Efficacy of nutrition therapy with food rich in methionine for treating nonalcoholic fatty liver / Eficacia de la terapia nutricional con alimentos ricos en metionina para el tratamiento de hígado graso no alcohólico

Non-Alcoholic Fatty Liver disease (NAFLD) can lead to Non Alcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. The treatment for NAFLD involves modification of caloric intake and physical activity. NAFLD has a pro-oxidant nature; therefore, it is logical to suppose that the antioxidant methionine can be used as a treatment for this disease. Aim. This study aimed to evaluate the effect of high-methionine dietary therapy on patients with NAFLD. Materials and methods. A randomized clinical study was conducted over three months. In this study, 121 NAFLD patients participated, and the age of the participants was ≥ 20 years (experimental group included 56 and control group 65), all of whom were randomized and matched by sex, recluted from the ISSSTE hospital in Xalapa, Mexico. The patients were instructed to consume food to cover the recommended methionine daily doses, and the daily amount consumed was calculated. Methionine effect was measured as NAFLD regression and quality of life improvement. Results. Nutritional therapy induced NAFLD regression and diminished central fat accumulation, blood pressure, and the fatty liver index. Some parameters, such as liver enzymes, did not changed. The quality of life of patients improved after treatment. Conclusions. In this study, we show a hepatoprotective effect induced only in three months of chances in the diet, thus, a longer diet may generate more relevant benefits in the resistant parameters of our study(AU)

La enfermedad del hígado graso no alcohólico (NAFLD) puede conducir a la esteatohepatitis no alcohólica (NASH), la cirrosis y el cáncer de hígado. El tratamiento para NAFLD es la modificación de la ingesta calórica y la actividad física. Debido a que NAFLD tiene una naturaleza pro-oxidante; es lógico suponer que el antioxidante metionina puede utilizarse en el tratamiento de esta enfermedad. Objetivo. el presente trabajo evaluó el papel de la terapia nutricional con alimentos ricos en metioninaen pacientes con NAFLD. Materiales y Métodos. Se realizó un ensayo clínico aleatorizado durante tres meses. Participaron en el estudio 121 pacientes con NAFLD con edad ≥ 20 años (56 en el grupo experimental y 65 en el control), todos aleatorizados y pareados por sexo, reclutados de la Clínica Hospital ISSTE en la ciudad de Xalapa, México, en el año 2015. Se instruyó a los pacientes en consumir los alimentos hasta completar la dosis diaria recomendada de metioninay se calculó la cantidad diaria consumida. Su efecto se midió como la regresión de NAFLD y la mejora de la calidad de vida. Resultados. La terapia nutricional retrocedió NAFLD; disminuyó la acumulación de grasa central, la presión arterial y el índice de hígado graso. Algunos parámetros, como las enzimas de la función hepática, no se modificaron con el tratamiento. Otro parámetro fue la mejora de la calidad de vida de los pacientes tratados. Conclusiones. En este trabajo mostramos un impacto hepatoprotector producido con tan solo tres meses de cambios en la dieta, por lo que una dieta más prolongada podría generar beneficios aún más significativos en los parámetros resistentes en nuestro protocolo(AU)

Effects of Methionine Restriction on Proliferation, Cell Cycle, and Apoptosis of Human Acute Leukemia Cells / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of methionine restriction on proliferation, cell cycle and apoptosis of human acute leukemia cells.@*METHODS@#Cell Counting Kit-8 (CCK-8) assay was used to detect the effect of methionine restriction on HL-60 and Jurkat cells proliferation. The effect of methionine restriction on cell cycle of HL-60 and Jurkat cells was examined by PI staining. Annexin V-FITC / PI double staining was applied to detect apoptosis of HL-60 and Jurkat cells following methionine restriction. The expression of cell cycle-related proteins cyclin B1, CDC2 and apoptosis-related protein Bcl-2 was evaluated by Western blot assay.@*RESULTS@#Methionine restriction significantly inhibited the proliferation of HL-60 and Jurkat cells in a time-dependent manner (HL-60: r =0.7773, Jurkat: r =0.8725), arrested the cells at G2/M phase (P < 0.001), and significantly induced apoptosis of HL-60 and Jurkat cells (HL-60: P < 0.001; Jurkat: P < 0.05). Furthermore, Western blot analysis demonstrated that methionine restriction significantly reduced the proteins expression of Cyclin B1 (P < 0.05), CDC2 (P < 0.01) and Bcl-2 (P < 0.001) in HL-60 and Jurkat cells.@*CONCLUSION@#Acute leukemia cells HL-60 and Jurkat exhibit methionine dependence. Methionine restriction can significantly inhibit the proliferation, promote cell cycle arrest and induce apoptosis of HL-60 and Jurkat cells, which suggests that methionine restriction may be a potential therapeutic strategy for acute leukemia.

