Consideraciones político-criminales sobre el tratamiento penal de los delincuentes impugnables peligrosos

La creciente preocupación por los delincuentes peligrosos (terroristas, delincuentes sexuales, asesinos en serie, etc.) ha dado lugar en los últimos años a diferentes reformas legislativas, tanto en España como en otros muchos países. Por lo general, estas reformas sirven para ampliar las penas de prisión o para establecer medidas de seguridad complementarias a la pena. Se pretende con ello evitar que los delincuentes peligrosos vuelvan a delinquir. No se les impone una sanción por el delito que han cometido sino por el delito que pueden cometer en el futuro. De esta forma, se produce un importante cambio en la concepción del Derecho penal, pues la sanción penal ya no se fundamenta en la culpabilidad, sino en la peligrosidad. El objetivo de este trabajo es explicar las implicaciones político-criminales de esta concepción del Derecho penal basada en la peligrosidad y criticar, a partir de ahí, las últimas reformas del Código Penal españolGrowing concern about dangerous offenders (terrorists, sex offenders, serial murderers, etc.) has led to several legislative reforms in recent years, both in Spain and in many other countries. Generally, the penalties are expanded or complemented with preventive measures to prevent dangerous criminals from re-offending. In this way, a sanction is imposed not by the crime they have committed, but for the crime they may commit in the future. This represents a signifi cant change in the conception of criminal law, because punishment is no longer based on guilt but on dangerousness. The aim of this paper is to explain the political implications of this conception and from that point criticize recents reforms of Spanish Penal Cod

El principio de confianza en derecho penal: un estudio sobre la aplicación del principio de autorresponsabilidad en la teoría de la imputación objetiva

Tesis doctoral inédita, con calificación cum laude. Universidad Autónoma de Madrid, Falcultad de Derecho, 200

The Apoptotic Microtubule Network During the Execution Phase of Apoptosis

Apoptosis is a regulated energy-dependent process of cell death characterized by specific morphological and biochemical features in which caspase activation has a central role. During apoptosis, cells undergo characteristic morphological rearrangements in which the cytoskeleton participates actively. From a historical point of view, this reorganization has been assigned mainly to actinomyosin ring contraction with microtubule and intermediate filaments, both reported to be depolymerized at early stages of apoptosis. However, recent results have shown that the microtubule cytoskeleton is reformed during the execution phase of apoptosis, forming an apoptotic microtubule network (AMN). AMN is closely associated with the plasma membrane, forming a cortical ring or cellular “cocoon.” Apoptotic microtubules’ reorganization has been reported in many cell types and under many apoptotic inducers. Recently, it has been proposed that AMN is essential for preserving plasma membrane permeability and cell morphology during the execution phase of apoptosis. Apoptotic microtubules’ depolymerization leads cells to secondary necrosis and the release of toxic intracellular contents that can harm surrounding cells and initiate inflammation. Therefore, microtubules’ reorganization in physiological apoptosis during development and in the adult organism or in pathological apoptosis induced by anticancer treatments or chronic inflammation is essential for tissue homeostasis, preventing cell damage and inflammation

Apoptotic cells subjected to cold/warming exposure disorganize apoptotic microtubule network and undergo secondary necrosis

Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath the plasma membrane which plays a critical role in preserving cell morphology and plasma membrane integrity. The aim of this study was to examine the effect of cold/warming exposure on apoptotic microtubules and plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptotic H460 cells that cold/warming exposure disorganized apoptotic microtubules and allowed the access of active caspases to the cellular cortex and the cleavage of essential proteins in the preservation of plasma membrane permeability. Cleavage of cellular cortex and plasma membrane proteins, such as ¿-spectrin, paxilin, focal adhesion kinase and calcium ATPase pump (PMCA-4) involved in cell calcium extrusion resulted in increased plasma permeability and calcium overload leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the addition of the pan-caspase inhibitor z-VAD during cold/warming exposure that induces AMN depolymerization avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Likewise, apoptotic microtubules stabilization by taxol during cold/warming exposure also prevented cellular cortex and plasma membrane protein cleavage and secondary necrosis. Furthermore, microtubules stabilization or caspase inhibition during cold/warming exposure was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that cold/warming exposure of apoptotic cells induces secondary necrosis which can be prevented by both, microtubule stabilization or caspase inhibition.This work was supported by FIS PI10/00543 Grant, FIS EC08/00076 Grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), SAS 111242 Grant, Servicio Andaluz de Salud-Junta de Andalucía, Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, and by Asociación de Enfermos de Patología Mitocondrial (AEPMI).Peer Reviewe

