Association between genetic variations at 8q24 and prostate cancer risk in Mexican Men.

BACKGROUND: Variants of 8q24 locus have been associated with prostate cancer (PCa) susceptibility. This study aims to analyze the genetic basis of PCa susceptibility in Mexican men by analyzing SNPs in the 8q24 locus for the first time. METHODS: A case-control study was performed in 875 men recruited from the Mexican Social Security Institute, 326 patients with PCa, and 549 non-PCa patients (88 with benign prostatic hyperplasia BPH and 461 healthy controls). The 8q24 locus SNPs: rs16901979, rs16983267, rs1447295, and rs7837328 were genotyped by allelic discrimination assays using TaqMan probes. Statistical analysis was performed using Epi Info statistical 7.0 and SNPstats softwares. RESULTS: All genotype frequencies were in Hardy-Weinberg Equilibrium. No differences were observed in genotype distribution between PCa and non-PCa patients for rs6983267. Under different inheritance models, the rs16901979, rs1447295, and rs7837328 SNPs were associated with PCa (OR = 2.8, 1.8, and 1.72, respectively; Pc < 0.001) when comparing PCa patients against controls. This association remains between PCa and BPH patients under different models (OR = 8.5, 2.2, and 1.9, respectively; Pc < 0.001). There were no significant differences in allele and genotype distribution among BPH patients and controls. The combined effect of the alleles CGAA for the SNPs rs16901979, rs6983267, rs1447295, and rs7837328 showed significant differences between PCa patients and controls (OR = 2.9, 95% CI = 1.48-5.83, Pc = 0.008). Four 8q24 variants were not associated with D'Amico score, age at diagnosis, and bone metastases. CONCLUSIONS: Our study provides the first confirmation that variants rs16901979, rs1447295, and 7837328 at 8q24 locus are associated with PCa susceptibility in Mexican men.

A dietary intervention with functional foods reduces metabolic endotoxaemia and attenuates biochemical abnormalities by modifying faecal microbiota in people with type 2 diabetes.

AIM: To study the effects of a functional food-based dietary intervention on faecal microbiota and biochemical parameters in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This placebo-controlled, randomized, double-blind study included 81 patients with T2D divided into two 3-month treatment groups: one following a reduced-energy diet with a dietary portfolio (DP) comprising high-fibre, polyphenol-rich and vegetable-protein functional foods; the other taking a placebo (P). The primary outcome was the effect of the DP on faecal microbiota. Secondary endpoints were biochemical parameters, lipopolysaccharide, branched-chain amino acids, trimethylamine N-oxide, glycosylated haemoglobin (HbA1c) and free fatty acids (FFAs). RESULTS: Patients with T2D exhibited intestinal dysbiosis characterized by an increase in Prevotella copri. Dietary intervention with functional foods significantly modified faecal microbiota compared with P by increasing alpha diversity and modifying the abundance of specific bacteria, independently of antidiabetic drugs. There was a decrease in P. copri and increases in Faecalibacterium prausnitzii and Akkermansia muciniphila, two bacterial species known to have anti-inflammatory effects. The DP group also exhibited significant reductions in areas under the curve for glucose, total and LDL cholesterol, FFAs, HbA1c (P< 0.05), triglycerides and CRP, and an increase in antioxidant activity (P< 0.01) vs. the P group. CONCLUSION: Long-term adherence to a high-fibre, polyphenol-enriched and vegetable-protein-based diet provides benefits for the composition of faecal microbiota, and may offer potential therapies for improvement of glycaemic control, dyslipidaemia and inflammation.

Amino acid profiles of young adults differ by sex, body mass index and insulin resistance.

BACKGROUND AND AIMS: An increase in plasma branched-chain amino acids is associated with a higher risk of developing type 2 diabetes and cardiovascular diseases. However, little is known about the basal plasma amino acid concentrations in young adults. Our aim was to determine the plasma amino acid profiles of young adults and to evaluate how these profiles were modified by sex, body mass index (BMI) and insulin resistance (IR). METHODS AND RESULTS: We performed a transversal study with 608 Mexican young adults aged 19.9 ± 2.4 years who were applicants to the Universidad Autónoma de San Luis Potosí. The subjects underwent a physical examination and provided a clinical history and a blood sample for biochemical, hormonal and amino acid analyses. The women had higher levels of arginine, aspartate and serine and lower levels of α-aminoadipic acid, cysteine, isoleucine, leucine, methionine, proline, tryptophan, tyrosine, urea and valine than the men. The obese subjects had higher levels of alanine, aspartate, cysteine, ornithine, phenylalanine, proline and tyrosine and lower levels of glycine, ornithine and serine than the normal weight subjects. Subjects with IR (defined as HOMA > 2.5) had higher levels of arginine, alanine, aspartate, isoleucine, leucine, phenylalanine, proline, tyrosine, taurine and valine than the subjects without IR. Furthermore, we identified two main groups in the subjects with obesity and/or IR; one group was composed of amino acids that positively correlated with the clinical, biochemical and hormonal parameters, whereas the second group exhibited negative correlations. CONCLUSION: This study demonstrates that young adults with obesity or IR have altered amino acid profiles characterized by an increase in alanine, aspartate, proline and tyrosine and a decrease in glycine.