Clinical characteristics and genetic analysis of a child with Galactosemia due to compound heterozygous variants of GALT gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genetic basis of a child with Galactosemia.@*METHODS@#A child who had presented at the Children's Hospital Affiliated to Zhengzhou University on November 20, 2019 was selected as the study subject. Clinical data of the child was collected. Whole exome sequencing was carried out for the child. Candidate variants were validated by Sanger sequencing.@*RESULTS@#Clinical manifestations of the child have included anemia, feeding difficulty, jaundice, hypomyotonia, abnormal liver function and coagulation abnormality. Tandem mass spectrometry showed increased citrulline, methionine, ornithine and tyrosine. Urine organic acid analysis showed increased phenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenyllactic acid, 4-hydroxyphenylpyruvate and N-acetyltyrosine. Genetic testing revealed that the child has harbored compound heterozygous variants of the GALT gene, namely c.627T>A (p.Y209*) and c.370G>C (p.G124R), which were respectively inherited from her healthy parents. Among these, c.627T>A (p.Y209*) was known as a likely pathogenic variant, while c.370G>C (p. G124R) was unreported previously and also predicted as a likely pathogenic variant(PM1+PM2_Supporting+PP3_Moderate+PPR).@*CONCLUSION@#Above discovery has expanded the spectrum of the GALT gene variants underlying Galactosemia. Patients with thrombocytopenia, feeding difficulties, jaundice, abnormal liver function and coagulation abnormality without obvious causes should be analyzed by screening of metabolic diseases in combination with genetic testing.

Synthesis and application of the methyl analogues of S-adenosyl-L-methionine / 生物工程学报

Methylation plays a vital role in biological systems. SAM (S-adenosyl-L-methionine), an abundant cofactor in life, acts as a methyl donor in most biological methylation reactions. SAM-dependent methyltransferases (MTase) transfer a methyl group from SAM to substrates, thereby altering their physicochemical properties or biological activities. In recent years, many SAM analogues with alternative methyl substituents have been synthesized and applied to methyltransferases that specifically transfer different groups to the substrates. These include functional groups for labeling experiments and novel alkyl modifications. This review summarizes the recent progress in the synthesis and application of SAM methyl analogues and prospects for future research directions in this field.

Efficient synthesis of L-methionine by engineering the one carbon module of Escherichia coli / 生物工程学报

L-methionine, also known as L-aminomethane, is one of the eight essential amino acids required by the human body and has important applications in the fields of feed, medicine, and food. In this study, an L-methionine high-yielding strain was constructed using a modular metabolic engineering strategy based on the M2 strain (Escherichia coli W3110 ΔIJAHFEBC/PAM) previously constructed in our laboratory. Firstly, the production of one-carbon module methyl donors was enhanced by overexpression of methylenetetrahydrofolate reductase (methylenetetrahydrofolate reductase, MetF) and screening of hydroxymethyltransferase (GlyA) from different sources, optimizing the one-carbon module. Subsequently, cysteamine lyase (hydroxymethyltransferase, MalY) and cysteine internal transporter gene (fliY) were overexpressed to improve the supply of L-homocysteine and L-cysteine, two precursors of the one-carbon module. The production of L-methionine in shake flask fermentation was increased from 2.8 g/L to 4.05 g/L, and up to 18.26 g/L in a 5 L fermenter. The results indicate that the one carbon module has a significant impact on the biosynthesis of L-methionine, and efficient biosynthesis of L-methionine can be achieved through optimizing the one carbon module. This study may facilitate further improvement of microbial fermentation production of L-methionine.

Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies / 中华妇产科杂志

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (β=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (β=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Mechanism of active ingredients in Periploca forrestii compound against rheumatoid arthritis based on integrative metabolomics and network pharmacology / 中国中药杂志

