Ramón Mauricio Coral-Vázquez

The FTO gene is associated with adulthood obesity in the Mexican population.

Common polymorphisms in the fat mass and obesity‐associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican‐Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single‐nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B‐cell function (HOMA‐B), and with higher homeostasis model assessment of insulin sensitivity (HOMA‐S) only in nonobese individuals (P dom = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican‐Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.

The ATP-Binding Cassette Transporter A1 R230C Variant Affects HDL Cholesterol Levels and BMI in the Mexican Population: Association With Obesity and Obesity-Related Comorbidities

Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low–HDL cholesterol but not in high–HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.

Methylenetetrahydrofolate Reductase C677T and Glutathione S-Transferase P1 A313G Are Associated with a Reduced Risk of Preeclampsia in Maya-Mestizo Women

Preeclampsia, a common complication of pregnancy, is characterized by elevated blood pressure and proteinuria developing after 20 weeks’ gestational age. Susceptibility to this syndrome is believed to have a genetic component. The aim of this study was to investigate whether or not the 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and glutathione S−transferase P1 (GSTP1) A313G polymorphisms are associated with preeclampsia in Maya-Mestizo women. A case-control study was performed, in which 125 preeclamptic patients and 274 healthy controls were genotyped for the MTHFR C677T and GSTP1 A313G polymorphisms by real-time PCR allelic discrimination. Allele and genotype frequencies were compared using the χ2 tests. The MTHFR 677T allele and the 677TT genotype were significantly more frequent in the controls, suggesting an association with a decreased risk of preeclampsia (p=0.017 and p=0.007, respectively). Similarly, GSTP1 313GG/GC genotypes and the G allele were more frequent in controls, showing a significant association with reduced risk of preeclampsia (p=0.008 and p=0.013, respectively). Our results suggest, for the first time, that the MTHFR 677T and GSTP1 313G polymorphisms confer a significantly decreased risk of developing preeclampsia in the Mexican Maya-Mestizo population.

Reduction of no-reflow and reperfusion injury with the synthetic 17β-aminoestrogen compound Prolame is associated with PI3K/Akt/eNOS signaling cascade.

A high proportion of primary percutaneous coronary interventions performed in the setting of acute myocardial infarction, concur with inadequate myocardial perfusion at the microvascular level. This phenomenon, known as “no-reflow” contributes to reperfusion injury, poor prognosis and to unfavorable clinical outcome. In this study, we evaluated the hypothesis that the synthetic 17β-aminoestrogen Prolame, may confer cardioprotection and prevent against no-reflow. In an open-chest model of 30-min ischemia and 90-min reperfusion, male Wistar rats were randomly assigned to different groups: Control, Prolame, Prolame followed by the nitric oxide synthase inhibitor (l-NAME), and 17β-estradiol. Areas of risk, infarct size and no-reflow were determined by planimetry with triphenyltetrazolium chloride and thioflavin-S stains. Structural damage of the vasculature was measured as capillary compression in clarified tissue after intra-atrial injection of Microfil. Hemodynamic function was obtained at the end of stabilization, ischemia and reperfusion; nitric oxide (NO·) content was determined indirectly using the Griess reaction. Activation of the eNOS signaling cascade was determined by western blot. Prolame reduced the infarcted area, decreased the zones of no-reflow and capillary compression by activating the PI3K/Akt/eNOS signaling pathway in correlation with NO· increase. Prolame also activated endothelial cells augmenting NO· production, which was inhibited by ICI182780 (a selective estrogen receptor down-regulator), supporting the notion that the cardioprotective effect of Prolame involves the preservation of endothelium through the activation of estrogen receptor downstream signaling. Our results provide evidence that Prolame has potential therapeutic application in patients with AMI, as it prevents from both vascular and cardiac tissue damage.

Preotection againstTrichinella spiralis induced by purified stage-specific surface antigens of infective larvae

The stage-specific surface antigens of the infective larvae ofTrichinella spiralis, isolated using an affinity column of monoclonal antibody (Mab) NIM-M1, consisted of four components with molecular weights of 72, 65, 52, and 47 kDa, respectively. These four components may have unique as well as shared structural features and appear to be products of the stichosome. When injected i.p. as an emulsion in complete Freunds adjuvant, the purified antigens induced protection against infection of BALB/c mice withT. spiralis, as assessed by reductions in both the muscle larvae load and the number of adult intestinal worms.

Perturbations in skeletal muscle sarcomere structure in patients with heart failure and Type 2 diabetes: restorative effects of ( − )-epicatechin- rich cocoa

HF (heart failure) and T2D (Type 2 diabetes) associate with detrimental alterations in SkM (skeletal muscle) structure/function. We have demonstrated recently that (-)-ERC (epicatechin-rich cocoa) improves SkM mitochondrial structure [Taub, Ramirez-Sanchez, Ciaraldi, Perkins, Murphy, Naviaux, Hogan, Ceballos, Maisel, Henry et al. (2012) Clin. Trans. Sci. 5, 43-47]. We hypothesized that an improved mitochondrial structure may facilitate the reversal of detrimental alterations in sarcomeric microstructure. In a pilot study, five patients with HF and T2D consumed ERC for 3 months; treadmill testing [VO2max (maximum oxygen consumption)] and SkM biopsies were performed. Western blot analysis, immunohistochemistry and electron microscopy were used. We report severe perturbations in components of the DAPC (dystrophin-associated protein complex) as well as sarcomeric microstructure at baseline. ERC induced recovery/enhancement of DAPC protein levels, sarcomeric microstructure and, in a co-ordinated fashion, alterations in markers of SkM growth/differentiation consistent with myofibre regeneration. VO2max increased (~24%) but did not reach statistical significance. These initial results warrant further rigorous investigation, since the use of ERC (or pure epicatechin) may represent a safe and novel means of improving muscle function.

