Medicina molecular y genética

Myeloproliferative neoplasms (MPN) are chronic hematological neoplasms arising from the accumulation of genetic mutations in hematopoietic stem cells (HSCs). This notion is supported by genomic studies on MPN patients, in which recurrent mutations on genes such as JAK2, CALR, and MPL have been identified. Interestingly, recent studies using MPN mouse models have demonstrated that the HSC niche, where HSCs are located and maintained in the bone marrow (BM), plays an important role in MPN initiation and progression. Changes in the BM microenvironment alone can serve as a driver for altered hematopoiesis and hematological malignancies. Additionally, during MPN progression mutant HSCs remodel the HSC niche into a hospitable microenvironment for themselves that accelerates disease progression, creating a positive feedback loop where mutant HSCs thrive, and continue to alter the BM microenvironment to their advantage. In an attempt to provide a fresh perspective in understanding MPN pathogenesis, this review highlights the studies conducted that explore the role of the HSC niche in MPN pathogenesis and progression.

There was evidence of genetic susceptibility to poliomyelitis, but in the mid 1930's that evidence and the idea of genetic susceptibility disappeared from the literature and the collective research psyche. Alternative hypotheses, not amenable to test, were adopted but seldom formulated. Subsequent evidence for genetic susceptibility was ignored. I suggest that the ill-fated vaccine trials in 1935 presented a psychological watershed for researchers. The later vaccines owed their success to unwritten and untested hypotheses: genetic susceptibility might have been an insuperable barrier to testing vaccines in children. Now that eradication is probable, new research suggests that many people may be susceptible to paralysis and that plans must be made for possible reappearance of the disease.

Colon diseases are more common in the world with an increasing trend. Despite the different etiology and physiology, the epithelial-mesenchymal transition (EMT), is crucial during transformation, migration and invasive ability of colon cancer cells. Several genes are implicated in the control of EMT (Wnt, Notch, Src, Ras, etc.). The homeobox genes are a transcription factor family, they are arranged in several classes. Class I homeobox genes (Hox in mice and HOX in humans), are 39 transcription factors, mainly involved in the regulation of embryonic development program. In the present study, we have analyzed the expression of HOX genes, during tumor cell lines differentiation (CaCo2) and compared with the expression of HOX gene network, in the normal intestinal mucosa

Many human diseases arise as the result of DNA mutations in the patient’s genome. The neurodevelopmental diseases of early childhood have proven difficult to model due to lack of access to embryonic tissue and ethical concerns. Federal restrictions on the use of embryonic material also preclude studying some stages of neurodevelopmental disease. The onset of illness in utero or early childhood is frequently preceded by normal development of critical milestones. Recent work has led to methodologies to transform somatic cells to embryoniclike stem cells using four exogenous transcription factors. With this approach, it is now possible to validate the use of human induced pluripotent stem cells (hiPSCs) to model aspects of neurodevelopmental diseases using a patient’s donated cells or genome editing of hiPSC cells to contain known disease mutations. The reprogramming of somatic cells to hiPSC requires dedifferentiation and resetting of epigenetic signatures in the genome. The newest approaches are evaluating propagating the cells in three dimensions on artificial matrices to recapitulate regional neural cyto-architecture within the brain. Newer genome editing techniques that rely on site-specific sequence recognition by synthetic enzymes can be used to generate hiPSC neurodevelopmental disease models. A hiPSC disease model has several advantages, the patient’s own cells may be transduced to provide the investigative cell model and compared to other patient’s cells with the same disease. Additionally, a hiPSC model addresses some of the concerns about gene engineered animal models accurately recapitulating human disease since the model context is a patient-specific human cell line. Here we review the emerging use of hiPSC to model neurodevelopmental diseases.

Tuberculosis (TB) is a world-leading infectious disease caused by Mycobacterium tuberculosis (Mtb). The current treatment lasts 6 months and has contributed to the development of multidrug resistant (MDR) strains that nowadays cause almost half a million deaths around the globe. Forty years of research have rendered only 1 new drug to treat the new MDR strains. In the current review we present emerging trends to treat TB particularly focused on natural and synthetic peptides. The ability of some of these peptides to display multifunctional roles in TB treatment, particularly immune system modulation through autophagy and direct antimicrobial activity against Mtb, may present advantages to control the impact of this disease. We review the mechanisms of action relevant in the development of multifunctional peptides that may lead to evaluate new ways to treat TB, a disease that has accompanied human society for centuries

Williams-Beuren syndrome is the consequence of a large contiguous-gene deletion on the seventh human chromosome that includes the elastin gene. Elastin is an extracellular matrix protein responsible for the cardiovascular abnormalities associated with Williams’s syndrome, including hypertension and aortic stenosis. A high percentage of individuals with Williams’s syndrome also have impaired glucose tolerance, independent of traditional risk factors for diabetes. Here, we show that murine adipose tissue does assemble elastic fibers; however, isolated elastin insufficiency (Eln+/-) in mice does not independently influence glucose metabolism or tissue lipid accumulation. Similarly, isolated ApoE deficiency (ApoE-/-), a model of hyperlipidemia and atherosclerosis, does not impair insulin sensitivity. However, Eln+/-; ApoE-/- double mutant mice exhibit notable hyperglycemia, adipocyte hypertrophy, inflammation of adipose tissue, and ectopic lipid accumulation in liver tissue. Further, Eln+/-; ApoE-/- mutants have significant impairment of insulin sensitivity by insulin tolerance testing, independent of body weight or diet, suggesting that elastin insufficiency predisposes to metabolic disease in susceptible individuals.