Critical role of AMP-activated protein kinase in the balance between mitophagy and mitochondrial biogenesis in MELAS disease

MELAS syndrome is a mitochondrial disorder that is caused mainly by the m.3243A > G mutation in mitochondrial DNA. Here, we report on how the severity of pathophysiological alterations is differently expressed in fibroblasts derived from patients with MELAS disease. We evaluated mitophagy activation and mitochondrial biogenesis which are the main mechanisms regulating the degradation and genesis of mitochondrial mass in MELAS fibroblasts and transmitochondrial cybrids. Our results suggest a critical balance between mitophagy and mitochondrial biogenesis which leads to the expression of different degrees of pathological severity among MELAS fibroblast cell lines according to their heteroplasmy load and the activation of AMP-activated protein kinase (AMPK). AMPK-activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) or coenzyme Q10 (CoQ) increased peroxisome proliferator-activated receptor alpha (PGC-1α) nuclear translocation, mitochondrial biogenesis, antioxidant enzyme system response, autophagic flux and improved pathophysiological alterations in MELAS fibroblasts with the most severe phenotype. Our findings support the hypothesis that mitochondrial biogenesis, increased antioxidant response and autophagy clearance serve as compensatory mechanisms in response to mitophagic degradation of dysfunctional mitochondria and point out that AMPK is an important player in this balance.This work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de AndalucíaCTS-5725, and by AEPMI (Asociación de Enfermos de Patología Mitocondrial).Peer Reviewe

Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells

Systemic treatments for hepatocellular carcinoma (HCC) have been largely unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved early mitophagy activation that subsequently switched to apoptosis. Amitriptyline induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibited mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (ΔΨm) and increased reactive oxygen species (ROS) production. Transmission electron microscopy (TEM) studies revealed structurally abnormal mitochondria that were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitophagy activation, fluorescence microscopy analysis showed mitochondrial Parkin recruitment and colocalization of mitochondria with autophagosome protein markers. Pharmacological or genetic inhibition of autophagy exacerbated the deleterious effects of Amitriptyline on hepatoma cells and led to increased apoptosis. These results suggest that mitophagy acts as an initial adaptive mechanism of cell survival. However persistent mitochondrial damage induced extensive and lethal mitophagy, autophagy stress and autophagolysome permeabilization leading eventually to cell death by apoptosis. Amitriptyline also induced cell death in hepatoma cells lines with mutated p53 and non-sense p53 mutation. Our results support the hypothesis that Amitriptyline-induced mitochondrial dysfunction can be a useful therapeutic strategy for HCC treatment, especially in tumors showing p53 mutations and/or resistant to genotoxic treatments.This work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermedades Neurodegenerativas por Acumulación Cerebral de Hierro).Peer Reviewe

Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease

This is an open access article distributed under the terms of the Creative Commons Attribution License.[Introduction]: Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia. [Methods]: We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX™ and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker™ Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells. [Results]: We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy. [Conclusions]: These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.This work was supported by grants FIS PI080500 and FIS EC08/00076, Ministerio de Sanidad, Spain. The authors dedicate this manuscript to FM patients and AFIBROSE (Asociación de Fibromialgia de Sevilla) for their unconditional help.Peer Reviewe

Stabilization of apoptotic cells: generation of zombie cells

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Apoptosis is characterized by degradation of cell components but plasma membrane remains intact. Apoptotic microtubule network (AMN) is organized during apoptosis forming a cortical structure beneath plasma membrane that maintains plasma membrane integrity. Apoptotic cells are also characterized by high reactive oxygen species (ROS) production that can be potentially harmful for the cell. The aim of this study was to develop a method that allows stabilizing apoptotic cells for diagnostic and therapeutic applications. By using a cocktail composed of taxol (a microtubule stabilizer), Zn2+ (a caspase inhibitor) and coenzyme Q10 (a lipid antioxidant), we were able to stabilize H460 apoptotic cells in cell cultures for at least 72 h, preventing secondary necrosis. Stabilized apoptotic cells maintain many apoptotic cell characteristics such as the presence of apoptotic microtubules, plasma membrane integrity, low intracellular calcium levels and mitochondrial polarization. Apoptotic cell stabilization may open new avenues in apoptosis detection and therapy.This work was supported by FIS PI10/00543 grant, Ministerio de Sanidad, Spain, and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), SAS 111242 grant, Servicio Andaluz de Salud-Junta de Andalucía, Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, BFU2012-38208 and by AEPMI (Asociación de Enfermos de Patología Mitocondrial).Peer Reviewe