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1.
Stroke ; 52(1): 172-180, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33349021

RESUMO

BACKGROUND AND PURPOSE: B-vitamin supplements lower circulating concentrations of homocysteine and may reduce stroke incidence. Homocysteine concentrations are associated with the incidence of stroke but other sulfur-containing compounds in the related metabolic pathway have not yet been investigated for an association with incident cerebrovascular diseases. METHODS: Nested within the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk cohort, we established a case-control study with 480 incident cases of cerebrovascular diseases and 480 controls matched by age, sex, and year of baseline examination (1993-1997). Using baseline plasma samples, we assayed sulfur-containing compounds including methionine, homocysteine, cystathionine, cysteine, glutathione, and taurine with liquid chromatography-tandem mass spectrometry. We examined the association of concentrations of each of the compounds and the ratio of methionine to homocysteine (representing activity of one-carbon metabolism) with risk of incident cerebrovascular diseases, adjusted for potential confounders. RESULTS: Plasma methionine and the methionine/homocysteine ratio were inversely associated with risk of cerebrovascular diseases, with odds ratios per 1 SD of 0.83 (95% CI, 0.72-0.96) and 0.82 (95% CI, 0.71-0.95), respectively. The association of methionine remained significant after adjustment for homocysteine. None of the other examined compounds was significantly associated with incident cerebrovascular diseases. CONCLUSIONS: These findings suggest that greater availability of methionine, an essential amino acid, may play a role in the prevention of cerebrovascular diseases and explain the previously recognized link between elevated homocysteine and stroke. Further research is needed to determine causation and the potential of circulating methionine as a target in cerebrovascular disease prevention.


Assuntos
Transtornos Cerebrovasculares/sangue , Metionina/sangue , Idoso , Aminoácidos Sulfúricos/sangue , Estudos de Casos e Controles , Transtornos Cerebrovasculares/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
2.
Proc Natl Acad Sci U S A ; 117(23): 13000-13011, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32434918

RESUMO

Extensive studies in prostate cancer and other malignancies have revealed that l-methionine (l-Met) and its metabolites play a critical role in tumorigenesis. Preclinical and clinical studies have demonstrated that systemic restriction of serum l-Met, either via partial dietary restriction or with bacterial l-Met-degrading enzymes exerts potent antitumor effects. However, administration of bacterial l-Met-degrading enzymes has not proven practical for human therapy because of problems with immunogenicity. As the human genome does not encode l-Met-degrading enzymes, we engineered the human cystathionine-γ-lyase (hMGL-4.0) to catalyze the selective degradation of l-Met. At therapeutically relevant dosing, hMGL-4.0 reduces serum l-Met levels to >75% for >72 h and significantly inhibits the growth of multiple prostate cancer allografts/xenografts without weight loss or toxicity. We demonstrate that in vitro, hMGL-4.0 causes tumor cell death, associated with increased reactive oxygen species, S-adenosyl-methionine depletion, global hypomethylation, induction of autophagy, and robust poly(ADP-ribose) polymerase (PARP) cleavage indicative of DNA damage and apoptosis.


Assuntos
Cistationina gama-Liase/farmacologia , Metionina/antagonistas & inibidores , Mutagênese Sítio-Dirigida , Neoplasias da Próstata/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Cistationina gama-Liase/genética , Cistationina gama-Liase/isolamento & purificação , Cistationina gama-Liase/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Ensaios Enzimáticos , Humanos , Masculino , Metionina/sangue , Metionina/metabolismo , Camundongos , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/sangue , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
3.
JAMA Netw Open ; 3(5): e205316, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432712

