Estudio de la reacción de la hemoperoxidasa híbrida tipo A de Trypanosoma cruzi (APx-CcP) con peroxinitrito in vitro e in vivo

Trypanosoma cruzi, agente causal de la enfermedad de Chagas, es un parásito intracelular obligado capaz de invadir y proliferar en células de mamíferos. Para establecer la infección, el parásito debe sobrevivir al ataque nitro-oxidativo del macrófago en respuesta a la invasión (generación de superóxido (O2 •- ), peróxido de hidrógeno (H2O2) y peroxinitrito (ONOOH/ONOO- )). Dentro de las enzimas antioxidantes de T. cruzi, se encuentra una hemoperoxidasa (APx-CcP) que incrementa la infectividad parasitaria tanto in vitro como in vivo. Se trata de una peroxidasa híbrida, que reduce H2O2 utilizando ascorbato o citocromo c como sustrato reductor. Motivados por la reactividad de otras hemoperoxidasas con peroxinitrito y dado que la enzima se localiza en la membrana plasmática en las formas infectivas, nos propusimos estudiar la reacción de la APx-CcP con peroxinitrito y su rol en la detoxificación de este oxidante en la infección a macrófagos. Mediante métodos de cinética rápida y de competencia, determinamos que la enzima reacciona rápidamente con el peroxinitrito (k = 3-4 x 106 M-1s -1 , pH 7.4 y 25°C) mediante la formación de un compuesto tipo I (FeIV=O,Trp•+) que detectamos por análisis espectroscópico y experimentos de inmunospin trapping con DMPO. Finalmente evidenciamos que parásitos sobreexpresantes de APx-CcP son más infectivos que los WT en macrófagos inmunoestimulados (IFN-γ/LPS) y que la sobreexpresión de la enzima resulta en una menor detección del oxidante en el macrófago durante la invasión (citometría de flujo, sonda fluoresceína boronato). Los resultados obtenidos en este trabajo indican que la APx-CcP reacciona con el peroxinitrito protegiendo al parásito de sus efectos citotóxicos

Administración del cambio organizacional en las empresas familiares para la implementación de la responsabilidad social empresarial

La investigación desarrollada tuvo como objetivo caracterizar las dificultades y la posible orientación que debe desarrollarse en las empresas familiares para implementar la responsabilidad social en ellas. La investigación se basó en una revisión bibliográfica con respecto a: caracterí­sticas de las Empresas Familiares, Responsabilidad Social Empresarial y la Administración del Cambio utilizando para ello Google Académico que se complementó con la revisión del Journal Citation Report (JCR) y del Social Science Citation Index (SSCI) a partir de 1961. Se destacan como conclusiones que el capital gerencial social es una habilidad clave que debe manejarse en una empresa familiar, para manejar en forma oportuna las relaciones y ví­nculos sociales tanto internos y externos de esta. Un programa de responsabilidad social a la vez genera costos, que, en una empresa familiar, en donde el patrimonio familiar está siendo afectado, pueden ser crí­ticos, aunque existe evidencia empí­rica que indica que a largo plazo se generan beneficios cuando se aplican los principios de RSE. Es imprescindible que la gerencia propietaria de la empresa familiar realice una planificación que contemple las acciones que permitan enfrentar los difí­ciles problemas que conlleva la resistencia al cambio

Ferroptosis in health and disease

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.Fil: Berndt, Carsten. Heinrich-Heine University; AlemaniaFil: Alborzinia, Hamed. Heidelberg Institute for Stem Cell Technology and Experimental Medicine; AlemaniaFil: Amen, Vera Skafar. University of Würzburg; AlemaniaFil: Ayton, Scott. University of Melbourne; AustraliaFil: Barayeu, Uladzimir. Heidelberg University; Alemania. German Cancer Research Center; Alemania. Tohoku University Graduate School of Medicine; JapónFil: Bartelt, Alexander. Ludwig Maximilians Universitat; AlemaniaFil: Bayir, Hülya. Columbia University; Estados UnidosFil: Bebber, Christina M.. University of Cologne; AlemaniaFil: Birsoy, Kivanc. The Rockefeller University; Estados UnidosFil: Böttcher, Jan P.. Universitat Technical Zu Munich; AlemaniaFil: Brabletz, Simone. Friedrich-Alexander University of Erlangen-Nürnberg; AlemaniaFil: Brabletz, Thomas. Friedrich-Alexander University of Erlangen-Nürnberg; AlemaniaFil: Brown, Ashley R.. Columbia University; Estados UnidosFil: Brunner Bernhardt, Mauricio Andrés. Goethe Universitat Frankfurt; AlemaniaFil: Bulli, Giorgia. Ludwig Maximilians Universitat; AlemaniaFil: Bruneau, Alix. Goethe Universitat Frankfurt; AlemaniaFil: Chen, Quan. Nankai University; ChinaFil: DeNicola, Gina M.. Moffitt Cancer Center; Estados UnidosFil: Dick, Tobias P.. Ruprecht Karls Universitat Heidelberg; AlemaniaFil: Distefano, Ayelen Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Dixon, Scott J.. University of Stanford; Estados UnidosFil: Engler, Jan B.. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Pagnussat, Gabriela Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Biológicas. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; ArgentinaFil: Wilhelm, Christoph. Universitat Bonn; AlemaniaFil: Wölk, Michele. University Hospital Carl Gustav Carus; AlemaniaFil: Wu, Katherine. University of New York; Estados UnidosFil: Yang, Xin. Columbia University; Estados UnidosFil: Yu, Fan. Nankai University; ChinaFil: Zou, Yilong. Westlake University; ChinaFil: Conrad, Marcus. Helmholtz Center Munich; Alemani

Ferroptosis in health and disease.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis

Ferroptosis in health and disease

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis

Chronic coronary syndromes without standard modifiable cardiovascular risk factors and outcomes: the CLARIFY registry

Background and Aims: It has been reported that patients without standard modifiable cardiovascular (CV) risk factors (SMuRFs—diabetes, dyslipidaemia, hypertension, and smoking) presenting with first myocardial infarction (MI), especially women, have a higher in-hospital mortality than patients with risk factors, and possibly a lower long-term risk provided they survive the post-infarct period. This study aims to explore the long-term outcomes of SMuRF-less patients with stable coronary artery disease (CAD). Methods: CLARIFY is an observational cohort of 32 703 outpatients with stable CAD enrolled between 2009 and 2010 in 45 countries. The baseline characteristics and clinical outcomes of patients with and without SMuRFs were compared. The primary outcome was a composite of 5-year CV death or non-fatal MI. Secondary outcomes were 5-year all-cause mortality and major adverse cardiovascular events (MACE—CV death, non-fatal MI, or non-fatal stroke). Results: Among 22 132 patients with complete risk factor and outcome information, 977 (4.4%) were SMuRF-less. Age, sex, and time since CAD diagnosis were similar across groups. SMuRF-less patients had a lower 5-year rate of CV death or non-fatal MI (5.43% [95% CI 4.08–7.19] vs. 7.68% [95% CI 7.30–8.08], P = 0.012), all-cause mortality, and MACE. Similar results were found after adjustments. Clinical event rates increased steadily with the number of SMuRFs. The benefit of SMuRF-less status was particularly pronounced in women. Conclusions: SMuRF-less patients with stable CAD have a substantial but significantly lower 5-year rate of CV death or non-fatal MI than patients with risk factors. The risk of CV outcomes increases steadily with the number of risk factors