La diabetes tipo 1 (DT1) es el resultado de una destrucción progresiva de las células β secretoras de insulina con una dependencia de por vida consecutiva a la insulina exógena. Para evitar la destrucción masiva de células β en la etapa terminal mediante estrategias de prevención primaria y secundaria es necesario comprender los eventos moleculares iniciales que conducen a la insulinaopenia. Aunque la desregulación autoinmune es predominante en la DT1, se han identificado factores predisponentes ambientales y genéticos que en parte explican la heterogeneidad de la enfermedad. El uso de bases de datos de pacientes y el desarrollo de nuevas tecnologías para el cribado genético ayudarán a identificar a los individuos en riesgo en la población general o en familias con hermanos afectados. En este artículo, analizamos los últimos avances en la identificación de los determinantes genéticos de la DT1 y su uso para la evaluación del riesgo de la enfermedad.

Se estima que las enfermedades mitocondriales afectan a 1 de cada 5.000-10.000 nacidos vivos. En la actualidad, no existe cura para las enfermedades mitocondriales y los tratamientos actuales se limitan a reducir los síntomas y retrasar la progresión de la enfermedad. La prevención de la transmisión de enfermedades mitocondriales es de vital importancia para los padres con una enfermedad mitocondrial que desean tomar decisiones reproductivas informadas. Este artículo proporciona una evaluación crítica de las diversas técnicas establecidas y experimentales involucradas en la prevención y el tratamiento de la enfermedad del mtADN a nivel de la línea germinal, incluida la fertilización con ovocitos de donantes, el diagnóstico genético preimplantacional, el muestreo de vellosidades coriónicas. , la amniocentesis, la transferencia citoplasmática, la transferencia de vesículas germinales, la transferencia pronuclear y la transferencia de complejos huso-cromosómicos; las dos últimas de las cuales han sido respaldadas públicamente por la Autoridad de Fertilización Humana y Embriología del Reino Unido en 2014 como métodos potenciales útiles y seguros para la prevención de la transmisión de enfermedades graves del mtADN.

El inhibidor del activador del plasminógeno-1 (PAI-1; SERPINE1) es un miembro de la superfamilia de inhibidores de la serina proteasa (SERPIN) y el inhibidor fisiológico predominante de los activadores del plasminógeno de tipo tisular (tPA) y de la uroquinasa. (UPA). Este sistema restringe de manera efectiva, tanto espacial como temporal, la conversión del plasminógeno en plasmina, regulando así la remodelación estromal fisiológica y patofisiológica. La desregulación de esta cascada con frecuencia produce anomalías en la respuesta de reparación tisular. Los niveles elevados de PAI-1 son un factor causal en varias formas de enfermedad vascular y síndromes fibróticos tisulares. Independientemente de su papel en la proteólisis, el PAI-1 estimula la motilidad celular al interactuar con la proteína relacionada con el receptor de lipoproteínas de baja densidad-1 (LRP1), activando varias vías de señalización celular. El PAI-1 también regula la disponibilidad de las integrinas de la superficie celular al promover su endocitosis de una manera dependiente de LRP-1 a través de los complejos PAI-1/uPA/uPAR (receptor uPA)/LRPI/integrina. Este proceso afina el control especial de la proteólisis pericelular y la cadencia general de desprendimiento/readhesión celular requerida para una migración celular eficiente. Estos datos sugieren que el PAI-1 modula la motilidad celular en varios contextos, tanto a través de sus propiedades antiproteolíticas establecidas como como iniciador de la señalización.

El estrés oxidativo es un factor importante que contribuye a una variedad de enfermedades neurodegenerativas y vasculares. La evaluación in vitro de una especie reactiva de óxido de nitrógeno (RNOS) oxidante principal utilizando dihidrorodamina 123 (DHR 123) es un ensayo útil para cuantificar las especies reactivas de oxígeno en una célula. DHR 123, un colorante láser no fluorescente, penetra libremente en la membrana celular y tiñe las mitocondrias. La densidad de la tinción varía con el nivel de peroxinitrito (O=NOO-); como resultado de la interacción del anión superóxido (O2-) y el óxido nítrico (NO). La fluorescencia se lee utilizando un espectrofotómetro. Las células se siembran en una placa de 24 o 96 pocillos y se agrega la solución de trabajo DHR 123 después del tratamiento apropiado. La fluorescencia se lee después de 60 minutos de incubación a 485/528 nm con un espectrofotómetro. Este ensayo es más sensible y forma un producto final estable que otros ensayos comparables y tarda 90 minutos en completarse.