RESUMO

Importance: Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. Objectives: To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidity development in older adults and to explore the role of methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in this association. Design, Setting, and Participants: The Swedish National Study on Aging and Care in Kungsholmen is a cohort study of randomly selected individuals aged 60 years or older. The present study included data on 1969 individuals with complete information and without CV diseases at baseline, collected from the baseline examination (2001-2004) to the fourth follow-up (2013-2016). Data analysis was conducted from January to May 2019. Exposures: Concentrations of tHcy and Met were measured from nonfasting venous blood samples. The Met:tHcy ratio was considered a possible indicator of methylation activity. MTHFR status was dichotomized as any T carriers vs noncarriers. Main Outcome and Measures: The number of CV diseases at each wave was ascertained based on medical interviews and records, laboratory test results, and drug data. Linear mixed models were used to study the association of baseline tHcy and Met levels and the rate of CV multimorbidity development, adjusting for sociodemographic characteristics, CV risk factors, chronic disease burden, and drug use. Results: Of 1969 participants, most were women (1261 [64.0%]), with a mean (SD) age of 70.9 (9.8) years; 1703 participants (86.6%) had at least a high school level of education. Baseline measurements of serum tHcy, Met, and the Met:tHcy ratio were associated with the rate of CV disease accumulation (tHcy: ß = 0.023 per year; 95% CI, 0.015 to 0.030; P < .001; Met: ß = -0.007 per year; 95% CI, -0.013 to -0.001; P = .02; Met:tHcy ratio: ß = -0.017 per year; 95% CI, -0.023 to -0.011; P < .001). The association between low Met concentrations and the rate of CV multimorbidity development was restricted to the group with CT/TT alleles of MTHFR (ß = 0.023 per year; 95% CI, 0.006 to 0.041; P = .009). Results remained largely significant when individual CV diseases were removed from the total count 1 at a time (eg, ischemic heart disease, tHcy: ß = 0.023 per year; 95% CI, 0.013 to 0.027; P < .001; Met: ß = -0.006 per year; 95% CI, -0.011 to -0.0003; P = .04; Met:tHcy ratio: ß = -0.015 per year; 95% CI, -0.020 to -0.009; P < .001). Conclusions and Relevance: In this study, high tHcy and low Met levels were associated with faster CV multimorbidity development in older age. The interactive association of Met concentrations and MTHFR polymorphism, together with the association found for the Met:tHcy ratio, point toward the relevance of impaired methylation in the pathogenesis of CV aging.


Assuntos
Doenças Cardiovasculares/etiologia , Homocisteína/sangue , Metionina/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Multimorbidade , Fatores Etários , Idoso , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Suécia/epidemiologia
4.
PLoS One ; 15(5): e0233174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401813

RESUMO

OBJECTIVES: Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes. METHODS: In this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA. RESULTS: In the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27-0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16-3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23-0.28, p<0.05), while pentosidine correlated with soft/mixed plaque volume (r = 0.29, p = 0.008), also in the adjusted analysis. CONCLUSIONS: Low levels of collagen-bound methionine sulfoxide were associated with normal coronary arteries while glucuronidine/LW-1 was positively associated with established CHD in long-term type 1 diabetes, suggesting a role for metabolic and oxidative stress in the formation of atherosclerosis in diabetes.


Assuntos
Colágeno/sangue , Doença da Artéria Coronariana/sangue , Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 1/sangue , Glucuronídeos/sangue , Metionina/análogos & derivados , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Metionina/sangue , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada/sangue
5.
Appl Microbiol Biotechnol ; 104(3): 1227-1242, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853564

RESUMO

Maternal nutrition during late pregnancy and lactation is highly involved with the offspring's health status. The study was carried out to evaluate the effects of different ratios of methionine and cysteine (Met/Cys: 46% Met, 51% Met, 56% Met, and 62% Met; maintained with 0.78% of total sulfur-containing amino acids; details in "Materials and methods") supplements in the sows' diet from late pregnancy to lactation on offspring's plasma metabolomics and intestinal microbiota. The results revealed that the level of serum albumin, calcium, iron, and magnesium was increased in the 51% Met group compared with the 46% Met, 56% Met, and 62% Met groups. Plasma metabolomics results indicated that the higher ratios of methionine and cysteine (0.51% Met, 0.56% Met, and 0.62% Met)-supplemented groups enriched the level of hippuric acid, retinoic acid, riboflavin, and δ-tocopherol than in the 46% Met group. Furthermore, the 51% Met-supplemented group had a higher relative abundance of Firmicutes compared with the other three groups (P < 0.05), while the 62% Met-supplemented group increased the abundance of Proteobacteria compared with the other three groups (P < 0.05) in piglets' intestine. These results indicated that a diet consisting with 51% Met is the optimum Met/Cys ratio from late pregnancy to lactation can maintain the offspring's health by improving the serum biochemical indicators and altering the plasma metabolomics profile and intestinal gut microbiota composition, but higher proportion of Met/Cys may increase the possible risk to offspring's health.


