Instituto Nacional Of Medicina Genomica Inmegen

Mexico City, Mexico

Instituto Nacional Of Medicina Genomica Inmegen

Mexico City, Mexico
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Valadez-Cano C.,National Polytechnic Institute of Mexico | Olivares-Hernandez R.,Metropolitan Autonomous University | Resendis-Antonio O.,National Autonomous University of Mexico | Resendis-Antonio O.,Instituto Nacional Of Medicina Genomica Inmegen | And 2 more authors.
BMC Evolutionary Biology | Year: 2017

Background: Genome degradation of host-restricted mutualistic endosymbionts has been attributed to inactivating mutations and genetic drift while genes coding for host-relevant functions are conserved by purifying selection. Unlike their free-living relatives, the metabolism of mutualistic endosymbionts and endosymbiont-originated organelles is specialized in the production of metabolites which are released to the host. This specialization suggests that natural selection crafted these metabolic adaptations. In this work, we analyzed the evolution of the metabolism of the chromatophore of Paulinella chromatophora by in silico modeling. We asked whether genome reduction is driven by metabolic engineering strategies resulted from the interaction with the host. As its widely known, the loss of enzyme coding genes leads to metabolic network restructuring sometimes improving the production rates. In this case, the production rate of reduced-carbon in the metabolism of the chromatophore. Results: We reconstructed the metabolic networks of the chromatophore of P. chromatophora CCAC 0185 and a close free-living relative, the cyanobacterium Synechococcus sp. WH 5701. We found that the evolution of free-living to host-restricted lifestyle rendered a fragile metabolic network where >80% of genes in the chromatophore are essential for metabolic functionality. Despite the lack of experimental information, the metabolic reconstruction of the chromatophore suggests that the host provides several metabolites to the endosymbiont. By using these metabolites as intracellular conditions, in silico simulations of genome evolution by gene lose recover with 77% accuracy the actual metabolic gene content of the chromatophore. Also, the metabolic model of the chromatophore allowed us to predict by flux balance analysis a maximum rate of reduced-carbon released by the endosymbiont to the host. By inspecting the central metabolism of the chromatophore and the free-living cyanobacteria we found that by improvements in the gluconeogenic pathway the metabolism of the endosymbiont uses more efficiently the carbon source for reduced-carbon production. In addition, our in silico simulations of the evolutionary process leading to the reduced metabolic network of the chromatophore showed that the predicted rate of released reduced-carbon is obtained in less than 5% of the times under a process guided by random gene deletion and genetic drift. We interpret previous findings as evidence that natural selection at holobiont level shaped the rate at which reduced-carbon is exported to the host. Finally, our model also predicts that the ABC phosphate transporter (pstSACB) which is conserved in the genome of the chromatophore of P. chromatophora strain CCAC 0185 is a necessary component to release reduced-carbon molecules to the host. Conclusion: Our evolutionary analysis suggests that in the case of Paulinella chromatophora natural selection at the holobiont level played a prominent role in shaping the metabolic specialization of the chromatophore. We propose that natural selection acted as a “metabolic engineer” by favoring metabolic restructurings that led to an increased release of reduced-carbon to the host. © 2017 The Author(s).

PubMed | Hospital Juarez Of Mexico, Instituto Nacional Of Medicina Genomica Inmegen and Instituto Nacional Of Ciencias Medicas Y Nutricion Salvador Zubiran
Type: Journal Article | Journal: PloS one | Year: 2017

