesion showed intense inflammatory infiltration in the middle dermis, erythrocyte extravasation, leukocytoclasia, and thrombus formation in a small diameter venule lumen. There were nonspecific findings in direct immunofluorescence examination. He was found as having MTHFR C677T homozygote and plasminogen activator inhibitor-1 4G/5G heterozygote gene mutation with high homocysteine level of 22.90 µmol/L, and he was diagnosed as hyperhomocysteinemia. He was recommended to quit smoking because it triggered thrombosis in hyperhomocysteinemia. Herein, we present a case of hyperhomocysteinemia due to MTHFR mutation, which is one of the rare hereditary thrombophilia causes.


Assuntos
Enoxaparina/administração & dosagem , Hiper-Homocisteinemia , Úlcera da Perna , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Compostos de Prata/administração & dosagem , Trombose Venosa , Talassemia beta , Bandagens , Biópsia/métodos , Diagnóstico Diferencial , Fibrinolíticos/administração & dosagem , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/genética , Úlcera da Perna/sangue , Úlcera da Perna/etiologia , Úlcera da Perna/patologia , Úlcera da Perna/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Trombofilia/diagnóstico , Trombofilia/etiologia , Trombose Venosa/complicações , Trombose Venosa/diagnóstico , Cicatrização , Talassemia beta/complicações , Talassemia beta/diagnóstico
6.
Eur J Dermatol ; 29(3): 287-293, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31389788

RESUMO

BACKGROUND: Livedoid vasculopathy (LV) has been shown to be associated with hypercoagulability. However, relevant genetic and exogenous thrombophilic factors are not fully determined. OBJECTIVES: To evaluate the frequency of hyperhomocysteinaemia (HHCE) and genotypes of hypercoagulative factors in LV patients. MATERIAL AND METHODS: Plasma homocysteine level was measured in 42 LV patients. Polymorphism of MTHFR (677C > T and 1298A > C), PAI1 (-675 5G/4G and -844A > G), and F2 (20210G > A), and the F5 Leiden mutation, as well as biochemical parameters for hypercoagulability, were analysed. RESULTS: Of the LV patients, 62% revealed mild HHCE. Polymorphisms of MTHFR were observed in 75% and 56% and the PAI1 -675 5G/4G polymorphism in 100% and 83% of patients with and without HHCE, respectively. All LV patients with renal failure had mild HHCE. A high level of comorbidity of hypertension (99%) and diabetes type 2 (44%) were noted. CONCLUSION: HHCE seems to play a major pathogenetic role in LV. A high prevalence of further procoagulative factors might support the view that LV is a "complex disease".


Assuntos
Transtornos da Coagulação Sanguínea/genética , Predisposição Genética para Doença , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Síndrome de Nicolau/etiologia , Adulto , Transtornos da Coagulação Sanguínea/epidemiologia , Estudos de Coortes , Feminino , Genótipo , Humanos , Hiper-Homocisteinemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndrome de Nicolau/genética , Síndrome de Nicolau/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Estudos Prospectivos , Medição de Risco
7.
Int J Mol Sci ; 20(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319489

RESUMO

Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia-a pregnancy disorder characterized by hypertension and proteinuria. We previously generated mice lacking cystathionine γ-lyase (Cth) as cystathioninuria models and found them to be with cystathioninemia/homocysteinemia. We investigated whether Cth-deficient (Cth-/-) pregnant mice display any features of preeclampsia. Cth-/- females developed normally but showed mild hypertension (~10 mmHg systolic blood pressure elevation) in late pregnancy and mild proteinuria throughout development/pregnancy. Cth-/- dams had normal numbers of pups and exhibited normal maternal behavior except slightly lower breastfeeding activity. However, half of them could not raise their pups owing to defective lactation; they could produce/store the first milk in their mammary glands but not often provide milk to their pups after the first ejection. The serum oxytocin levels and oxytocin receptor expression in the mammary glands were comparable between wild-type and Cth-/- dams, but the contraction responses of mammary gland myoepithelial cells to oxytocin were significantly lower in Cth-/- dams. The contraction responses to oxytocin were lower in uteruses isolated from Cth-/- mice. Our results suggest that elevated homocysteine or other unknown factors in preeclampsia-like Cth-/- dams interfere with oxytocin that regulates milk ejection reflex.