In this study, an ultra-performance liquid chromatography-quadrupole time-of-flight high resolution mass spectrometer(UPLC-Q-TOF-HRMS) was used to investigate the effects of the active ingredients in Periploca forrestii compound on spleen metabolism in rats with collagen-induced arthritis(CIA), and its potential anti-inflammatory mechanism was analyzed by network pharmacology. After the model of CIA was successfully established, the spleen tissues of rats were taken 28 days after administration. UPLC-Q-TOF-HRMS chromatograms were collected and analyzed by principal component analysis(PCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and MetPA. The results showed that as compared with the blank control group, 22 biomarkers in the spleen tissues such as inosine, citicoline, hypoxanthine, and taurine in the model group increased, while 9 biomarkers such as CDP-ethanolamine and phosphorylcholine decreased. As compared with the model group, 21 biomarkers such as inosine, citicoline, CDP-ethanolamine, and phosphorylcholine were reregulated by the active ingredients in P. forrestii. Seventeen metabolic pathways were significantly enriched, including purine metabolism, taurine and hypotaurine metabolism, glycerophospholipid metabolism, and cysteine and methionine metabolism. Network pharmacology analysis found that purine metabolism, glycerophospholipid metabolism, and cysteine and methionine metabolism played important roles in the pathological process of rheumatoid arthritis. This study suggests that active ingredients in P. forrestii compound can delay the occurrence and development of inflammatory reaction by improving the spleen metabolic disorder of rats with CIA. The P. forrestii compound has multi-target and multi-pathway anti-inflammatory mechanism. This study is expected to provide a new explanation for the mechanism of active ingredients in P. forrestii compound against rheumatoid arthritis.

Assessment of MTR Rs1805087 SNP as Possible Modifier ofSickle Cell Disease Severity in a Nigerian Population

BACKGROUND: Sickle cell disease is the commonest geneticdisorder in Nigeria, affecting 2­3% of an estimated population of 160million people. The role of genetic mutations in folate cycle genes,and the variable phenotypic expressions constituting disease severity,needs to be critically examined.OBJECTIVE: This study was carried out to establish the pattern ofmethionine synthase gene mutations (rs1805087 SNP), and its possibleassociation with disease severity in adults with sickle cell anaemia inLagos, Nigeria.METHODOLOGY: This is a cross-sectional study of seventy (70)subjects with sickle cell disease (HbSS) matched for age and genderwith known apparently healthy haemoglobin genotype AA (HbAA)subjects, as cases and controls respectively. Structured questionnaireswere used to obtain demographic, clinical and other phenotypic dataneeded to compute disease severity. Pattern of MTR A2756G genemutation and homocysteine assay (Hcy) were assessed by PolymeraseCh ain Reaction and Enzyme- linked Immun osorbent Assayrespectively. Full blood count analysis of participants was done usingthe KX-21 Automated Analyzer (Sysmex Corporation, Japan).RESULTS: The mutant genotypes MTR 2756 AG/GG were recordedin 46.4% (n =55) of subjects with disease severity score >7. Elevatedplasma homocysteine (HHcy) was significantly associated withdisease severity among HbSS subjects (OR=17.2, CI: 3.490-86.079;p=0.0001). Conversely, no significant association was observed withthe mutant genotypes MTR 2756 AG/GG and disease severity(p>0.05).CONCLUSION: While HHcy is significantly associated withphenotypic expression of HbSS, the MTR 2756 SNPs did not appearto independently influence homocysteine level or disease severity inHbSS subjects

Metabolomic changes of neonatal sepsis: an exploratory clinical study / 中国当代儿科杂志

OBJECTIVES@#To study the metabolic mechanism of neonatal sepsis at different stages by analyzing the metabolic pathways involving the serum metabolites with significant differences in neonates with sepsis at different time points after admission.@*METHODS@#A total of 20 neonates with sepsis who were hospitalized in the Department of Neonatology, Hunan Provincial People's Hospital, from January 1, 2019 to January 1, 2020 were enrolled as the sepsis group. Venous blood samples were collected on days 1, 4, and 7 after admission. Ten healthy neonates who underwent physical examination during the same period were enrolled as the control group. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for the metabonomic analysis of serum samples to investigate the change in metabolomics in neonates with sepsis at different time points.@*RESULTS@#On day 1 after admission, the differentially expressed serum metabolites between the sepsis and control groups were mainly involved in the biosynthesis of terpenoid skeleton. For the sepsis group, the differentially expressed serum metabolites between days 1 and 4 after admission were mainly involved in pyruvate metabolism, and those between days 4 and 7 after admission were mainly involved in the metabolism of cysteine and methionine. The differentially expressed serum metabolites between days 1 and 7 after admission were mainly involved in ascorbic acid metabolism.@*CONCLUSIONS@#The metabolic mechanism of serum metabolites varies at different stages in neonates with sepsis and is mainly associated with terpenoid skeleton biosynthesis, pyruvate metabolism, cysteine/methionine metabolism, and ascorbic acid metabolism.