Assuntos
Aminoácidos/administração & dosagem , Aminoácidos/sangue , Suplementos Nutricionais/análise , Microbioma Gastrointestinal , Lactação , Enxofre/administração & dosagem , Ração Animal/análise , Animais , Animais Recém-Nascidos/fisiologia , Cisteína/administração & dosagem , Cisteína/sangue , Feminino , Metabolômica , Metionina/administração & dosagem , Metionina/sangue , Gravidez , Suínos
6.
Biol Trace Elem Res ; 194(1): 135-144, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31066019

RESUMO

This study is aimed at evaluating the effect of dietary zinc-methionine (Zn-Met) supplementation during 3 months prepartum up to 9 months postpartum on reproductive performance, blood biochemical, and milk production of lactating she-camels besides growth performance of their calves. Twenty pregnant Maghrebi she-camels (439.49 ± 11.57 kg; 3-5 parties) were divided into four similar groups. Animals were fed the basal diet (G1) or the basal diet supplemented with Zn-Met at levels of 30 mg (G2), 40 mg (G3), and 50 mg (G4)/kg diet. Results revealed that IgA, IgM, and IgG concentrations in colostrum, monthly milk yield, and lactation period were significantly increased in Zn-Met-supplemented groups. Milk contents of fat, ash, and total solids improved (P < 0.05) in G4 as compared with other groups. Pre- and postpartum Zn, T3, T4, P4, and E2 concentrations in plasma and milk Zn level were higher (P < 0.05) in all Zn-Met-supplemented groups. Postpartum first estrus interval, number of services/conception, days open, pregnancy rate, duration of placental drop, and calving interval improved (P < 0.05) in G4. Weaning weight and average daily gain of calves were enhanced all in Zn-Met-supplemented groups. Conclusively, the inclusion of Zn-Met especially at a level of 50 mg/kg diet, 3 months prepartum up to 9 months postpartum, led to better productive and reproductive performance, immunity of she-camels, and growth performance of their offspring.


Assuntos
Suplementos Nutricionais , Metionina/farmacologia , Leite/efeitos dos fármacos , Prenhez , Reprodução/efeitos dos fármacos , Zinco/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Camelus , Feminino , Metionina/administração & dosagem , Metionina/sangue , Gravidez , Zinco/administração & dosagem , Zinco/sangue
7.
J Sep Sci ; 43(6): 1100-1106, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858708

RESUMO

A green and fast analytical method for the determination of l-methionine in human plasma is presented in this study. Preconcentration of the analyte was carried out by switchable solvent liquid phase microextraction after ethyl chloroformate derivatization reaction. Instrumental detection of the analyte was performed by means of gas chromatography-mass spectrometry. N,N-Dimethyl benzylamine was used in the synthesis of switchable solvent. Protonated N,N-dimethyl benzylamine volume, volume/concentration of sodium hydroxide, and vortex period were meticulously fixed to their optimum values. Besides, ethyl chloroformate, pyridine, and ethanol volumes were optimized in order to get high derivatization yield. After the optimization studies, limit of detection and quantitation values were attained as 3.30 and 11.0 ng/g, respectively, by the developed switchable solvent liquid phase microextraction gas chromatography-mass spectrometry method that corresponding to 76.7-folds enhancement in detection power of the gas chromatography-mass spectrometry system. Applicability and accuracy of the switchable solvent liquid phase microextraction-gas chromatography-mass spectrometry method were also checked by spiking experiments. Percent recovery results were ranged from 97.8 to 100.5% showing that human plasma samples could be analyzed for its l-methionine level by the proposed method.