Assuntos
Cistationina gama-Liase/deficiência , Hiper-Homocisteinemia , Transtornos da Lactação , Pré-Eclâmpsia , Animais , Modelos Animais de Doenças , Feminino , Hiper-Homocisteinemia/enzimologia , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/terapia , Transtornos da Lactação/enzimologia , Transtornos da Lactação/genética , Transtornos da Lactação/patologia , Camundongos , Camundongos Knockout , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Gravidez
8.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252610

RESUMO

Hyperhomocysteinemia (HHcy) exerts a wide range of biological effects and is associated with a number of diseases, including cardiovascular disease, dementia, neural tube defects, and cancer. Although mechanisms of HHcy toxicity are not fully uncovered, there has been a significant progress in their understanding. The picture emerging from the studies of homocysteine (Hcy) metabolism and pathophysiology is a complex one, as Hcy and its metabolites affect biomolecules and processes in a tissue- and sex-specific manner. Because of their connection to one carbon metabolism and editing mechanisms in protein biosynthesis, Hcy and its metabolites impair epigenetic control of gene expression mediated by DNA methylation, histone modifications, and non-coding RNA, which underlies the pathology of human disease. In this review we summarize the recent evidence showing that epigenetic dysregulation of gene expression, mediated by changes in DNA methylation and histone N-homocysteinylation, is a pathogenic consequence of HHcy in many human diseases. These findings provide new insights into the mechanisms of human disease induced by Hcy and its metabolites, and suggest therapeutic targets for the prevention and/or treatment.


Assuntos
Epigênese Genética , Hiper-Homocisteinemia/genética , Animais , Metilação de DNA , Código das Histonas , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/metabolismo , RNA não Traduzido/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-31202182

RESUMO

The multifactorial nature of Late Onset Alzheimer's Disease (LOAD), the AD form of major relevance on epidemiological and social aspects, has driven the original investigation by LC-MS and top-down proteomics approach of the protein repertoire of the brain tissue of TgCRND8 model mice fed with a diet deficient in B vitamins. The analysis of the acid-soluble fraction of brain tissue homogenates identified a list of proteins and peptides, proteoforms and PTMs. In order to disclose possible modulations, their relative quantification in wild type and AD model mice under both B vitamin deficient and control diets was performed. The levels of metallothionein III, guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 and brain acid soluble protein 1 showed statistically significant alterations depending on genotype, diet or both effects, respectively. Particularly, metallothionein III exhibited increased levels in TgCRND8 mice under B vitamin deficient diet with respect to wild type mice under both diets. Brain acid soluble protein 1 showed the opposite, revealing decreased levels in all diet groups of AD model mice with respect to wild type mice in control diet. Lower levels of brain acid soluble protein 1 were also observed in wild type mice under deficiency of B vitamins. These results, besides contributing to increase the knowledge of AD at molecular level, give new suggestions for deeply investigating metallothionein III and brain acid soluble protein 1 in AD.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Hiper-Homocisteinemia/metabolismo , Proteoma/metabolismo , Complexo Vitamínico B/análise , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Química Encefálica , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Cromatografia Líquida , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Hiper-Homocisteinemia/etiologia , Hiper-Homocisteinemia/genética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteoma/química , Proteoma/genética , Complexo Vitamínico B/metabolismo
10.
J Neurol ; 266(10): 2434-2439, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31203424

RESUMO

Combined homocysteinemia with methylmalonic aciduria (MMA/HCY) are genetic disorders of intracellular cobalamin (cbl) transport and processing that cause downstream deficiencies in methylcobalamin and adenosylcobalamin. Untreated disease is characterized biochemically by methylmalonic aciduria and hyperhomocysteinemia, while the clinical features are variable. When spastic paraplegia (SP) dominates, it is difficult to differentiate from hereditary spastic paraplegia (HSP). Clinical, biochemical and imaging features were reviewed in eight patients with MMA/HCY that mimicked HSP. Seven males and one female were enrolled. The median onset age was 13 years old (range 7-26 years old). The median time delay of diagnosis was 20.5 months (range 2-60 months). Spastic gait was the first symptom in four patients, while the other four patients presented with chronic emotional abnormalities or cognitive impairment. The main clinical manifestation was SP, and other neurological symptoms included cognitive impairment (5/8), spastic dysuria (3/8), personality change and depression (3/8), ataxia (2/8), seizures (2/8), limb numbness (2/8), and developmental delay (2/8). When patients were diagnosed, the mean serum homocysteine level, the methylmalonic acid level in urine, the serum propionylcarnitine (C3) level and the ratios of C3-to-acetylcarnitine (C2) and free carnitine (C0) were all dramatically elevated. Cranial MRIs showed nothing remarkable except mild brain atrophy. All spinal MRIs were normal except for case 8. Definite compound heterozygous mutations in MMACHC were detected in five cases. Follow-up indicated partial improvement in all the patients after intramuscular cbl, oral betaine and folate, supporting the diagnosis of MMA/HCY. Our data highlight the need for extensive investigation of intracellular cbl transport and processing, when spastic paraparesis is a prominent component of the clinical picture. Testing for urine methylmalonic acid and serum homocysteine levels is a simple but critical approach in suspected cases. Genetic testing, especially for MMACHC gene mutations, is needed. Raising awareness of this disorder could result in the timely initiation of targeted treatment, which may significantly improve patient outcomes.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Hiper-Homocisteinemia/diagnóstico , Paraplegia/diagnóstico , Paraplegia Espástica Hereditária/diagnóstico , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Criança , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Masculino , Paraplegia/etiologia , Estudos Retrospectivos , Adulto Jovem
11.
J Obstet Gynaecol Res ; 45(8): 1442-1447, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172624