Preliminary exploration of the metabolic profile and metabolic pathways in newly diagnosed multiple myeloma / 中华肿瘤杂志

Objective: To explore the metabolite profile and metabolic pathways of newly diagnosed multiple myeloma (MM). Methods: Gas chromatography-mass spectrometry (GC-MS) was employed for the high-throughput detection and identification of serum samples from 55 patients with MM and 37 healthy controls matched for age and sex from 2016 to 2017 collected at the First Affiliated Hospital of Soochow University. The relative standard deviation (RSD) of quality control (QC) samples was employed to validate the reproducibility of GC-MS approach. The differential metabolites between patients with MM and healthy controls were detected by partial least squares discrimination analysis (PLS-DA), and t-test with false discovery rate (FDR) correction. Metabolomics pathway analysis (MetPA) was employed to construct metabolic pathways. Results: There were 55 MM patients, including 34 males and 21 females. The median age was 60 years old (42-73 years old). There were 30 cases of IgG type, 9 cases of IgA type, 1 case of IgM type, 2 cases of non-secreted type, 1 case of double clone type and 12 cases of light chain type, including 3 cases of kappa light chain type and 9 cases of lambda light chain type. The result of QC sample test showed that the proportion of compounds with the RSD of the relative content of metabolites < 15% was 70.21% obtained by the reproducibility of GC-MS experimental data, which implied that the experimental data were reliable. A total of 17 metabolites were screened differently with the healthy control group, including myristic acid, hydroxyproline, cysteine, palmitic acid, L-leucine, stearic acid, methionine, phenylalanine, glycerin, serine, isoleucine, tyrosine, valine, citric acid, inositol, threonine, and oxalic acid (VIP>1, P<0.05). Metabolic pathway analysis suggested that metabolic disorders in MM patients comprised mainly phenylalanine metabolism, glyoxylic acid and dicarboxylic acid metabolism, phosphoinositide metabolism, cysteine and methionine metabolism, glycerolipid metabolism, glycine, serine, and threonine metabolism. Conclusion: Compared with normal people, patients with newly diagnosed MM have obvious differences in metabolic profiles and metabolic pathways.

Effect of chromium-methionine supplementation on meat quality of broilers reared under heat stress / [Efeito da suplementação de cromo-metionina na qualidade da carne de frangos de corte criados em estresse por calor]

Objetivou-se avaliar o efeito da suplementação de cromo-metionina em dietas para frangos de corte criados em estresse por calor, no período de 22 a 43 dias de idade, nos parâmetros de qualidade da carne. Foram utilizados 336 frangos de corte, machos, da linhagem Cobb 500, com 21 dias de idade, distribuídos em delineamento em blocos inteiramente ao acaso, com quatro blocos (cada câmara climática), seis tratamentos (0; 0,10; 0,20; 0,40; 0,80 e 1,20mgkg-1 de Cr na forma de Cr-metionina), oito repetições e sete aves por unidade experimental. Aos 43 dias de idade, duas aves por unidade experimental foram selecionadas e abatidas para avaliação da qualidade da carne de peito, por meio dos parâmetros de pH15min, pH24h, luminosidade (L*), teor de vermelho (a*), teor de amarelo (b*), croma (C*), ângulo hue (Hº), capacidade de retenção de água, perda de peso por cozimento e força de cisalhamento. Houve efeito quadrático (P=0,0070) na capacidade de retenção de água da carne de peito. A suplementação de CrMet não afetou (P>0,05) os demais parâmetros de qualidade da carne. Assim, recomenda-se a suplementação de 0,59mgkg-1 de CrMet para frangos de corte para melhoria da capacidade de retenção de água do peito.(AU)

Avaliação nutricional e metabólica de borregas alimentadas com níveis crescentes de aminoácidos protegidos / [Nutritional and metabolic evaluation of feeding lambs with growing levels of protein amino acids]

Objetivou-se avaliar a inclusão de níveis de lisina e metionina protegidas na dieta sobre os parâmetros nutricionais e metabólicos energéticos e hepáticos de borregas em crescimento. Utilizaram-se cinco borregas ½ sangue Dorper x Santa Inês, com aproximadamente oito meses de idade e peso médio de 50 ± 2,3kg, distribuídas em esquema quadrado latino 5x5 (cinco tratamentos, cinco animais e cinco períodos). Os tratamentos consistiram na inclusão de diferentes níveis de lisina e metionina protegidas da degradação ruminal (MicroPEARLS LM®) na ração, sendo: 0g, 8g, 16g, 24g e 32g por dia. A dieta era composta por silagem de milho e concentrado na relação 30V:70C. Realizou-se um ensaio de digestibilidade para determinar consumo e digestibilidade da matéria seca (CMS/DGMS), balanço de nitrogênio e metabólitos sanguíneos. O CMS (kg/dia) em relação ao peso metabólico apresentou equação linear positiva, sendo maior no tratamento que ofertou 32g de aminoácidos por dia, assim como o nitrogênio ingerido e o balanço de nitrogênio, sendo positivo em todos os tratamentos. Não houve diferença (P>0,05) para a digestibilidade da MS e o metabolismo energético e hepático. Lisina e metionina protegidas da degradação ruminal podem ser incluídas na ração de borregas em crescimento até 32g/dia sem causar efeitos negativos na digestibilidade da MS e no metabolismo.(AU)