Assuntos
Aminas/química , Ésteres do Ácido Fórmico/química , Microextração em Fase Líquida , Metionina/sangue , Ondas Ultrassônicas , Aminas/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Voluntários Saudáveis , Humanos , Estrutura Molecular , Solventes/química
9.
Klin Lab Diagn ; 64(9): 516-524, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31610102

RESUMO

The level of homoarginine (hArg) in terms of prognostic significance may exceed the natriuretic peptides and other well-known markers according to the latest data about the progression of cardiovascular diseases. The lack of data on the association of hArg levels with levels of other metabolites makes it difficult to understand its role in the pathogenesis of cardiovascular diseases. Relationships of hArg and other amino acids, including methionine (Met) and total homocysteine (tHcy), and their ratio in patients with ischemic heart disease were evaluated. The study included 74 patients with coronary heart disease (57 men and 17 women) aged 62 (57 - 67) years before coronary artery bypass surgery and 27 healthy people of similar age. In patients, the level of hArg was almost 2 times lower (p < 0.05) than in healthy individuals and rates lower than 1.4 µM were in half of them. The statistically significant decrease (p = 0.0025) of the Met/tHcy ratio corresponded to a decrease in the level of hArg. This ratio did not correlate with glucose level or body mass index. Less statistical significance of hArg correlation with levels of Met or tHcy separately was observed. In the subgroup of patients with hAarg level above 2.1 µM, a lower incidence of myocardial infarction was noted. Thus, a low hArg level is associated with impaired metabolism of sulfur-containing amino acids involved in transmethylation reactions, in patients with ischemic heart disease. The Met/tHcy ratio, closely correlating with the level of hArg, apparently reveals a link between the reactions of creatine formation and transmethylation, highlighting a cohort of patients with the most profound and dangerous changes in tissue metabolism.


Assuntos
Homoarginina/sangue , Homocisteína/sangue , Metionina/sangue , Isquemia Miocárdica/diagnóstico , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Food Funct ; 10(9): 5910-5921, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31468055

RESUMO

Sulfur-containing amino acids (SAAs) such as methionine (Met) and cysteine (Cys) are involved in the control of oxidative states and may serve as mediators of metabolism and cellular functions. The purpose of this study was to evaluate the influence of different Met/Cys ratios (46% Met, 51% Met, 56% Met, and 61% Met, with Met accounting for 0.78% of the total SAAs and Cys for the remainder; see Methods section for details) on the plasma metabolomics, intestinal microflora of the sow in late pregnancy and survival rate of piglets. The results demonstrated that the 51% Met group increased the survival rate of piglets and improved the level of low-density lipoprotein, albumin, and phosphorus of serum in comparison with the 56% Met group. The resulting plasma metabolomic profile indicated that the 51% Met group had enhanced levels of ß-alanine, uracil, hydrouracil, phosphoserine, vitamin D3, and α-tocotrienol compared with the 46% Met group. Moreover, the ratio of Bacteroidetes and Firmicutes was increased in the 51% Met and 62% Met groups in relation to the 56% Met group. In addition, Pearson's correlation analysis found that there were negative correlations between vitamin D3 and Ruminococcaceae_UCG-002 and between α-tocotrienol and Ruminococcaceae_UCG-002; there was a positive correlation between allantoin and Parabacteroides spp. These results suggested that 51% Met is the optimal Met/Cys ratio for sows in late pregnancy, because it increased the survival percentage of piglets and enhanced the increase in serum metabolites required for optimal sow health during late pregnancy.


Assuntos
Cisteína/sangue , Microbioma Gastrointestinal , Metionina/sangue , Terceiro Trimestre da Gravidez/sangue , Suínos/sangue , Animais , Animais Recém-Nascidos , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Feminino , Masculino , Metabolômica , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-Natal , Suínos/microbiologia
11.
Am J Hypertens ; 32(11): 1109-1117, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31350549

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is a severe progressive disease with systemic metabolic dysregulation. Monocrotaline (MCT)-induced and hypoxia-induced pulmonary hypertension (PH) rodent models are the most widely used preclinical models, however, whether or not these preclinical models recapitulate metabolomic profiles of PAH patients remain unclear. METHODS: In this study, a targeted metabolomics panel of 126 small molecule metabolites was conducted. We applied it to the plasma of the 2 preclinical rodent models of PH and 30 idiopathic pulmonary arterial hypertension (IPAH) patients as well as 30 healthy controls to comparatively assess the metabolomic profiles of PAH patients and rodent models. RESULTS: Significantly different metabolomics profiling and pathways were shown among the 2 classical rodent models and IPAH patients. Pathway analysis demonstrated that methionine metabolism and urea cycle metabolism were the most significant pathway involved in the pathogenesis of hypoxia-induced PH model and MCT-induced model, respectively, and both of them were also observed in the dysregulated pathways in IPAH patients. CONCLUSIONS: These 2 models may develop PAH through different metabolomic pathways and each of the 2 classical PH model resembles IPAH patients in certain aspects.


