More than one way to die: apoptosis, necrosis and reactive oxygen damage.
ABSTRACT Cell death is an essential phenomenon in normal development and homeostasis, but also plays a crucial role in various pathologies. Our understanding of the molecular mechanisms involved has increased exponentially, although it is still far from complete. The morphological features of a cell dying either by apoptosis or by necrosis are remarkably conserved for quite different cell types derived from lower or higher organisms. At the molecular level, several gene products play a similar, crucial role in a major cell death pathway in a worm and in man. However, one should not oversimplify. It is now evident that there are multiple pathways leading to cell death, and some cells may have the required components for one pathway, but not for another, or contain endogenous inhibitors which preclude a particular pathway. Furthermore, different pathways can co-exist in the same cell and are switched on by specific stimuli. Apoptotic cell death, reported to be non-inflammatory, and necrotic cell death, which may be inflammatory, are two extremes, while the real situation is usually more complex. We here review the distinguishing features of the various cell death pathways: caspases (cysteine proteases cleaving after particular aspartate residues), mitochondria and/or reactive oxygen species are often, but not always, key components. As these various caspase-dependent and caspase-independent cell death pathways are becoming better characterized, we may learn to differentiate them, fill in the many gaps in our understanding, and perhaps exploit the knowledge acquired for clinical benefit.
Full-textDOI: · Available from: Rudi Beyaert, Aug 04, 2014
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ABSTRACT: Tomatine adjuvant, consisting of tomatine, n-octyl-β-d-glucopyranoside (OGP), phosphatidylethanolamine and cholesterol is unique in that when combined with soluble protein antigen it elicits a cytotoxic T lymphocyte (CTL) response in immunized animals. The mechanisms underlying this property are unknown. In an attempt to understand how tomatine activates cellular immunity, we examined its potential to induce apoptosis. Thus in the present study, cell death of EL4 thymoma cells induced by whole adjuvant and the surface-active components in the formulation was examined. Cytotoxicity was monitored using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and lactate dehydrogenase release assays, apoptosis and necrosis were quantified by flow cytometry using Annexin V and propidium iodide staining, and morphology was examined by Hoechst 33342 staining. Flow cytometric analysis demonstrated the appearance of the sub-G1 phase in cells treated with these agents and Annexin V/PI staining showed that all three agents induced both apoptosis and necrosis in EL4 cells in a concentration-dependent manner. Tomatine was effective at much lower concentrations than OGP, suggesting that the majority of the effect of whole adjuvant could be attributed to this component. Microscopic examination of EL4 cells after treatment with these agents revealed morphological features of apoptosis, including chromatin condensation and DNA fragmentation. Pretreatment with zVAD-fmk did not block cell death induced by these agents, showing that tomatine adjuvant-induced EL4 cell apoptosis is caspase-independent.Vaccine 06/2004; 22(17-18):2316-2327. DOI:10.1016/S0264-410X(03)00817-X · 3.49 Impact Factor
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ABSTRACT: In the present study, we investigated the neuroprotective effects of GPP1, a purified polysaccharide from Gynostemma pentaphyllum, on Aβ (25-35)-induced neuronal toxicity and explore its potential mechanisms in PC12 cells. The results showed pretreatment with GPP1 prior to Aβ (25-35) exposure significantly protected PC12 cells from Aβ (25-35)-induced cell death, lactate dehydrogenase (LDH) release, DNA damage, intracellular free calcium concentration ([Ca(2+)]i) influx, mitochondrial dysfunction and mitochondrial cytochrome c (Cyt-C) release. In addition, pretreatment with GPP1 also protected PC12 cells against Aβ (25-35)-induced the accumulation of reactive oxygen species (ROS) and lipid peroxidation product MDA, the reduction in glutathione (GSH) level and superoxide dismutase (SOD) activity, the increased Bax/Bcl-2 protein expression ratio and caspase-3 activation. Our findings suggest that GPP1 exerts a neuroprotective effect against Aβ (25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative stress and suppressing the mitochondrial apoptotic pathway. Copyright © 2015 Elsevier Ltd. All rights reserved.Carbohydrate Polymers 05/2015; 122. DOI:10.1016/j.carbpol.2014.12.032 · 3.92 Impact Factor