The objective was to evaluate the inclusion of protected lysine and methionine levels on the diet, over the nutritional parameters and energetic and hepatic metabolites of growing lambs. Five lambs ½ blood Dorper x Santa Inês, with approximately eight months of age and average weight of 50kg, were distributed in a 5x5 latin square scheme (five treatments and five replicates). The treatments consisted of the inclusion of different levels of lysine and methionine protected from ruminal degradation (MicroPEARLS LM®) in the diet, being: 0g, 8g, 16g, 24g and 32g. The diet was composed of corn silage and concentrated 30V:70C in the ratio. A digestibility assay was performed to determine dry matter intake and digestibility (DMI/DDMI), nitrogen balance and blood metabolites. The DMI (kg/day) in relation to the metabolic weight had a positive linear equation, being higher in treatment 32g, as well as the ingested nitrogen and nitrogen balance, being positive in all treatments. There was no difference (P>0.05) for the digestibility of DM, energetic and hepatic metabolism. Lysine and methionine protected from ruminal degradation can be included in the diet of growing lambs up to 32g without causing negative effects on DM digestibility and metabolism.(AU)

Níveis Séricos do BDNF na Proteção Cardiovascular e em Resposta ao Exercício / Serum Levels of BDNF in Cardiovascular Protection and in Response to Exercise

Resumo As doenças cardiovasculares (DCV) são atualmente a maior causa de morte no Brasil e no mundo. Em 2016 as DCV foram responsáveis por mais de 17 milhões de mortes, representando 31% de todas as mortes em nível global. Mecanismos moleculares e genéticos podem estar envolvidos na proteção cardiovascular e devem ser considerados nas novas abordagens terapêuticas. Nesse sentido, recentes estudos têm relatado que o Fator Neurotrófico Derivado do Encéfalo (Brain-Derived Neurotrophic Factor, BDNF) está reduzido em indivíduos predispostos a desenvolverem DCV, e que o treinamento físico aeróbio aumenta as quantidades de BDNF circulante. O BDNF é uma neurotrofina encontrada em altas concentrações no hipocampo e córtex cerebral, sendo considerada molécula-chave na manutenção da plasticidade sináptica e na sobrevivência das células neuronais. Além da plasticidade neuronal, BDNF também é importante na função vascular, promovendo angiogênese por meio da regulação por espécies reativas de oxigênio (ROS). Entretanto, uma variante do gene do BDNF em humanos, o polimorfismo Val66Met (substituição do aminoácido valina por uma metionina na posição 66 do códon), que ocorre em 20-30% da população caucasiana, pode afetar as concentrações de BDNF no plasma e sua atividade em todos os tecidos periféricos contendo receptores tirosina quinase B (TrkB), como o endotélio. De fato, recentemente observamos que o polimorfismo Val66Met prejudica a reatividade vascular e o BDNF circulante em resposta ao treinamento físico. Dessa forma, apresentaremos a seguir uma discussão sobre os níveis séricos de BDNF na proteção cardiovascular, a variante genética Val66Met na reatividade vascular e o efeito do exercício físico.

Abstract Cardiovascular disease (CVD) is currently the leading cause of death in Brazil and worldwide. In 2016, CVD accounted for more than 17 million deaths, representing 31% of all deaths globally. Molecular and genetic mechanisms may be involved in vascular protection and should be considered in new therapeutic approaches. In this sense, recent studies have reported that brain-derived neurotrophic factor (BDNF) is reduced in individuals predisposed to develop CVD, and that aerobic physical training increases the amounts of circulating BDNF. BDNF is a neurotrophin found at high concentrations in the hippocampus and cerebral cortex and is considered a key molecule for the maintenance of synaptic plasticity and survival of neuronal cells. In addition to neuronal plasticity, BDNF is also important in vascular function, promoting angiogenesis through the regulation of reactive oxygen species (ROS). However, a variant of the BDNF gene in humans, the Val66Met polymorphism (substitution of the amino acid valine for a methionine at position 66 of the codon), occurring in 20-30% of the Caucasian population, may affect plasma BDNF concentrations and its activity in all peripheral tissues containing tyrosine kinase B receptors (TrkB), such as the endothelium. Thus, we will present a discussion about the role of serum BDNF levels in cardiovascular protection, Val66Met genetic variant in vascular reactivity and the effect of physical exercise.