RESUMO

AIM: The aim of this study is to determine the association between C677T polymorphism in MTHFR gene and plasma homocysteine concentration in recurrent fetal miscarriages. METHODS: Overall, 100 women were included in the research, the case group comprised of 50 women who had a history of spontaneously recurrent miscarriage with unspecified cause, and 50 of whom had experienced at least two successful pregnancy, as controls. Methods used in the study included PCR-RFLP with limited effective HinfI enzyme in order to investigate MTHFR polymorphism and enzyme-linked immunosorbent assay analysis to investigate plasma homocysteine concentration. RESULTS: There was a significant increase in the prevalence of mutant TT genotype among women with miscarriage history. Also, the mean homocysteine level in the case group was significantly higher than that in the control group (P = 0.002) and higher level of homocysteine was found in the carriers of T allele. CONCLUSION: Our data suggest that C677TT genotype may be a risk factor for miscarriage and CC wild type genotype supposed to have protective effect on hyperhomocysteinemia.


Assuntos
Aborto Habitual/sangue , Aborto Habitual/genética , Homocisteína/sangue , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Feminino , Humanos , Polimorfismo Genético , Gravidez
12.
Br J Nutr ; 122(1): 39-46, 2019 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-30935434

RESUMO

No risk assessment tools for the efficacy of folic acid treatment for hyperhomocysteinaemia (HHcy) have been developed. We aimed to use two common genetic risk score (GRS) methods to construct prediction models for the efficacy of folic acid therapy on HHcy, and the best gene-environment prediction model was screened out. A prospective cohort study enrolling 638 HHcy patients was performed. We used a logistic regression model to estimate the associations of two GRS methods with the efficacy. Performances were compared using area under the receiver operating characteristic curve (AUC). The simple count genetic risk score (SC-GRS) and weighted genetic risk score (wGRS) were found to be independently associated with the efficacy of folic acid treatment for HHcy. Using the SC-GRS, per risk allele increased with a 1·46-fold increased failure risk (P < 0·001) after adjustment for traditional risk factors, including age, sex, BMI, smoking, alcohol consumption, history of diabetes, history of hypertension, history of hyperlipidaemia, history of stroke and history of CHD. When used the wGRS, the association was strengthened (OR = 2·08, P < 0·001). Addition of the SC-GRS and wGRS to the traditional risk model significantly improved the predictive ability by AUC (0·859). A precise gene-environment predictive model with good performance was developed for predicting the treatment failure rate of folic acid therapy for HHcy.


Assuntos
Ácido Fólico/uso terapêutico , Hiper-Homocisteinemia/tratamento farmacológico , Hiper-Homocisteinemia/genética , Adulto , Idoso , Feminino , Ácido Fólico/administração & dosagem , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo de Nucleotídeo Único
13.
Redox Biol ; 24: 101199, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31026769

