Una lectura de la neurobiología actual desde la antropología trascendental de Leonardo Polo

La noción poüana de "potencia formal" permite teorizar los datos de las neurociencias. El cerebro constituye una unidad funcional con dinámica epigenética que armoniza múltiples y diversas funciones, en orden al conocimiento, en orden a lo tendencial, a lo motor, etc., porque existe una "función unitaria de conexión". La unidad no es fija sino que esta función armoniza las variaciones, interrupciones y comienzos. La regulación de la dinámica funcional, que indetermina y libera las estructuras psíquicas humanas del automatismo neurológico, supone el frenado intrínseco de los flujos de información cognitiva y emocional de los procesos neuronales. Se describe la integración de áreas cognitivas-afectivas de los circuitos que permiten evaluar la información sensorial, elaborar la respuesta en relación con los demás, o tomar decisiones. Tal función reguladora de la integración dinámica de las múltiples facultades cerebrales se ejerce en la cúspide de la jerarquía del sistema nervioso, la corteza cerebral, especialmente el lóbulo frontal

La investigación con células troncales y la creatividad científica

La descripción del itinerario investigador de la biología de las células troncales permite una reflexión sobre la racionalidad de la creatividad científica. En 1998 aparecieron las células troncales procedentes de embriones humanos. Inmediatamente llegaron, motivadas por razones ideológicas, políticas y económicas, las especulaciones sobre sus posibilidades terapéuticas. Pero las dificultades para su uso médico resultaron insuperables. En 2007 aparecieron las células troncales humanas de pluripotencialidad inducida (iPS). Esta trayectoria investigadora revela aspectos claves del pensamiento creativo en ciencia: a) La importancia de la motivación ética para encontrar un punto de partida no destructivo que marca la racionalidad del camino: los procesos fisiológicos ocurren en la unidad de un organismo vivo. b) La necesidad de un conocimiento profundo de la experiencia científica acumulada para escoger la vía más natural. c) La visión de futuro que agota las posibilidades que ofrecen las pruebas en animales, y que encuentra aplicaciones útiles a los conocimientos que se van obteniendo. d) La imprescindible responsabilidad sobre las consecuencias.Human Embryonic Stem Cells were discovered in 1998 and many speculations arose about their therapeutic possibilities, motivated by ideological, political and economic aspects. The difficulties were insurmountable. However, induced Pluripotent Stem Cells appeared in 2007 and this research trajectory showed key aspects of creative thinking. a) Motivation ethics to find a nondestructive starting point to mark the rationality of that way: the physiological processes occur within the unit of an organism. b) A thorough knowledge of the scientific experience to choose the most natural way. c) Future vision exhausting possibilities offered by animal testing and finding useful applications for the knowledge obtained. d) Responsibility for the consequences

Differential hypertrophic effects of cardiotrophin-1 on adult cardiomyocytes from normotensive and spontaneously hypertensive rats

Cardiotrophin-1 (CT-1) produces longitudinal elongation of neonatal cardiomyocytes, but its effects in adult cardiomyocytes are not known. Recent observations indicate that CT-1 may be involved in pressure overload left ventricular hypertrophy (LVH). We investigated whether the hypertrophic effects of CT-1 are different in cardiomyocytes isolated from adult normotensive and spontaneously hypertensive rats (SHR). Hypertrophy was evaluated by planimetry and confocal microscopy, contractile proteins were quantified by Western blotting and real-time RT-PCR, and intracellular pathways were analyzed with specific chemical inhibitors. CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains. In Wistar cells, CT-1 augmented cell length (p<0.01) but did not modify either the transverse diameter or cell depth. In SHR cells, CT-1 increased cell length (p<0.05), cell width (p<0.01) and cell depth, augmented the expression of myosin light chain-2v (MLC-2v) and skeletal alpha-actin (p<0.01) and enhanced MLC-2v phosphorylation (p<0.01). The blockade of gp130 or LIFR abolished CT-1-induced growth in the two cell types. All distinct effects observed in cardiomyocytes from SHR were mediated by STAT3. Baseline angiotensinogen expression was higher in SHR cells, and CT-1 induced a 1.7-fold and 3.2-fold increase of angiotensinogen mRNA in cardiomyocytes from Wistar rats and SHR respectively. In addition, AT1 blockade inhibited the specific effects of CT-1 in SHR cells. Finally, ex vivo determinations revealed that adult SHR exhibited enhanced myocardial CT-1 (mRNA and protein, p<0.01), increased cell width (p<0.01) and concentric LVH compared with pre-hypertensive SHR. These findings reveal a specific cell-broadening effect of CT-1 in cardiomyocytes from adult SHR and suggest that the hypertensive phenotype of these cells may influence the hypertrophic effects of CT-1, probably by means of an exaggerated induction of angiotensinogen expression. We suggest that CT-1 might facilitate LVH in genetic hypertension through a cross-talk with the renin-angiotensin system

Loss of myocardial LIF receptor in experimental heart failure reduces cardiotrophin-1 cytoprotection. A role for neurohumoral agonists?