The effect of interleukin 33 (IL-33) in the inflammatory process generates significant interest in the potential significance of IL-33 as a biomarker for coronary artery disease (CAD). Here, our objective was to analyze whether IL-33 gene polymorphisms are associated with premature CAD in a case-control association study.Four IL-33 polymorphisms (rs7848215, rs16924144, rs16924159 and rs7044343) were genotyped by 5 exonuclease TaqMan assays in 1095 patients with premature CAD and 1118 controls.The rs7044343 T allele was significantly associated with a diminished risk of premature CAD (OR = 0.81, 95% CI: 0.69-0.97, Pdom = 0.020; OR = 0.85, 95% CI: 0.75-0.96, Padd = 0.019) and central obesity (OR = 0.74, 95% CI: 0.58-0.93, Pdom = 0.0007), respectively. When patients were divided into groups with and without type 2 diabetes mellitus (T2DM), the rs7044343 T allele was associated with a reduced risk of premature CAD in patients without (OR = 0.85, 95% CI: 0.73-0.99, Padd = 0.038) and with T2DM (OR = 0.61, 95% CI: 0.38-0.97, Pdom = 0.039; OR = 0.69, 95% CI: 0.49-0.97, Padd = 0.035). In order to establish the functional effect of the rs7044343 polymorphism, the production of IL-33 was determined in monocytes of selected individuals. Monocytes from individuals with rs7044343 CC genotype produced higher levels of IL-33 than monocytes from individuals with other genotypes.The results suggest that the IL-33 rs7044343 T allele could be a susceptibility marker for premature CAD and central obesity. The rs7044343 polymorphism could be involved in regulating the production of IL-33.

Binia A.,Nestlé | Contreras A.V.,Instituto Nacional Of Medicina Genomica Inmegen | Canizales-Quinteros S.,National Autonomous University of Mexico | Alonzo V.A.,Molecular Genetics Laboratory | And 2 more authors.
Genes and Nutrition | Year: 2014

High levels of plasma homocysteine are associated with an increased risk of many health conditions influenced by both environmental and genetic factors. The objective of this study was to provide the geographical distribution of folate pathway genetic polymorphisms in Mexico and the comparison with the reported frequencies in different continental populations. This study included the analysis of the genotypic frequencies of eight polymorphisms in genes of the folate/homocysteine metabolic pathway in 1,350 Mestizo and Amerindian subjects from different regions in Mexico and 836 individuals from European, African and Asian populations of the 1,000 Genomes Project. In Mexican Mestizo and Amerindian populations, the MTHFR C677T risk genotype (TT) was highly prevalent (frequency: 25 and 57 %, respectively). In Mestizos, the frequency showed clear regional variation related to ancestry; the Guerrero subpopulation with the highest Amerindian contribution had the highest TT frequency (33 %). The MTHFD1 G1958A AA risk genotype was also enriched in Mexican Mestizos and Amerindians (frequency: 34 and 58 %, respectively), whereas in African and Asian ancestry populations the frequency for AA was low (~4 %). All together risk genotypes showed regional differences, and Sonora had significantly different genetic frequencies compared with the other regions (P value <0.05). Our study illustrates differential geographical distribution of the risk variants in the folate/homocysteine metabolic pathway relative to ethnic background. This work supports that certain areas of the world have increased needs for folic acid and vitamin B supplementation, and this information needs to be considered in public health guidelines and eventually policies. © 2014, The Author(s).

Rivera-Chavez J.,National Autonomous University of Mexico | Gonzalez-Andrade M.,Instituto Nacional Of Medicina Genomica Inmegen | Del Carmen Gonzalez M.,National Autonomous University of Mexico | Glenn A.E.,U.S. Department of Agriculture | Mata R.,National Autonomous University of Mexico
Phytochemistry | Year: 2013

