RESUMEN
Prostaglandin reductase-1 (Ptgr1) is an alkenal/one oxidoreductase that is involved in the catabolism of eicosanoids and lipid peroxidation such as 4-hydroxynonenal (4-HNE). Recently, we reported that Ptgr1 is overexpressed in human clinical and experimentally induced samples of hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated and its role in carcinogenesis are not yet known. Here, we studied parameters associated with antioxidant responses and the mechanisms underlying the induction of Ptgr1 expression by the activation of Nuclear Factor (erythroid-derived-2)-like-2 (NRF2). For these experiments, we used two protocols of induced hepatocarcinogenesis in rats. Furthermore, we determined the effect of PTGR1 on cell proliferation and resistance to oxidative stress in cell cultures of the epithelial liver cell line, C9. Ptgr1 was overexpressed during the early phase in altered hepatocyte foci, and this high level of expression was maintained in persistent nodules until tumors developed. Ptgr1 expression was regulated by NRF2, which bound to an antioxidant response element at -653bp in the rat Ptgr1 gene. The activation of NRF2 induced the activation of an antioxidant response that included effects on proteins such as glutamate-cysteine ligase, catalytic subunit, NAD(P)H dehydrogenase quinone-1 (NQO1) and glutathione-S-transferase-P (GSTP1). These effects may have produced a reduced status that was associated with a high proliferation rate in experimental tumors. Indeed, when Ptgr1 was stably expressed, we observed a reduction in the time required for proliferation and a protective effect against hydrogen peroxide- and 4-HNE-induced cell death. These data were consistent with data showing colocalization between PTGR1 and 4-HNE protein adducts in liver nodules. These findings suggest that Ptgr1 and antioxidant responses act as a metabolic adaptation and could contribute to proliferation and cell-death evasion in liver tumor cells. Furthermore, these data indicate that Ptgr1 could be used to design early diagnostic tools or targeted therapies for HCC.
Asunto(s)
Oxidorreductasas de Alcohol/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Factor 2 Relacionado con NF-E2/genética , Animales , Antioxidantes/metabolismo , Carcinogénesis/genética , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/genética , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Peroxidación de Lípido/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Estrés Oxidativo/genética , Ratas , Transducción de Señal/genéticaRESUMEN
Pesticides and heavy metals were analyzed in sentinel Crassostrea gigas oysters placed in six aquaculture sites close to a contaminated agricultural region. Each site was sampled twice. Tests revealed the presence of organochlorine (OC) pesticides in the oysters at concentrations varying from 31.8 to 72.5 µg/kg for gamma-hexachlorocyclohexane (γ-HCH); from 1.2 to 3.1 µg/kg for dichlorodiphenyldichloroethylene (4,4-DDE); from 1.6 to 2.3 µg/kg for endosulfan I; and from 1.4 to 41.2 µg/kg for endosulfan II, as well as heavy metals in concentrations that exceeded Mexican tolerance levels (405.5 to 987.8 µg/g for zinc; 4.2 to 7.3 µg/g for cadmium; and 7.2 to 9.9 µg/g for lead). Significant levels of DNA damage in oyster hemocytes were also detected. There was a significant, positive correlation between genotoxic damage and concentration of nickel or the presence of endosulfan II. Cellular viability evaluated by cytotoxic analyses was found to be high at 80%. Marked inhibition in activity of acetylcholinesterase (AChE ) and induction of glutathione S-transferase (GST) activity was noted. Data demonstrated a significant relation between AChE activity inhibition and presence of endosulfan II, γ-HCH, copper, lead, and 4,4-DDE, as well as between AChE and GST activity at different sites.