Assuntos
Hipertensão Pulmonar Primária Familiar/sangue , Hipertensão Pulmonar/sangue , Metabolômica , Metionina/sangue , Ureia/sangue , Adulto , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Modelos Animais de Doenças , Hipertensão Pulmonar Primária Familiar/diagnóstico , Hipertensão Pulmonar Primária Familiar/etiologia , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipóxia/complicações , Masculino , Monocrotalina , Ratos Sprague-Dawley
12.
Br J Haematol ; 187(2): 219-226, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31257573

RESUMO

The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6·9 years, 340 patients developed a recurrence (incidence rate, 2·8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 µmol/l increase (hazard ratio [HR] 0·98 (95% confidence interval [CI], 0·90-1·04)) nor when levels were >95th (>23·0 µmol/l) percentile (HR 1·03 (95% CI, 0·65-1·64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.


Assuntos
Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/epidemiologia , Metionina/sangue , Trombose Venosa/sangue , Trombose Venosa/epidemiologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hiper-Homocisteinemia/complicações , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Trombose Venosa/etiologia
13.
J Dairy Sci ; 102(9): 8305-8318, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31301838

RESUMO

Although choline requirements are unknown, enhanced postruminal supply may decrease liver triacylglycerol (TAG) storage and increase flux through the methionine cycle, helping cows during a negative energy balance (NEB). The objective was to investigate effects of postruminal choline supply during NEB on hepatic activity of betaine-homocysteine methyltransferase (BHMT), methionine synthase (MTR), methionine adenosyltransferase, transcription of enzymes, and metabolite concentrations in the methionine cycle. Ten primiparous rumen-cannulated Holstein cows (158 ± 24 d postpartum) were used in a replicated 5 × 5 Latin square design with 4-d treatment periods and 10 d of recovery (14 d/period). Treatments were unrestricted intake with abomasal infusion of water (A0), restricted intake (R; 60% of net energy for lactation requirements to induce NEB) with abomasal infusion of water (R0) or R plus abomasal infusion of 6.25, 12.5, or 25 g/d of choline ion. Liver tissue was collected on d 5 after the infusions ended, blood on d 1 to 5, and milk on d 1 to 4. Statistical contrasts were A0 versus R0 (CONT1) and tests of linear (L), quadratic (Q), and cubic (C) effects of choline dose. Plasma choline increased with R (CONT1) and choline (L). Although R decreased milk yield (CONT1), choline increased milk yield and liver phosphatidylcholine (PC), but decreased TAG (L). No differences were observed in plasma PC or very-low-density lipoprotein concentrations with R or choline. Activity and mRNA abundance of BHMT were greater with R (CONT1) and increased with choline (L). Although activity of MTR was lower with R (CONT1), it tended to increase with choline (L). No effect of R was detected for activity of methionine adenosyltransferase, but it changed cubically across dose of choline. Those responses were associated with linear increases in the concentrations of liver tissue (+13%) and plasma methionine concentrations. The mRNA abundance of CPT1A, SLC22A5, APOA5, and APOB, genes associated with fatty acid oxidation and lipoprotein metabolism, was upregulated by choline (Q). Overall, enhanced supply of choline during NEB increases hepatic activity of BHMT and MTR to regenerate methionine and PC, partly to help clear TAG. The relevance of these effects during the periparturient period merits further research.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Betaína-Homocisteína S-Metiltransferase/metabolismo , Bovinos/metabolismo , Colina/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Fígado/metabolismo , Metionina/metabolismo , Abomaso/efeitos dos fármacos , Animais , Betaína-Homocisteína S-Metiltransferase/genética , Colina/sangue , Ácidos Graxos/metabolismo , Feminino , Lactação/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Metionina/sangue , Oxirredução , Parto/metabolismo , Gravidez , RNA Mensageiro/análise
14.
J Korean Med Sci ; 34(13): e104, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30950250