Bioassay-guided fractionation of the bio-active organic extract obtained from solid-media culture of MEXU 27095, an endophytic fungus isolated from the Mexican medicinal plant Hintonia latiflora (Rubia-ceae), led to separation of three tridepsides which were identified as thielavins A, J and K. All three compounds inhibited Saccharomyces cerevisieae α-glucosidase (αGHY) in a concentration-dependent manner with IC50 values of 23.8, 15.8, and 22.1 μM, respectively. Their inhibitory action was higher than that of acarbose (IC50 = 545 μM), used as a positive control. Kinetic analysis established that the three compounds acted as non-competitive inhibitors with ki values of 27.8, 66.2 and 55.4 μM, respectively (α= 1.0, 1.2, 0.7, respectively); acarbose behaved as competitive inhibitor with a ki value of 156.1 μM. Thielavin J inhibited the activity of a-glucosidase from Bacillus stearothermophilus (aGHBs) with an IC50 of 30.5 μM, being less active than acarbose (IC50 = 0. 015 μM); in this case, compound (2) (ki = 20.0 μM and α = 2.9) and acarbose (ki = 0.008 μM and α = 1.9) behaved as non-competitive inhibitors. Docking analysis predicted that all three thielavins and acarbose bind to homologated αGHBs and to αGHY (PDB: 3A4A) in a pocket close to the catalytic site for maltose and isomaltose, respectively. The α-gluco-sidase inhibitory properties of thielavin K (3) were corroborated in vivo since it induced a noted antihy-perglycemic action during an oral sucrose tolerance test (3.1, 10.0 and 31.6mg/kg) in normal and nicotinamide-streptozotocin diabetic mice. In addition, at a dose of 10 mg/kg, it provoked a moderate hypoglycemic activity in diabetic mice. © 2013 Elsevier Ltd. All rights reserved.

Borgonio Cuadra V.M.,Instituto Nacional Of Rehabilitacion Inr | Gonzalez-Huerta N.C.,Instituto Nacional Of Rehabilitacion Inr | Romero-Cordoba S.,Instituto Nacional Of Medicina Genomica Inmegen | Hidalgo-Miranda A.,Instituto Nacional Of Medicina Genomica Inmegen | Miranda-Duarte A.,Instituto Nacional Of Rehabilitacion Inr
PLoS ONE | Year: 2014

Objective: To analyze a set of circulating microRNA (miRNA) in plasma from patients with primary Osteoarthritis (OA) and describe the biological significance of altered miRNA in OA based on an in silico analysis of their target genes. Methods: miRNA expression was analyzed using TaqMan Low Density Arrays and independent assays. The search for potential messenger RNA (mRNA) targets of the differentially expressed miRNA was performed by means of the miRWalk and miRecords database; we conducted the biological relevance of the predicted miRNA targets by pathway analysis with the Reactome and DAVID databases. Results: We measured the expression of 380 miRNA in OA; 12 miRNA were overexpressed under the OA condition (p value, ≤0.05; fold change, >2). These results were validated by the detection of some selected miRNA by quantitative PCR (qPCR). In silico analysis showed that target messenger RNA (mRNA) were potentially regulated by these miRNA, including genes such as SMAD1, IL-1B, COL3A, VEGFA, and FGFR1, important in chondrocyte maintenance and differentiation. Some metabolic pathways affected by the miRNA: mRNA ratio are signaling Bone morphogenetic proteins (BMP), Platelet-derived growth factor (PDGF), and Nerve growth factor (NGF), these latter two involved in the process of pain. Conclusions: We identified 12 miRNA in the plasma of patients with primary OA. Specific miRNA that are altered in the disease could be released into plasma, either due to cartilage damage or to an inherent cellular mechanism. Several miRNA could regulate genes and pathways related with development of the disease; eight of these circulating miRNA are described, to our knowledge, for first time in OA. © 2014 Borgonio Cuadra et al.

Resendis-Antonio O.,Instituto Nacional Of Medicina Genomica Inmegen | Gonzalez-Torres C.,Instituto Nacional Of Medicina Genomica Inmegen | Jaime-Munoz G.,Instituto Nacional Of Medicina Genomica Inmegen | Jaime-Munoz G.,National Autonomous University of Mexico | And 4 more authors.
Seminars in Cancer Biology | Year: 2015