Estimación del balance de metionina y lisina metabolizable en vacas de leche en pastoreo / Estimation of the balance of metabolizable lysine and methionine for grazing dairy cows

RESUMEN Objetivos. El objetivo de este trabajo fue estimar en vacas en pastoreo, tanto la reproducibilidad como la precisión del balance de metionina (Met) y lisina (Lis), aminoácidos más limitantes en la producción de leche, cuando se comparan los valores predichos versus los valores observados. Materiales y métodos. Se usaron 12 vacas durante un periodo de 20 días. Control: animales pastoreando y suplementados con alimento balanceado; Met-Lis: igual al control y el suplemento se ajustó con Lis y Met protegida. Para los valores predichos para la suplementación de Met y Lis, se tuvo en cuenta el promedio del consumo de materia seca (CMS) del hato, basado en la oferta y el consumo de pasto y los valores de proteína microbiana. Los valores observados se determinaron con base en el CMS individual usando marcadores externos e internos, además, la producción individual de proteína microbiana. Se realizó una prueba de t pareada y un modelo de predicción para determinar la eficiencia fue determinado usando el error cuadrático medio de predicción (ECMP) y el coeficiente de concordancia (CCC). Resultados. Se encontraron diferencias significativas entre la suplementación y el balance de Met y Lis, entre los valores predichos y los valores observados para el CMS del forraje, la digestibilidad de la proteína microbiana, la producción de proteína microbiana, el suministro y el balance de Lis y Met. El CCC del balance de Lis y Met fue bajo (0.10), el ECMP fue alto, excepto para el CMS, que tuvo una concordancia moderada (0.63) y un bajo ECMP(4.42). Conclusiones. Estos resultados demuestran la falta de precisión de las herramientas que se usan para balancear las raciones individuales de vacas en pastoreo, ya que subestiman la suplementación y el balance de los aminoácidos.

ABSTRACT Objective. The aim of this study was to determine in grazing cows, the reproducibility and accuracy of the balance between predicted values, when compared with the observed values for the most limiting amino acids in milk protein synthesis, the methionine (Met) and Lysine (Lys). Materials and methods. Twelve lactating cows were used for a 20-day experimental period. Control: animals grazing and supplemented with balanced food; Met-Lys: same as control and supplemented with adjusted rumen protected Met and Lys. For Met and Lys supply predicted values, it was taking in account the average of the dry matter intake (DMI) of the herd, based in offer and foraging control and values of microbial protein data. Observed values were determined based in the individual DMI intake, using external and internal markers and the individual microbial protein production. A t-paired-sample test was performed and the efficiency of the model's prediction was determined using the mean square prediction error (MSPE) and the concordance coefficient (CCC). Results. Significant differences were found between the predicted and observed values for DMI forage, digestible microbial protein and microbial protein production, supply and the balance of Lys and Met. The CCC for Lys and Met balance were low (0.10), the MSPE was high except for the total DMI with a moderate concordance (0.63) and low MSPE (4.42). Conclusions. These results indicate a lack of precision of the tools, which underestimates the supply and balance of amino acids in individual grazing cows.

Utilidad de la 18f-colina pet/tc en hiperparatiroidismo primario persistente o recurrente: experiencia inicial / Usefulness of 18f-choline pet / tc in persistent or recurrent primary hyperparathyroidism: initial experience

El hiperparatiroidismo persistente/recurrente representa un desafío en la localización del tejido paratiroideo hiperfuncionante. En esta subpoblación, los métodos convencionales ofrecen un menor rédito diagnóstico. La 18F-colina PET/TC podría ser una buena alternativa dada su mejor resolución espacial, capacidad de detectar glándulas ectópicas y la conjunción de la imagen molecular y anatómica. Sin embargo, la evidencia en este subgrupo de pacientes es escasa. Objetivo: evaluar la utilidad de la 18F-colina PET/TC como método de localización en el hiperparatiroidismo persistente o recurrente. Materiales y métodos: se analizaron los pacientes con 18F-colina PET/TC para hiperparatiroidismo entre diciembre de 2015 y enero de 2018 en un centro terciario de alto volumen. Se analizaron el número de lesiones, su localización, tamaño y el Standard Uptake Value máximo (SUV max) en las imágenes tempranas y tardías. Se compararon los resultados con los métodos convencionales. Resultados: 7 de 15 pacientes habían sido operados previamente (persistentes/recurrentes). La 18F-colina PET/TC detectó 6/7 casos (83,33%), la ecografía cervical 1/4 (25%) y el SPECT de paratiroides y la resonancia nuclear magnética 2/5 (40%). El SUV max obtenido fue variable, en la mitad de los casos a los 10 minutos y en los restantes a la hora; el tamaño promedio de las lesiones fue 8,61 mm (6-12 mm). Conclusiones: la 18F-colina PET/TC muestra una alta tasa de detección en los pacientes con hiperparatiroidismo persistente/recurrente. La combinación del comportamiento biológico del PET con los hallazgos morfológicos aportados por la TC con contraste endovenoso le ofrecería ventajas sobre otros estudios que podrían posicionarlo como método de primera línea en esta subpoblación. (AU)