RESUMO

Hyperhomocysteinemia (Hhcy), or increased levels of the excitatory amino acid homocysteine (Hcy), is implicated in glaucoma, a disease characterized by increased oxidative stress and loss of retinal ganglion cells (RGCs). Whether Hhcy is causative or merely a biomarker for RGC loss in glaucoma is unknown. Here we analyzed the role of NRF2, a master regulator of the antioxidant response, in Hhcy-induced RGC death in vivo and in vitro. By crossing Nrf2-/- mice and two mouse models of chronic Hhcy (Cbs+/- and Mthfr+/- mice), we generated Cbs+/-Nrf2-/- and Mthfr+/-Nrf2-/- mice and performed systematic analysis of retinal architecture and visual acuity followed by assessment of retinal morphometry and gliosis. We observed significant reduction of inner retinal layer thickness and reduced visual acuity in Hhcy mice lacking NRF2. These functional deficits were accompanied by fewer RGCs and increased gliosis. Given the key role of Müller glial cells in maintaining RGCs, we established an ex-vivo indirect co-culture system using primary RGCs and Müller cells. Hhcy-exposure decreased RGC viability, which was abrogated when cells were indirectly cultured with wildtype (WT) Müller cells, but not with Nrf2-/- Müller cells. Exposure of WT Müller cells to Hhcy yielded a robust mitochondrial and glycolytic response, which was not observed in Nrf2-/- Müller cells. Taken together, the in vivo and in vitro data suggest that deleterious effects of Hhcy on RGCs are likely dependent upon the health of retinal glial cells and the availability of an intact retinal antioxidant response mechanism.


Assuntos
Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Células Ganglionares da Retina/metabolismo , Animais , Biomarcadores , Contagem de Células , Técnicas de Cocultura , Modelos Animais de Doenças , Eletrorretinografia , Células Ependimogliais/metabolismo , Células Ependimogliais/patologia , Glicólise , Hiper-Homocisteinemia/genética , Pressão Intraocular , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Retina/diagnóstico por imagem , Retina/metabolismo , Células Ganglionares da Retina/patologia
14.
Niger J Clin Pract ; 22(3): 380-385, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30837427

RESUMO

Background: Hyperhomocysteinemia (HHcy) is the risk factor for cardiovascular disease and stroke. However, the impacts on the genetic variation of methylene tetrahydrofolate reductase (MTHFR) on plasma homocysteine levels in the Northeast Chinese population have not been studied. Therefore, this study was carried out to determine the relationship between HHcy and MTHFR gene variation, and whether it was influenced by age and sex of the population in Northeast China. Materials and Methods: A total of 466 subjects were randomly enrolled in this study. According to the homocysteine levels (Hcy ≥ 15 µmol/L) of the subjects, they were divided into hyperhomocysteine (HHcy = 206) and normal homocysteine (Hcy = 260). Polymerase chain reaction/high-resolution dissolution curve and homocysteine determination kit methods were used for genotype testing and homocysteine detection, respectively. Results: High plasma homocysteine levels are associated with MTHFR 677T and 1298A [P < 0.00, odds ratio (confidence interval) = 1.842 (1.418-2.394) >1], which is related to increasing age (Prange = 0.0005-0.0161), with the homocysteine levels of males higher than females (P < 0.0001). Conclusion: High plasma homocysteine levels were linked to the MTHFR gene mutation. In addition, plasma homocysteine levels increased significantly with age with male's homocysteine levels higher than that of females.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Homocisteína/sangue , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Adulto , Fatores Etários , Idoso , Doenças Cardiovasculares/etiologia , China , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hiper-Homocisteinemia/complicações , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/etiologia
15.
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
16.
Am J Physiol Heart Circ Physiol ; 316(5): H1039-H1046, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30767669

RESUMO

Endothelial inflammation plays an important role in hyperhomocysteinemia (HHcy)-associated vascular diseases. High mobility group box 1 (HMGB1) is a pro-inflammatory danger molecule produced by endothelial cells. However, whether HMGB1 is involved in vascular endothelial inflammation of HHcy is poorly understood. Neuropilin-1 (NRP1) mediates inflammatory response and activates mitogen-activated protein kinases (MAPKs) pathway that has been reported to be involved in regulation of HMGB1. The aim of this study was to determine the alteration of HMGB1 in HHcy, and the role of NRP1 in regulation of endothelial HMGB1 under high homocysteine (Hcy) condition. In the present study, we first observed that the plasma level of HMGB1 was elevated in HHcy patients and an experimental rat model, and increased HMGB1 was also observed in the thoracic aorta of an HHcy rat model. HMGB1 was induced by Hcy accompanied with upregulated NRP1 in vascular endothelial cells. Overexpression of NRP1 promoted expression and secretion of HMGB1 and endothelial inflammation; knockdown of NRP1 inhibited HMGB1 and endothelial inflammation induced by Hcy, which partially regulated through p38 MAPK pathway. Furthermore, NRP1 inhibitor ATWLPPR reduced plasma HMGB1 level and expression of HMGB1 in the thoracic aorta of HHcy rats. In conclusion, our data suggested that Hcy requires NRP1 to regulate expression and secretion of HMGB1. The present study provides the evidence for inhibition of NRP1 and HMGB1 to be the novel therapeutic targets of vascular endothelial inflammation in HHcy in the future. NEW & NOTEWORTHY This study shows for the first time to our knowledge that the plasma level of high mobility group box 1 (HMGB1) is elevated in hyperhomocysteinemia (HHcy) patients, and homocysteine promotes expression and secretion of HMGB1 partially regulated by neuropilin-1 in endothelial cells, which is involved in endothelial inflammation. Most importantly, these new findings will provide a potential therapeutic strategy for vascular endothelial inflammation in HHcy.