Given the multi-factorial nature of cancer, uncovering its metabolic alterations and evaluating their implications is a major challenge in biomedical sciences that will help in the optimal design of personalized treatments. The advance of high-throughput technologies opens an invaluable opportunity to monitor the activity at diverse biological levels and elucidate how cancer originates, evolves and responds under drug treatments. To this end, researchers are confronted with two fundamental questions: how to interpret high-throughput data and how this information can contribute to the development of personalized treatment in patients. A variety of schemes in systems biology have been suggested to characterize the phenotypic states associated with cancer by utilizing computational modeling and high-throughput data. These theoretical schemes are distinguished by the level of complexity of the biological mechanisms that they represent and by the computational approaches used to simulate them. Notably, these theoretical approaches have provided a proper framework to explore some distinctive metabolic mechanisms observed in cancer cells such as the Warburg effect. In this review, we focus on presenting a general view of some of these approaches whose application and integration will be crucial in the transition from local to global conclusions in cancer studies. We are convinced that multidisciplinary approaches are required to construct the bases of an integrative and personalized medicine, which has been and remains a fundamental task in the medicine of this century. © 2014 The Authors.

Hernandez Patino C.E.,National Autonomous University of Mexico | Jaime-Munoz G.,National Autonomous University of Mexico | Resendis-Antonio O.,Instituto Nacional Of Medicina Genomica Inmegen
Frontiers in Physiology | Year: 2013

One of the main objectives in systems biology is to understand the biological mechanisms that give rise to the phenotype of a microorganism by using high-throughput technologies (HTs) and genome-scale mathematical modeling. The computational modeling of genome-scale metabolic reconstructions is one systemic and quantitative strategy for characterizing the metabolic phenotype associated with human diseases and potentially for designing drugs with optimal clinical effects. The purpose of this short review is to describe how computational modeling, including the specific case of constraint-based modeling, can be used to explore, characterize, and predict the metabolic capacities that distinguish the metabolic phenotype of cancer cell lines. As we show herein, this computational framework is far from a pure theoretical description, and to ensure proper biological interpretation, it is necessary to integrate high-throughput data and generate predictions for later experimental assessment. Hence, genome-scale modeling serves as a platform for the following: (1) the integration of data from HTs, (2) the assessment of how metabolic activity is related to phenotype in cancer cell lines, and (3) the design of new experiments to evaluate the outcomes of the in silico analysis. By combining the functions described above, we show that computational modeling is a useful methodology to construct an integrative, systemic, and quantitative scheme for understanding the metabolic profiles of cancer cell lines, a first step to determine the metabolic mechanism by which cancer cells maintain and support their malignant phenotype in human tissues. © 2013 Hernández Patiño, Jaime-Muñoz and Resendis-Antonio.

Gonzalez-Covarrubias V.,Leiden University | Gonzalez-Covarrubias V.,Instituto Nacional Of Medicina Genomica Inmegen
Biogerontology | Year: 2013

The role of classical lipids in aging diseases and human longevity has been widely acknowledged. Triglyceride and cholesterol concentrations are clinically assessed to infer the risk of cardiovascular disease while larger lipoprotein particle size and low triglyceride levels have been identified as markers of human longevity. The rise of lipidomics as a branch of metabolomics has provided an additional layer of accuracy to pinpoint specific lipids and its association with aging diseases and longevity. The molecular composition and concentration of lipid species determine their cellular localization, metabolism, and consequently, their impact in disease and health. For example, low density lipoproteins are the main carriers of sphingomyelins and ceramides, while high density lipoproteins are mostly loaded with ether phosphocholines, partly explaining their opposing roles in atherogenesis. Moreover, the identification of specific lipid species in aging diseases and longevity would aid to clarify how these lipids alter health and influence longevity. For instance, ether phosphocholines PC (O-34:1) and PC (O-34:3) have been positively associated with longevity and negatively with diabetes, and hypertension, but other species of phosphocholines show no effect or an opposite association with these traits confirming the relevance of the identification of molecular lipid species to tackle our understanding of healthy aging and disease. Up-to-date, a minor fraction of the human plasma lipidome has been associated to healthy aging and longevity, further research would pinpoint toward specific lipidomic profiles as potential markers of healthy aging and metabolic diseases. © 2013 Springer Science+Business Media Dordrecht.

