Biochemical basis of the high resistance to oxidative stress in Dictyostelium discoideum.

Aerobic organisms experience oxidative stress due to generation of reactive oxygen species during normal aerobic metabolism. In addition, several chemicals also generate reactive oxygen species which induce oxidative stress. Thus oxidative stress constitutes a major threat to organisms living in aerobic environments. Programmed cell death or apoptosis is a physiological mechanism of cell death, that probably evolved with multicellularity, and is indispensable for normal growth and development. Dictyostelium discoideum, an eukaryotic developmental model, shows both unicellular and multicellular forms in its life cycle and exhibits apparent caspase-independent programmed cell death, and also shows high resistance to oxidative stress. An attempt has been made to investigate the biochemical basis for high resistance of D. discoideum cell death induced by different oxidants. Dose-dependent induction of cell death by exogenous addition of hydrogen peroxide (H2O2), in situ generation of H2O2 by hydroxylamine, and nitric oxide (NO) generation by sodium nitroprusside treatment in D. discoideum were studied. The AD50 doses (concentration of the oxidants causing 50% of the cells to die) after 24 h of treatment were found to be 0.45 mM, 4 mM and 1 mM, respectively. Studies on enzymatic antioxidant status of D. discoideum when subjected to oxidative stress, NO and nutrient stress reveal that superoxide dismutase and catalase were unchanged; a significant induction of glutathione peroxidase was observed. Interestingly, oxidative stress-induced lipid membrane peroxidative damage could not be detected. The results shed light on the biochemical basis for the observed high resistance to oxidative stress in D. discoideum.

Programmed cell death and its clinical implications.

Cell death is a highly regulated process that is ubiquitous in all eukaryotes. Programmed cell death (PCD) is an integral part of both animal and plant development. Studies on apoptosis, the well characterized form of programmed cell death led to the identification of a central tripartite death switch i.e. apoptosome consisting of Apaf-1, Apaf-2 and Apaf-3. The caspases, a family of cysteine-dependent aspartate directed-proteases, constitute the central executioners of apoptosis. Much of the attention on programmed cell death is focused on caspases, however, cell death can still occur even when the caspase cascade is blocked, revealing the existence of nonapoptotic alternative pathway(s) of cell death. The mitochondrial release of cytochrome C following a PCD inducing stimulus in both plants and animals suggests the evolutionary conservation of death pathways. Dysregulation of apoptosis may be related to the development of several disease states as well as ageing. Excessive apoptosis is associated with neurodegenerative disorders, AIDS etc., whereas deficient apoptosis is associated with cancer, auto-immunity, viral infections etc. Understanding the regulation of programmed cell death would throw light in designing drugs and gene therapies that can target specific molecules in the apoptotic pathway opening the vistas for new therapeutic endeavors in many areas of medicine.