RESUMO

BACKGROUND: The left internal thoracic artery (LITA) has been used as the first conduit of choice in coronary artery bypass grafting (CABG) because of excellent long-term patency and outcomes. However, no studies have examined substances other than nitric oxide that could be beneficial for the bypass conduit, native coronary artery or ischemic myocardium. This study was conducted to evaluate differences in metabolic profiles between the LITA and ascending aorta using gas chromatography-time of flight-mass spectrometry (GC-TOF-MS). METHODS: Twenty patients who underwent CABG using the LITA were prospectively enrolled. Plasma samples were collected simultaneously from the LITA and ascending aorta. GC-TOF-MS based untargeted metabolomic analyses were performed and a 2-step volcano plot analysis was used to identify distinguishable markers from two plasma metabolome profiles. Semi-quantitative and quantitative analyses were performed using GC-TOF-MS and enzyme-linked immunosorbent assay, respectively, after selecting target metabolites based on the metabolite set enrichment analysis. RESULTS: Initial volcano plot analysis demonstrated 5 possible markers among 851 peaks detected. The final analysis demonstrated that the L-cysteine peak was significantly higher in the LITA than in the ascending aorta (fold change = 1.86). The concentrations of intermediate metabolites such as L-cysteine, L-methionine and L-cystine in the 'cysteine and methionine metabolism pathway' were significantly higher in the LITA than in the ascending aorta (2.0-, 1.4- and 1.2-fold, respectively). Quantitative analysis showed that the concentration of hydrogen sulfide (H2S) was significantly higher in the LITA. CONCLUSION: The plasma metabolome profiles of the LITA and ascending aorta were different, particularly higher plasma concentrations of L-cysteine and H2S in the LITA.


Assuntos
Aorta/cirurgia , Artéria Torácica Interna/cirurgia , Metaboloma , Idoso , Ponte de Artéria Coronária , Cisteína/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Metionina/sangue , Pessoa de Meia-Idade , Análise de Componente Principal , Sulfitos/sangue
15.
Nutrition ; 65: 202-207, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30879954

RESUMO

OBJECTIVE: In neonates on total parenteral nutrition (TPN), amino acids may be a risk factor for developing total parenteral nutrition-associated cholestasis (TPNAC). We aimed, first, to compare methionine, cysteine, and taurine plasma levels between neonates on TPN who were receiving an intravenous amino acid solution based on a breast milk aminogram and those on an intravenous solution of pediatric amino acids based on an umbilical cord aminogram, and second, to determine the frequency of TPNAC. METHODS: A double-blind randomized controlled trial was conducted. Ninety-four neonates with a birthweight of 1000g or more and a gestational age of 30 wk or older were admitted and enrolled. Blood samples were obtained at 0, 7, and 14 d of TPN, and plasma amino acid concentrations were determined by ultra-high-resolution liquid chromatography. Continuous variables were compared using the Wilcoxon rank-sum test or Student's t test; categorical variables were compared using the Fisher exact test. RESULTS: Thirty-five neonates completed the study (Primene, n = 14; TrophAmine, n = 21). On day 14, methionine plasma concentrations were significantly lower in the Primene group than in the TrophAmine group (27 µmol/L versus 32.9 µmol/L, P = 0.044); the taurine concentration was significantly higher in the same group (72.4 µmol/L versus 45.3 µmol/L, P < 0.0001). There were no differences in TPNAC incidence. CONCLUSIONS: Administering an intravenous solution of pediatric amino acids based on the umbilical cord aminogram yielded a higher taurine and lower methionine plasma concentration than did administering a similar solution based on the breast milk aminogram.