[Homocysteine metabolism and risk of cardiovascular diseases: importance of the nutritional status on folic acid, vitamins B6 and B12]. / Metabolismo de la homocisteína y riesgo de enfermedades cardiovasculares: importancia del estado nutricio en ácido fólico, vitaminas B6 y B12.

Homocysteine is a thiol-containing amino acid derived from methionine metabolism that can be degraded through two enzymatic pathways: remethylation and trans-sulfuration. In remethylation, homocysteine regenerates methionine. In the trans-sulfuration pathway, homocysteine forms cysteine. Due to the rapid metabolic utilization, the plasma concentration of this amino acid is low. Homocysteine circulates as free thiol, homocystine, or bound to free cysteine or to cysteine residues of proteins. Genetic defects of some enzymes in the homocysteine metabolism, or nutritional deficiencies of folic acid, vitamin B6 and B12 lead to an increase in homocysteine plasma concentration and is associated to an increment in cardiovascular diseases. On the basis of clinical and epidemiological studies, homocysteine plasma concentration is considered to be an independent risk factor for the development of atherothrombotic and cardiovascular diseases. The present review describes the homocysteine metabolism, the epidemiological evidence showing the association between homocysteine and the incidence of cardiovascular diseases. The mechanisms by which homocysteine produces vascular damage are indicated. Finally, some recommendations are given for the nutritional therapy of patients with hyperhomocysteinemia.

Use of sulfhydryl reagents to investigate branched chain alpha-keto acid transport in mitochondria.

The goal of this paper was to determine the contribution of the mitochondrial branched chain aminotransferase (BCATm) to branched chain alpha-keto acid transport within rat heart mitochondria. Isolated heart mitochondria were treated with sulfhydryl reagents of varying permeability, and the data suggest that essential cysteine residues in BCATm are accessible from the cytosolic face of the inner membrane. Treatment with 15 nmol/mg N-ethylmaleimide (NEM) inhibited initial rates of alpha-ketoisocaproate (KIC) uptake in reconstituted mitochondrial detergent extracts by 70% and in the intact organelle by 50%. KIC protected against inhibition suggesting that NEM labeled a cysteine residue that is inaccessible when substrate is bound to the enzyme. Additionally, the apparent mitochondrial equilibrium KIC concentration was decreased 50-60% after NEM labeling, and this difference could not be attributed to effects of NEM on matrix pH or KIC oxidation. In fact, NEM was a better inhibitor of KIC oxidation than rotenone. Measuring matrix aspartate and glutamate levels revealed that the effects of NEM on the steady-state KIC concentration resulted from inhibition of BCATm catalyzed transamination of KIC with matrix glutamate to form leucine. Furthermore, circular dichroism spectra of recombinant human BCATm with liposomes showed that the commercial lipids used in the reconstituted transport assay contain BCAT amino acid substrates. Thus BCATm is distinct from the branched chain alpha-keto acid carrier but may interact with the inner mitochondrial membrane, and it is necessary to inhibit or remove transaminase activity in both intact and reconstituted systems prior to quantifying transport of alpha-keto acids which are transaminase substrates.

Characterization of methylaminoisobutyric acid transport by system A in rat mammary gland.

During lactation, the mammary gland has a large demand for amino acids for the synthesis of milk proteins and fatty acids. Arteriovenous differences in amino acids across the mammary gland show an elevated uptake of small neutral amino acids that are mainly transported via system A. The purpose of this study was to characterize the transport of methylaminoisobutyric acid (MeAIB), an amino acid analog used to model transport by system A in lactating rat mammary gland explants. MeAIB accumulation in mammary gland cells increased steadily, and after 3 hours of incubation, the intracellular concentration of the analog was 8-fold higher than the concentration in the medium. MeAIB transport into mammary gland explants showed a Km of 3.3 +/- 0.4 mmol/L and a maximal velocity (Vmax) of 555 +/- 23 pmol/microL intracellular fluid (ICF) x min, indicating a system with high capacity but low affinity for its substrate. MeAIB transport into mammary tissue depended highly on Na+, and the uptake was inhibited by addition of natural and analog small neutral amino acids. Cationic, anionic, and large neutral amino acids did not reduce MeAIB transport into mammary gland explants. Preincubation of mammary gland explants in an amino acid-free medium stimulated MeAIB transport, suggesting an adaptive regulation. The addition of an equimolar mixture of alanine, glycine, and serine to the preincubation medium inhibited stimulation of MeAIB transport. Furthermore, stimulation of MeAIB uptake by amino acid starvation was also prevented by the addition of actinomycin D, cycloheximide, tunicamycin, and colchicine. Dibutyryl cyclic adenosine monophosphate (cAMP) increased MeAIB uptake, whereas phorbol 12-myristate 13-acetate (PMA) did not stimulate MeAIB transport. During the first postweaning days, kinetic analyses showed a decrease of 27% in the Vmax. Injection of rat lactating mammary gland mRNA into Xenopus laevis oocytes induced expression of the MeAIB transport system; however, the induction was only 83% above background MeAIB uptake. The results of this study provide a partial explanation for the formation of the metabolic pool of small neutral amino acids in the lactating mammary gland.