Medina-Urrutia A.,National Institute of Cardiology Ignacio Chavez | Posadas-Romero C.,National Institute of Cardiology Ignacio Chavez | Posadas-Sanchez R.,National Institute of Cardiology Ignacio Chavez | Jorge-Galarza E.,National Institute of Cardiology Ignacio Chavez | And 6 more authors.
Cardiovascular Diabetology | Year: 2015

Background: Experimental studies have shown that high free fatty acid (FFA) and low adiponectin (ADIPO) levels are involved in the mechanisms by which adiposity promotes insulin resistance (IR). However, no previous clinical studies have simultaneously analysed the relative contribution of FFA and ADIPO levels on the relation of abdominal visceral fat (AVF) with insulin resistance. Objective: To analyse the contribution of low ADIPO (adiponectin<=p25th: 8.67μg/mL in women and 5.30μg/mL in men), and high FFAs (FFAs>=p75th: 0.745mEq/L in women and 0.60mEq/L in men) to the association of high AVF (AVF>=p75th: 127cm2 in women; 152.7cm2 in men) with insulin resistance (HOMA-IR>=75th: 3.58 in women and 3.12 in men), in non-diabetic subjects. Material and methods: A cross-sectional analysis was performed including 1217 control participants of the Genetics of Atherosclerotic Disease study (GEA). Clinical, tomographic and biochemical parameters were measured in all participants. Logistic regression models were used to assess the association of high AVF with IR stratifying according to gender, and to normal or low ADIPO and normal or high FFA serum levels. Results: In comparison to referent group, in men low ADIPO unlike high FFA increased the risk of IR. Females with normal AVF and low ADIPO, or high AVF and normal ADIPO had aprox 3 folds risk of IR (OR [IC95%]: 3.7 [2.1-6.6], p<0.001, and 3.4 [2.0-5.7], p<0.001; respectively). The risk increased to 7.6 [4.2-13.8], p<0.001 when high AVF and low ADIPO were present. Irrespective of AVF, the effect of low ADIPO on IR was higher than that seen for high FFA. Besides, our results suggest an additive effect of high AVF, high FFA and low ADIPO on the IR prevalence. Conclusions: The present study provides novel and important information about the combined effect of high AVF and low ADIPO on the risk of IR. Furthermore, our data suggest that the effect of low adiponectin levels on the high AVF-IR association is stronger than that observed for high FFA, suggesting that adiponectin could be used as biomarker to identify subjects at high risk for T2DM and CAD. © 2015 Medina-Urrutia et al.

Zacapala-Gomez A.E.,Autonomous University of Guerrero | Del Moral-Hernandez O.,Autonomous University of Guerrero | Villegas-Sepulveda N.,CINVESTAV | Hidalgo-Miranda A.,Instituto Nacional Of Medicina Genomica Inmegen | And 5 more authors.
Virology | Year: 2016

We analyzed the effects of the expression of HPV 16 E6 oncoprotein variants (AA-a, AA-c, E-A176/G350, E-C188/G350, E-G350), and the E-Prototype in global gene expression profiles in an in vitro model. E6 gene was cloned into an expression vector fused to GFP and was transfected in C33-A cells. Affymetrix GeneChip Human Transcriptome Array 2.0 platform was used to analyze the expression of over 245,000 coding transcripts. We found that HPV16 E6 variants altered the expression of 387 different genes in comparison with E-Prototype. The altered genes are involved in cellular processes related to the development of cervical carcinoma, such as adhesion, angiogenesis, apoptosis, differentiation, cell cycle, proliferation, transcription and protein translation. Our results show that polymorphic changes in HPV16 E6 natural variants are sufficient to alter the overall gene expression profile in C33-A cells, explaining in part the observed differences in oncogenic potential of HPV16 variants. © 2015 The Authors.

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