Persistent or recurrent hyperparathyroidism represents a challenge regarding the localization of the hyper-functioning parathyroid tissue. In this subpopulation of hyperpharathyroid patients, conventional methods have a low diagnostic yield. The 18F-choline PET /CT could be a good alternative given its better spatial resolution, ability to detect ectopic glands, and the conjunction of the molecular and anatomical image. However, the evidence in this subgroup of patients is limited. Objective: to evaluate the utility of 18F-choline PET/ CT as a localization method in persistent or recurrent hyperparathyroidism. Materials and methods: patients with 18F-choline PET / CT for hyperparathyroidism between December 2015 and January 2018 in a high-volume tertiary center were included. The number of lesions, and their location, size, and maximum Standard Uptake Value (SUV) in the early and late images were analyzed. The results were compared to conventional methods. Results: 7 of 15 patients had been previously operated (persistent/recurrent). 18F-choline PET / CT detected 6/7 cases (83,33%), cervical ultrasound 1/4 (25%) and parathyroid SPECT and magnetic resonance 2/5 (40%). The maximum SUV was variable, one half at 10 minutes and the other half at 60 minutes; the average size of the lesions was 8.61 mm (6-12 mm). Conclusions: 18F-Choline PET / CT shows a high detection rate in patients with persistent / recurrent hyperparathyroidism. The combination of the biological behavior of PET with the morphological findings provided by CT with intravenous contrast would offer advantages over other studies that could position it as a first line method in this subpopulation. (AU)

Rumen-protected methionine in cattle: influences on reproduction, immune response, and productive performance / Metionina protegida da degradação ruminal em bovinos: influências na reprodução, resposta imune e desempenho produtivo

Nowadays, information and knowledge generated about the main ingredients used in cattle diets have enabled greater assertiveness in their formulation. Among the ingredients, amino acids stand out as a promising tool, capable of reducing total crude protein (CP) levels and adjusting optimal metabolizable protein concentrations in diets. Nutritional programs allow diets due to amino acid requirements, providing the opportunity to increase the efficiency of the use of dietary nitrogen, increasing the scarce protein concentrates, maintaining or even boosting performance. This review aimed to present the influences of methionine, in its formulation protected from ruminal degradation, according to reproductive parameters, immune response, and productive performance in cattle. Reproduction-related benefits are linked to the early days of embryonic implantation in the uterine environment, which initially secretes through the histotroph produced by endometrial glands, the nutrients needed to develop the conceptus until implantation, and vascular communication with the mother. Given the immune response, the main results are related to the benefits of innate immunity, with marked increase in phagocytic capacity of neutrophils and monocytes, as well as an important antioxidant effect mediated by methionine products, such as glutathione. When evaluating the influences on productivity, the most evident correlation is the increase in protein in the milk of cows supplemented with methionine. Over the past decade, studies investigating the potential benefits of this strategic supplementation in beef cattle were intensified, expanding the opportunities for the development of new experimental projects.(AU)

Atualmente, as informações e o conhecimento gerado sobre os principais ingredientes utilizados em dietas para bovinos possibilitaram maior assertividade em suas formulações. Dentre esses ingredientes, os aminoácidos se destacam como uma ferramenta promissora, capaz de levar à redução nos níveis totais de proteína bruta e ajustar as concentrações ideais de proteína metabolizável nas dietas. Programas nutricionais permitem formular dietas por exigências de aminoácidos, oportunizando o aumento na eficiência de utilização do nitrogênio dietético, reduzindo dispêndios com concentrados ricos em proteína, com a manutenção, ou ainda, incremento de desempenho. Esta revisão buscou apresentar as influências da metionina, em sua formulação protegida da degradação ruminal, frente a parâmetros reprodutivos, resposta imune e desempenho produtivo em bovinos. Os benefícios relacionados à reprodução se mostram ligados aos primeiros dias de implantação embrionária no ambiente uterino, que inicialmente secreta, através do histotrofo produzido por glândulas endometriais, os nutrientes necessários para o desenvolvimento do concepto até a implantação e comunicação vascular com a mãe. Dada a resposta imune, os principais resultados estão relacionados aos benefícios da imunidade inata, com aumento acentuado da capacidade fagocitária de neutrófilos e monócitos, assim como um importante efeito antioxidante mediado por produtos originários da metionina, como a glutationa. Por fim, quando avaliadas as influências em produtividade, a correlação mais evidente é o incremento em proteína no leite de vacas suplementadas com metionina. Na última década, os estudos que investigam os potenciais benefícios dessa suplementação estratégica em bovinos de corte foram intensificados, abrindo um caminho de oportunidades para o desenvolvimento de novos projetos experimentais.(AU)