Assuntos
Aminoácidos/administração & dosagem , Colestase/epidemiologia , Cisteína/sangue , Metionina/sangue , Nutrição Parenteral/efeitos adversos , Taurina/sangue , Peso ao Nascer , Colestase/etiologia , Método Duplo-Cego , Eletrólitos/administração & dosagem , Feminino , Idade Gestacional , Glucose/administração & dosagem , Humanos , Incidência , Recém-Nascido , Masculino , Leite Humano/química , Soluções/administração & dosagem , Cordão Umbilical/química
16.
Br J Nutr ; 121(11): 1279-1286, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30837009

RESUMO

Maternal one-carbon metabolism during pregnancy is crucial for fetal development and programming by DNA methylation. However, evidence on one-carbon biomarkers other than folate is lacking. We, therefore, investigated whether maternal plasma methyl donors, that is, choline, betaine and methionine, are associated with birth outcomes. Blood samples were obtained from 115 women during gestation (median 26·3 weeks, 90 % range 22·7-33·0 weeks). Plasma choline, betaine, methionine and dimethylglycine were measured using HPLC-tandem MS. Multivariate linear and logistic regression models were used to estimate the association between plasma biomarkers and birth weight, birth length, the risk of small-for-gestational-age and large-for-gestational-age (LGA). Higher level of maternal betaine was associated with lower birth weight (-130·3 (95 % CI -244·8, -15·9) per 1 sd increment for log-transformed betaine). Higher maternal methionine was associated with lower risk of LGA, and adjusted OR, with 95 % CI for 1 sd increase in methionine concentration was 0·44 (95 % CI 0·21, 0·89). Stratified analyses according to infant sex or maternal plasma homocysteine status showed that reduction in birth weight in relation to maternal betaine was only limited to male infants or to who had higher maternal homocysteine status (≥5·1 µmol/l). Higher maternal betaine status was associated with reduced birth weight. Maternal methionine was inversely associated with LGA risk. These findings are needed to be replicated in future larger studies.


Assuntos
Betaína/sangue , Peso ao Nascer , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Trimestres da Gravidez/sangue , Adulto , Colina/sangue , Feminino , Homocisteína/sangue , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Metionina/sangue , Gravidez , Sarcosina/análogos & derivados , Sarcosina/sangue
17.
Diabetes ; 68(4): 709-723, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30755400

RESUMO

Thioredoxin-interacting protein (TXNIP) is an α-arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes ß-cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.


Assuntos
Acidose Láctica/genética , Proteínas de Transporte/genética , Metionina/sangue , Mutação , Ácido Pirúvico/metabolismo , Acidose Láctica/metabolismo , Proteínas de Transporte/metabolismo , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Glicólise/fisiologia , Humanos , Masculino , Mitocôndrias/metabolismo
18.
Methods Mol Biol ; 1866: 163-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30725415

RESUMO

This chapter reviews how total methionine (MET) restriction (MR) of a human brain tumor xenograft, effected by the combination of recombinant L-methionine-α-deamino-γ-lyase (rMETase) and a MET-free diet, greatly potentiates standard chemotherapy for brain tumors in mouse models. The growth of human brain tumor Daoy, SWB77, and D-54 xenografts in nude mice was arrested after the depletion of mouse plasma methionine (MET) with a combination of an MR diet and rMETase and homocysteine to rescue normal cells and tissues. MET was depleted to below 5 µm by this treatment. MR for 10-12 days inhibited tumor growth, but did not prevent tumor regrowth after treatment cessation. A single dose of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), which was ineffective alone, was administered at the end of the MR regimen, and caused a more than 80-day growth delay for Daoy and D-54 and a 20-day growth delay for SWB77. The total MR treatment regimens also increased the efficacy of temozolomide (TMZ) against the SWB77 xenograft when administered at the end of the MET regimen.


Assuntos
Metionina/deficiência , Neoplasias/dietoterapia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colina , Homocisteína/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Metionina/sangue , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Methods Mol Biol ; 1866: 211-229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30725418