IMMUNODETECTION ANALYSIS OF MUSCULAR DYSTROPHIES IN MEXICO

Introduction: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fragility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. Methods: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystrophy. Using immunofluorescence staining, we searched for primary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear proteins. In addition, we analyzed calpain‐3 by immunoblot. Results: We identified 212 patients with varying degrees of protein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin‐3, calpain‐3, emerin, and merosin. Moreover, 78 biopsies showed normal expression of all investigated muscle proteins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerinopathies. Deficiencies in lamin A/C and telethonin were not detected. Conclusion: We have described the frequency of common muscular dystrophies in Mexico. Muscle Nerve, 2012

Risk factors and impact on bone mineral density in postmenopausal Mexican mestizo women.

Objective:Considering that the Mexican mestizo population seems to be the result of a genetic admixture, we proposed that further research is needed to evaluate the role of ethnicity in conjunction with health-related factors to better understand ethnic differences in bone mineral density (BMD). The aim of this study was to analyze several risk factors related to the development of osteoporosis in postmenopausal Mexican mestizo women. Methods:We included 567 postmenopausal Mexican mestizo women. A structured questionnaire for risk factors was applied and BMD was measured in total hip and lumbar spine by dual-energy x-ray absorptiometry. Nonconditional logistic regression was used to estimate crude and adjusted odds ratio. Results:Using World Health Organization criteria, 28.7% of postmenopausal women had osteoporosis, 46.4% had osteopenia, and 24.9% had normal BMD. Each clinical risk factor had a different significance for osteopenia/osteoporosis; however, duration of total breast-feeding, body mass index, and number of years since menopause remained significantly associated with osteopenia/osteoporosis after bone density was added to the nonconditional model. Interestingly, extended periods of accumulated breast-feeding for 24 and 36 months were, in both cases, significantly associated with osteopenia/osteoporosis. Conclusions:Our results confirm the importance of considering the duration of breast-feeding as an important risk factor for osteopenia/osteoporosis. In addition, we find that body mass index is positively associated with BMD. Because of the heterogeneity of the Mexican mestizo population, the risk factor for osteoporosis may not be the same in different ethnic groups.

Innate response of human endothelial cells infected with mycobacteria

Endothelial cells are susceptible to infection by several pathogens, but little is known about mycobacterial infection. We analyzed some features of mycobacteria-endothelial cell interactions and the innate response to the infection. Intracellular growth in human umbilical vein endothelial cells (HUVECs) of three Mycobacterium species: M. tuberculosis (MTB), M. abscessus (MAB) and M. smegmatis (MSM) was analyzed. M. smegmatis was eliminated; M. abscessus had an accelerate intracellular replication and M. tuberculosis did not replicate or was eliminated. M. abscessus infection induced profound cytoskeleton rearrangements, with M. tuberculosis infection changes were less marked, and with MSM were slight. Nitric oxide (NO) production was induced differentially: M. abscessus induced the highest levels followed by M. tuberculosis and M. smegmatis; the contrary was true for reactive oxygen species (ROS) production. Only M. tuberculosis infection caused beta-1 defensin over-expression. As a whole, our results describe some aspects of the innate response of HUVEC infected by mycobacteria with different virulence and suggest that a strong cytoskeleton mobilization triggers a high NO production in these cells.

Full-length SRY protein is essential for DNA binding

SRY directs testicular development. It has been suggested that the only high-mobility group (HMG) box of the SRY is important for the function of this protein; however, other studies have suggested that the N- and C-terminal regions are also involved in this process. Herein, we analysed and compared in vitro the DNA-binding activity of the full-length SRY and three mutants (HMG box alone, N-terminal less and C-terminal less SRY proteins). DNA-binding capability was analysed by mobility shift assays, optical density and dissociation constant by using pure non-fusion SRY proteins. The structure of the full-length SRY was carried out using a protein molecular model. The HMG box SRY alone and C-terminal less SRY proteins had a statistically diminished DNA binding in comparison with the full-length SRY. In contrast, the affinity for DNA of the N-terminal less SRY was relatively similar to the full-length SRY. Likewise, three-dimensional structure of the full-length SRY suggested that some residues of the C-terminal region of the SRY interact with DNA. We demonstrate the importance that full-length SRY has, particularly the C-terminal region of the protein, in DNA binding in vitro. Likewise, the affinity of the HMG box alone is clearly reduced when compared with the full-length SRY.