Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases.

Epigenetics affects gene expression and contributes to disease development by alterations known as epimutations. Hypermethylation that results in transcriptional silencing of tumor suppressor genes has been described in patients with hereditary cancers and without pathogenic variants in the coding region of cancer susceptibility genes. Although somatic promoter hypermethylation of these genes can occur in later stages of the carcinogenic process, constitutional methylation can be a crucial event during the first steps of tumorigenesis, accelerating tumor development. Primary epimutations originate independently of changes in the DNA sequence, while secondary epimutations are a consequence of a mutation in a cis or trans-acting factor. Secondary epimutations have a genetic basis in cis of the promoter regions of genes involved in familial cancers. This highlights epimutations as a novel carcinogenic mechanism whose contribution to human diseases is underestimated by the scarcity of the variants described. In this review, we provide an overview of secondary epimutations and present evidence of their impact on cancer. We propose the necessity for genetic screening of loci associated with secondary epimutations in familial cancer as part of prevention programs to improve molecular diagnosis, secondary prevention, and reduce the mortality of these diseases.

Applied genomic in cerebrovascular disease / Genómica funcional en la enfermedad vascular cerebral

Abstract Cerebrovascular disease involve the alterations caused by pathology process of the sanguineous vessels, affecting one or many brain areas. Cerebrovascular disease is also known like stroke or ictus; it is the third cause of death around the world and is the neurologic pathology with the most prevalence rate. Cerebrovascular disease induces several changes in genetic expression inside the neurovascular unit (glia cells, neurons and ependymal cells); principally, changes in the oxidative stress and calcium inflow into the cells, this could start cellular death and tissue destruction, causing an irreversible injury in brain, losing several functions. The injury causes the activation of signaling pathways to respond to the stress, where many molecules such as proteins and mRNA are involved to act as intermediaries to activate or deactivate stress mechanisms; these molecules are able to transmit extracellular signals into the nucleus activating early gene expression like proto-oncogenes and several transcription factors to repair the cerebral injury. It is important to know the relation of the changes in genetic expression and proteins to avoid the development of injury and to activate the brain recovery. This knowledge let us diagnose the injury rate and propose therapeutic mechanisms to reduce or avoid the adverse effects on time, before the cellular death start.

Resumen Las enfermedades cerebrovasculars implican las alteraciones causadas por el proceso patológico de los vasos sanguíneos, que afectan a una o varias áreas del cerebro. La enfermedad cerebro-vascular también se conoce como ictus o ictus; Es la tercera causa de muerte en todo el mundo y es la patología neurológica con mayor tasa de prevalencia. La enfermedad cerebrovascular induce varios cambios en la expresión genética dentro de la unidad neurovascular (células gliales, neuronas y células ependimales); Principalmente, los cambios en el estrés oxidativo y la entrada de calcio en las células, podrían iniciar la muerte celular y la destrucción del tejido, causando una lesión irreversible en el cerebro, perdiendo varias funciones. La lesión hace que la activación de las vías de señalización responda al estrés, donde muchas moléculas, como las proteínas y el ARNm, actúan como intermediarios para activar o desactivar los mecanismos de estrés; estas moléculas son capaces de transmitir señales extracelulares en el núcleo activando la expresión génica temprana como protooncogenes y varios factores de transcripción para reparar la lesión cerebral. Es importante conocer la relación de los cambios en la expresión genética y las proteínas para evitar el desarrollo de lesiones y activar la recuperación del cerebro. Este conocimiento nos permite diagnosticar la tasa de lesiones y proponer mecanismos terapéuticos para reducir o evitar los efectos adversos a tiempo, antes de que comience la muerte celular.

Influence of chronic food deprivation on structure-function relationship of juvenile rat fast muscles.

In the present study, we analyze the influence of chronic undernutrition on protein expression, muscle fiber type composition, and fatigue resistance of the fast extensor digitorum longus (EDL) muscle of male juvenile rats (45 ± 3 days of life; n = 25 and 31 rats for control and undernourished groups, respectively). Using 2D gel electrophoresis and mass spectrometry, we identified in undernourished muscles 12 proteins up-regulated (8 proteins of the electron transport chain and the glycolytic pathway, 2 cross-bridge proteins, chaperone and signaling proteins that are related to the stress response). In contrast, one down-regulated protein related to the fast muscle contractile system and two other proteins with no changes in expression were used as charge controls. By means of COX and alkaline ATPase histochemical techniques and low-frequency fatigue protocols we determined that undernourished muscles showed a larger proportion (15% increase) of Type IIa/IId fibers (oxidative-glycolytic) at the expense of Type IIb (glycolytic) fibers (15.5% decrease) and increased fatigue resistance (55.3%). In addition, all fiber types showed a significant reduction in their cross-sectional area (slow: 64.4%; intermediate: 63.9% and fast: 61.2%). These results indicate that undernourished EDL muscles exhibit an increased expression of energy metabolic and myofibrillar proteins which are associated with the predominance of oxidative and Type IIa/IId fibers and to a higher resistance to fatigue. We propose that such alterations may act as protective and/or adaptive mechanisms that counterbalance the effect of chronic undernourishment.

Plasmodium berghei: effect of protease inhibitors during gametogenesis and early zygote development.

Plasmodium berghei: The effect of five protease inhibitors, TPCK, TLCK, PMSF, leupeptin, and 1,10-phenanthroline on in vitro gametogenesis and early zygote development of P. berghei was investigated. PMSF and leupeptin showed no effect. Cysteine/serine protease inhibitors TPCK/TLCK at concentrations of 75 and 100 microM were effective on inhibiting exflagellation center formation, and this effect was reversible with the addition of l-cysteine. Exflagellation center formation was most effectively blocked by 1,10-phenanthroline (1mM), and exflagellation center numbers were restored by the addition of Zn(2+). A reduction of ookinete production was observed when TPCK/TLCK (100 microM) was added at 2h after gametogenesis, but no effect was observed with 1,10-phenanthroline (1mM). Our results suggest that proteolysis is important in both gametocyte activation and sexual development of P. berghei.

EGP-314 is expressed differentially in three brain zones at an early time in an experimentally induced ischemia rat model.

Gene expression in frontal, occipital, and hippocampal regions of rat brains at 15 min of ischemic injury was studied in a rat model by producing focal cerebral ischemia through middle cerebral artery (MCA) occlusion without reperfusion. Catalase, epithelial glycoprotein (EGP-314), cytochrome C oxidase-subunit 1, ribosomal L31 protein, and ceruloplasmin were found to be differentially expressed. Specific primers were designed to study this newly reported brain EGP-314, a cellular adhesion molecule involved in cell-cell and cell-extracellular matrix interactions and related with cytoskeletal organization, differentiation, and proliferation. In the frontal and occipital lobes, EGP-314 expression was low in control and ischemic conditions and increased in sham injured conditions, whereas in the hippocampal region its expression was induced only by ischemia. In situ hybridization and immunohistochemistry revealed that EGP-314 mRNA and the protein were present in the ischemic hippocampus pyramidal neurons. DNA fragmentation was demonstrated by TUNEL and LM-PCR analysis in hippocampus region. TUNEL positive pyramidal neurons were observed at 15 min of ischemia. DNA ladder was found at 12 and 15 min of ischemia.