Asunto(s)
Crassostrea/química , Daño del ADN , Metales Pesados/análisis , Mutágenos/análisis , Residuos de Plaguicidas/análisis , Plaguicidas/análisis , Contaminantes Químicos del Agua/análisis , Animales , Acuicultura , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores de la Colinesterasa/análisis , Inhibidores de la Colinesterasa/farmacología , Ensayo Cometa , Crassostrea/citología , Crassostrea/efectos de los fármacos , Crassostrea/crecimiento & desarrollo , Inducción Enzimática/efectos de los fármacos , Contaminación de Alimentos , Glutatión Transferasa/biosíntesis , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Hemocitos/citología , Hemocitos/efectos de los fármacos , Hemocitos/metabolismo , Metales Pesados/farmacología , Mutágenos/farmacología , Residuos de Plaguicidas/farmacología , Plaguicidas/farmacología , Vigilancia de Guardia , Mariscos/análisis , Mariscos/normas , Contaminantes Químicos del Agua/farmacología , Abastecimiento de Agua/análisisRESUMEN
The signaling pathways that control the life-death switch of a cell are a prime interest in Modern Biology. To this respect, NF-kappaB has emerged as a decisive transcription factor in the cell's response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, the liver, and nervous system. In this review we analyze the pivotal role of the transcription factor NF-kappaB in the normal functioning of the cardiac cell and its implication on some of the most frequent cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-kappaB is commonly found to be cytoprotective, there are a number of instances where it is proapoptotic depending on the inducing stimulus and the cell context. Significant progress has been made in understanding its mode of action and its interplay with other key factors. These studies identified many anti- and pro-apoptotic NF-kappaB regulated genes that mediate its activity, these important new insights fuel hope that novel approaches will be developed to control the effects of NF-kappaB in cardiac pathologies.
Asunto(s)
Apoptosis , Miocitos Cardíacos , FN-kappa B/fisiología , Animales , Apoptosis/genética , Apoptosis/fisiología , Cardiomegalia/fisiopatología , Células Cultivadas , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/genética , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Paro Cardíaco , Homeostasis , Humanos , Precondicionamiento Isquémico Miocárdico , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Isquemia Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , FN-kappa B/genética , Estrés Oxidativo , Fenotipo , Conejos , Ratas , Factores de TiempoRESUMEN
Para la biología de hoy las vías de señalización intracelular que controlan los procesos entre la vida y la muerte celular son de gran interés. Al respecto, el NF-κB destaca como un factor de transcripción decisivo de respuesta rápida que participa en la activación de las vías de señalización de la muerte celular programada. Lo relevante es que sus efectos tienen consecuencias en el desarrollo normal y/o la homeostasis en muchas células o tejidos, que incluyen entre otros al sistema inmune, los folículos capilares, apéndices epidermales, el riñon y el sistema nervioso. En esta revisión analizamos el papel central que juega el factor de transcripción NF-κB en el funcionamiento normal de la célula cardíaca y sus implicaciones en algunas de las patologías cardíacas más frecuentes como: el daño por isquemia-reperfusión, la isquemia precondicionada, la hipertrofia, la aterosclerosis, y el paro cardíaco. El NF-κB comúnmente funciona como un agente citoprotector, aunque hay algunos casos en los cuales resulta ser pro-apoptótico dependiendo del estímulo y del contexto celular. Se han logrado avances significativos a nivel molecular, que han permitido entender su modo de acción y el papel interactivo que juega con otros factores claves. Estos estudios han identificado muchos genes anti-apoptóticos y pro-apoptóticos regulados por la actividad del NF-κB abriendo novedosas aproximaciones que se pueden hacer sobre sus efectos en el desarrollo de patologías cardíacas.
The signaling pathways that control the life-death switch of a cell are a prime interest in Modern Biology. To this respect, NF-κB has emerged as a decisive transcription factor in the cell's response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, the liver, and nervous system. In this review we analyze the pivotal role of the transcription factor NF-κB in the normal functioning of the cardiac cell and its implication on some of the most frequent cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-κB is commonly found to be cytoprotective, there are a number of instances where it is proapoptotic depending on the inducing stimulus and the cell context. Significant progress has been made in understanding its mode of action and its interplay with other key factors. These studies identified many anti- and pro-apoptotic NF-κB regulated genes that mediate its activity, these important new insights fuel hope that novel approaches will be developed to control the effects of NF-κB in cardiac pathologies.