OBJECTIVES: Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR). METHODS: Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes. RESULTS: Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p<0.01) demonstrated by the increase in Bax/Bcl-2 ratio, caspase-3 activation and poly (ADP-ribose) polymerase (PARP) fragmentation. Failing SHR had a 7-fold diminished expression (p<0.01) of LIFR, no changes in gp130, and 1.6-fold increased myocardial expression (p<0.01) of CT-1. In cardiomyocytes isolated from non-failing SHR, recombinant CT-1 inhibited apoptotic and non-apoptotic cell death induced by angiotensin II or hydrogen peroxide. LIFR protein was entirely absent in cardiomyocytes isolated from failing SHR, which were resistant to the cytoprotective effects of CT-1. Finally, stimulation of non-failing SHR cardiomyocytes with angiotensin II, aldosterone, norepinephrine or endothelin-1 significantly decreased (p<0.01) LIFR expression. CONCLUSIONS: These data suggest that loss of CT-1-dependent survival mechanisms may contribute to the increase of cell death associated with HF in SHR. Neurohumoral activation may contribute to this alteration via suppression of LIFR

Las células troncales pluripotenciales en la terapia celular

Las células con pluripotencialidad inducida (iPS) son un nuevo tipo de célula troncal derivada de células somáticas humanas, mediante reprogramación con factores de transcripción. Estas células iPS tienen características de las células troncales embrionarias, como la capacidad de convertirse en todos los tipos de células diferenciadas del organismo. A corto plazo, las células de pacientes reprogramadas están siendo útiles para crear modelos celulares de enfermedades, en las que estudiar los procesos patológicos y probar fármacos. A pesar de algunas críticas, se ha ido acumulando evidencia en los trabajos preclínicos, sobre la efectividad de la terapia celular con los clones de iPS apropiadamente seleccionados. La generación de células iPS ha propiciado el desarrollo de otras técnicas,como por ejemplo, la transdiferenciación por la que se convierte directamente in vivo fibroblastos cardiacos en miocitos. Este tipo celular pluripotencial es de un gran valor en la investigación biomedicina y abre nuevas posibilidades a la terapia celular.Induced pluripotent stem (iPS) cells are a novel stem cell population derived from human somatic cells through reprogramming using a set of transcription factors. These iPS cells were shown to share the characteristics of embryonic stem cells, including the ability to give rise to differentiated cells of every tissue type of the body. In the shorter term, iPS cells will be useful for creating patient-identical disease model cells in which the pathological process can be studied and drugs can be tested. Despite critical attitudes, accumulating preclinical evidence supports the effectiveness of iPSCbased cell therapy on the selection of appropriate iPSC clones. The production of iPS cells has also spurred the development of other techniques, for example, transdifferentiation by researchers can now convert heart fibroblasts directly in vivo into myocytes by similar methods. This pluripotent cells is indeed of great value in medical research and it is opening new possibilities in cell therapy

Immunomodulation induced by synthetic peptides derived from Staphylococcus aureus protein A

Peptides from 10 to 22 amino acids containing sequences encompassed by Staphylococcus aureus protein A were synthesized. Some of these peptides, when present in cultures of lymphomononuclear cells from healthy donors or from cancer patients (melanoma, breast carcinoma, non-Hodgkin lymphoma and renal cell carcinoma) promoted: (i) changes in the phenotype of the lymphomononuclear population, (ii) stimulation of monocytes (release of IL-1 and TNF-alpha), and (iii) an increase in cytotoxicity against K562, Daudi and HT-29 cells. Isolated monocytes responded also to those peptides with a release of IL-1 and TNF alpha and an increase of cytotoxicity against HT-29 cells. It was found that the active peptides had the following structural pattern: a length of at least 15 amino-acid residues with a proline at position 6, valine, leucine, isoleucine, glycine, alanine or lysine at position 2, and glutamic or aspartic acid at position 11. Replacement of Pro at position 6 with any other residue turned the peptide inactive. Replacement of residues at positions 2 and 11 with amino-acid residues other than those required for activity resulted in compounds with a marked decrease in the immunomodulating properties described, or lacking these properties altogether

Inducible nitric oxide synthase in human lymphomononuclear cells activated by synthetic peptides derived from extracellular matrix proteins.

Synthetic peptides with sequences present in extracellular matrix proteins are capable of causing the expression of the inducible form of nitric oxide synthase (iNOS), detected by immunocytochemistry, and the release of NO by human lymphomononuclear cells incubated in their presence. Active peptides are 15-mers containing a characteristic 2-6-11 motif in which the amino acid residue at position 2 is Leu, Ile, Val, Gly, Ala or Lys; the residue at position 6 is always Pro; and residue 11 is Glu or Asp. The induction of iNOS in human monocytes and macrophages could be involved in the cytotoxicity against tumor cell lines also elicited by these peptides