Feasibility and Stability of Liver Biopsy before Treatment for Preclinical Nonalcoholic Fatty Liver Studies

BACKGROUND: The heterogeneity of histological findings in preclinical diet-induced nonalcoholic fatty liver disease (NAFLD) animal models is highly challenging. Here, we aimed to evaluate the feasibility and stability of repeated liver biopsy in NAFLD animal models. METHODS: Heterogeneity of diet-induced NAFLD was evaluated at different time points in 52 high-fat diet (HFD), 35 methionine choline-deficiency diet (MCD), and 166 western diet (WD) induced NAFLD mice. Serial liver biopsies (left lateral, right medial, and left medial lobes) were performed monthly for up to 3 months. Mortality rates and changes in food intake, body weight, and liver enzymes were assessed. RESULTS: At 12 weeks, of the HFD animals, 14% and 30% did not develop steatosis and lobular inflammation, respectively; of the MCD animals, 7% did not develop lobular inflammation; and of the WD animals, 14% and 51% did not develop steatosis and lobular inflammation, respectively. The mortality rate of repeated liver biopsy was 1.62% (2/123 mice died). Repeated liver biopsy can be used to trace disease progression. Although body weight, food intake, and liver enzymes slightly changed after biopsy, all recovered within a week. Repeated liver biopsy did not affect the degrees of inflammation and steatosis of the other liver lobes. CONCLUSION: The diet-induced NAFLD models were quite heterogeneous. Our results suggest that the repeated liver biopsy before treatment was applicable and stable in this NAFLD animal study.

Human tissue kallikrein-1 protects against the development of erectile dysfunction in a rat model of hyperhomocysteinemia / 亚洲男科学杂志(英文版)

The aim of this study was to investigate the mechanism by which a diet inducing high hyperhomocysteinemia (HHcy) leads to the deterioration of erectile function in rats and whether this is inhibited by expression of the human tissue kallikrein-1 (hKLK1) gene. We established a rat model of HHcy by feeding methionine (Met)-rich diets to male Sprague-Dawley (SD) rats. Male wild-type SD rats (WTRs) and transgenic rats harboring the hKLK1 gene (TGRs) were fed a normal diet until 10 weeks of age. Then, 30 WTRs were randomly divided into three groups as follows: the control (n = 10) group, the low-dose (4% Met, n = 10) group, and the high-dose (7% Met, n = 10) group. Another 10 age-matched TGRs were fed the high-dose diet and designated as the TGR+7% Met group. After 30 days, in all four groups, erectile function was measured and penile tissues were harvested to determine oxidative stress, endothelial cell content, and penis fibrosis. Compared with the 7% Met group, the TGR+7% Met group showed diminished HHcy-induced erectile dysfunction (ED), indicating the improvement caused by hKLK1. Regarding corpus cavernosum endothelial cells, hKLK1 preserved endothelial cell-cell junctions and endothelial cell content, and activated protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) signaling. Fibrosis assessment indicated that hKLK1 preserved normal penis structure by inhibiting apoptosis in the corpus cavernosum smooth muscle cells. Taken together, these findings showed that oxidative stress, impaired corpus cavernosum endothelial cells, and severe penis fibrosis were involved in the induction of ED by HHcy in rats, whereas hKLK1 preserved erectile function by inhibiting these pathophysiological changes.

Investigation of the association of idiopathic male infertility with polymorphisms in the methionine synthase (MTR) gene / 대한생식의학회지

OBJECTIVE: Spermatogenesis is a complex process that is regulated by a number of genes, some of which are involved in folate-dependent 1-carbon metabolism. Methionine synthase (encoded by MTR) is a key enzyme participating in this pathway. This study aimed to investigate the relationship of the MTR 2756A > G polymorphism with idiopathic male fertility in the Iranian population. METHODS: The participants of this study included 100 men with idiopathic infertility and 100 healthy men as the control group. Genotyping of MTR 2756A > G was performed using the polymerase chain reaction and restriction fragment length polymorphism technique. The obtained data were analyzed using SPSS ver. 20.0 with a level of confidence of p G single-nucleotide polymorphism is not a predisposing factor for idiopathic infertility in men.