Assuntos
Proteína HMGB1/metabolismo , Homocisteína/sangue , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hiper-Homocisteinemia/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Neuropilina-1/metabolismo , Adulto , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/genética , Inflamação/sangue , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Neuropilina-1/genética , Ratos Sprague-Dawley , Transdução de Sinais , Células THP-1 , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Medicine (Baltimore) ; 98(2): e13998, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633186

RESUMO

RATIONALE: Hereditary hyperhomocysteinemia results from a polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene that reduces folate metabolism. Mutations in the MTHFR gene are common in parents who have given birth to children with neural tube defects (NTDs). Most research has focused on the risk for fetal NTDs in women with hyperhomocysteinemia and MTHFR gene mutations. Studies investigating the association between hyperhomocysteinemia, MTHFR gene mutations, and the risk for fetal NTDs in men are scarce. PATIENT CONCERNS: Here, we report on 3 men with hyperhomocysteinemia and the MTHFR C677T homozygous TT genotype that have reproductive histories of fetal NTDs. DIAGNOSIS: these 3 men were diagnosed as hyperhomocysteinemia and MTHFR C677T homozygous TT genotype. INTERVENTIONS: Three men received homocysteine-lowering therapy. OUTCOMES: The first man's wife became pregnant, and a healthy infant was spontaneously delivered at term, the other 2 men's wives are still not pregnant. LESSONS: Findings from this case reports and published literature imply that hereditary hyperhomocysteinemia in men affects sperm quality and sperm DNA methylation and causes epigenetic modifications that can result in fetal NTDs. We recommend monitoring homocysteine and folate levels in men before conception and supplementing with folate as needed, especially in men with a reproductive history of fetuses with neural tube or other birth defects.


Assuntos
Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Defeitos do Tubo Neural/genética , Adulto , Humanos , Masculino , Mutação
18.
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
19.
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
20.
Sci Rep ; 8(1): 15226, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30323246

RESUMO

Previously, we have shown hyperhomocysteinemia (HHcy) to have a detrimental effect on bone remodeling, which is associated with osteoporosis. During transsulfuration, Hcy is metabolized into hydrogen sulfide (H2S), a gasotransmitter molecule known to regulate bone formation. Therefore, in the present study, we examined whether H2S ameliorates HHcy induced epigenetic and molecular alterations leading to osteoporotic bone loss. To test this mechanism, we employed cystathionine-beta-synthase heterozygote knockout mice, fed with a methionine rich diet (CBS+/- +Met), supplemented with H2S-donor NaHS for 8 weeks. Treatment with NaHS, normalizes plasma H2S, and completely prevents trabecular bone loss in CBS+/- mice. Our data showed that HHcy caused inhibition of HDAC3 activity and subsequent inflammation by imbalancing redox homeostasis. The mechanistic study revealed that inflammatory cytokines (IL-6, TNF-α) are transcriptionally activated by an acetylated lysine residue in histone (H3K27ac) of chromatin by binding to its promoter and subsequently regulating gene expression. A blockade of HDAC3 inhibition in CBS+/- mice by HDAC activator ITSA-1, led to the remodeling of histone landscapes in the genome and thereby attenuated histone acetylation-dependent inflammatory signaling. We also confirmed that RUNX2 was sulfhydrated by administration of NaHS. Collectively, restoration of H2S may provide a novel treatment for CBS-deficiency induced metabolic osteoporosis.


Assuntos
Cistationina beta-Sintase/genética , Histona Desacetilases/genética , Sulfeto de Hidrogênio/metabolismo , Osteoporose/genética , Acetilação/efeitos dos fármacos , Animais , Remodelação Óssea/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Cistationina beta-Sintase/antagonistas & inibidores , Epigênese Genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma/efeitos dos fármacos , Histonas/genética , Humanos , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/patologia , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/genética , Camundongos , Osteoporose/metabolismo , Osteoporose/patologia , Estresse Oxidativo/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
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