RESUMO

Methionine (MET) is a general metabolic therapeutic target in cancer, whereby cancer cells have an elevated requirement for MET, termed MET dependence. We have developed recombinant L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase, EC 4.4.1.11]) as targeted therapy of all cancer types. Pharmacokinetics, MET depletion, antigenicity, and toxicity of rMETase were examined in macaque monkeys. Pharmacokinetic analysis showed that rMETase was eliminated with a T1/2 of 2.49 h. A 2-week i.v. administration of 4000 units/kg every 8 h/day for 2 weeks resulted in a steady-state depletion of plasma MET to less than 2 µM. The only manifest toxicity was decreased food intake and slight weight loss. Serum albumin and red-cell values declined transiently during treatment. Rechallenge on day 28 resulted in anaphylactic shock and death in one animal. Pretreatment with hydrocortisone prevented the anaphylactic reaction. Anti-rMETase antibodies (at 10-3) were found after the first challenge, increased to 10-6 after the fourth challenge, and decreased to 10-2 by 2 months post-therapy. Therefore, the therapeutic potential of rMETase is limited by its short plasma half-life and immunologic effects, including high antibody production in mice and anaphylactic reactions in monkeys. To overcome these limits, rMETase has been coupled to methoxypolyethylene glycol succinimidyl glutarate polyethylene glycol (MEGC-PEG-5000). The pharmacokinetics, antigenicity, and toxicity of MEGC-PEG-rMETase in macaque monkeys were evaluated using an escalating-dose strategy. In pharmacokinetic studies, a single 4000 units/kg dose showed that MEGC-PEG-rMETase holoenzyme activity was eliminated with a biological half-life of 1.3 h, and the MEGC-PEG-rMETase apoenzyme was eliminated with a biological half-life of 90 h, a 36-fold increase compared with non-PEGylated rMETase. The disparity in the T½ of the apoenzyme and the holoenzyme reflects the loss of co-factor pyridoxal-L-phosphate of the circulating MEGC-PEG-rMETase. A 7-day i.v. administration of 4000 units/kg every 12 h resulted in a steady-state depletion of plasma MET to <5 µmol/L. The only manifest toxicity was decreased food intake and slight weight loss. Red cell values and hemoglobin declined transiently. Subsequent challenges did not result in any immunologic reactions. Anti-MEGC-PEG-rMETase antibodies were 100- to 1000-fold less than antibodies elicited by naked rMETase, thereby suggesting clinical potential of MEGC-PEG-rMETase as a broad anticancer agent.


Assuntos
Liases de Carbono-Enxofre/efeitos adversos , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Animais , Anticorpos/sangue , Liases de Carbono-Enxofre/imunologia , Metionina/sangue , Camundongos , Primatas , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Methods Mol Biol ; 1866: 231-242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30725419

RESUMO

Methionine (MET) has been shown to be a tumor-selective therapeutic target for cancer, since cancer cells require higher amounts of MET to divide and survive than normal cells. This phenomena is known as MET dependence and is probably due to MET overuse by cancer cells. A pilot clinical trial was initially carried out with non-recombinant METase (METase) produced from Pseudomonas putida and subsequently highly purified. No acute clinical toxicity was observed for any criteria measured in the three patients. The depletion of serum MET started within 30 min of the infusion and was maintained for 4 h after the infusion was completed in patient 1 and patient 2. The lowest serum MET levels were 35% and 19% of the pretreatment level, respectively, in patient 1 and patient 2. Patient 3 received a 10 h i.v. infusion of METase without any sign of side effects. MET was depleted over 200-fold from 23.1 to 0.1 µM by the 10-h infusion of patient 3. No clinical toxicity was observed in any criteria measured in patient 3. Subsequently, another pilot Phase I clinical trial was carried out of serum MET depletion in cancer patients by recombinant METase (rMETase) cloned from Pseudomonas putida and produced in E. coli. Patients with advanced breast cancer, lung cancer, renal cancer, and lymphoma were given a single rMETase treatment at doses ranging from 5000 to 20,000 units by i.v. infusion over 6-24 h. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels were measured at 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum MET levels in rMETase-treated patients were 0.1% of the pretreatment levels corresponding to approximately 0.1 µM, which also correlates to therapeutic levels in vitro as well as in vivo. The results of the METase and rMETase pilot Phase I clinical trials therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum MET, suggesting potential efficacy in future clinical trials.


Assuntos
Liases de Carbono-Enxofre/uso terapêutico , Metionina/sangue , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Liases de Carbono-Enxofre/isolamento & purificação , Liases de Carbono-Enxofre/farmacocinética , Fermentação , Humanos , Infusões Intravenosas , Estadiamento de Neoplasias , Neoplasias/sangue , Projetos Piloto
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