Programmed cell death (PCD) plays a central role during prenatal development, especially in morphogenesis, sexual differentiation and the emergence of the immune and nervous systems. Programmed cell death in the adult allows tissue homeostasis, elimination of damaged or abnormal cells and defense against infections. Conversely, PCD dysregulation has been proposed to participate in the pathogenesis of cancer, autoimmunity, infectious disease and neurodegeneration [4].

      Terminology. Cell death processes have been succes­sively named “chromatolysis,” “pyknosis,” “karyolysis,” “shrinkage necrosis,” “programmed cell death,” “cell sui­cide,” “self-destruction” and “apoptosis”. Program means “pre-written” and suggests a framework of design and finality, and favors confusion between pre-written genetic information and the multiple ways used by the cells and the body. However, it is not the survival or death of each individual cell that is programmed, but each cell’s capacity to induce or repress its self-destruction. “Cell suicide” and “self-destruction” also have an anthropomorphic reference, and favor confusion between the act of initiating self-dis­mantling that the cell indeed performs by activating an intrinsic cell death mechanism, and both the decision to destroy itself and the implementation of the death process that depends on the nature of interactions between the cell and the body, rather than on the cell itself. Apoptosis (the “fall,” as that of leaves in autumn), while being perceived as describing the death process itself, actually describes the stereotyped modifications usually associated with PCD. These involve cell shrinkage, plasma membrane blebbing with increased permeability, mitochondrial outer membrane permeabilization, nuclear chromatin condensa­tion and fragmentation, nuclear DNA fragmentation, cyto­skeletal modifications and segmentation of the cell into apoptotic bodies. Also involved is expression of various death signaling molecules that allows neighboring cells to rapidly ingest the dying cell. Programmed cell death, in contrast with passive and chaotic necrotic death (that in­volves cell swelling, plasma membrane rupture and cell content spillage), usually induces no lesions in the organ and tissue in which it occurs.

      Since apoptosis is the most typical but not the only phenotype of self-destruction, the term “apoptosis” should not be considered as a synonym of “programmed cell death,” “cell suicide” and “self-destruction” [4].

      Apoptosis. In mammalian cells, the apoptosis is medi­ated through an intrinsic or an extrinsic pathway, depend­ing on the origin of the death stimuli.

      The intrinsic pathway is mediated by mitochondria, which, in response to apoptotic stimuli, release several proteins from their intermembrane space into the cytosol. These include cytochrome c, SMAC (second mitochon-dria-derived activator of caspases)/DIABLO (direct in­hibitor of apoptosis (IAP)-binding protein with low pI), EndoG (endonuclease G) and OMI/HTRA2 (high-tem-perature-requirement protein A2) [5-8]. Critical in progres­sion of apoptosis is the formation of a “mitochondrial permeability transition pore,” which is regulated and con­trolled by the interactions of pro-(Bax, Bim, Bid, Bak and Noxa) and anti-apoptotic proteins (Bcl-2, Bcl_XL and Bcl-w) of the Bcl-2 family. After the formation of permeability transition pore in the outer membrane of mitochondria, the above-mentioned proteins are released into the cytosol. Cytochrome c, binds to and activates APAF1 (apoptotic protease activating factor 1) in the cytosol by inducing a conformational change that allows APAF1 to bind to ATP/ dATP and to form an apoptosome, which mediates activa­tion of procaspase-9 and triggers activation of a procas­pase cascade.

      The extrinsic pathway starts with the binding of an extracellular death ligand, such as FasL, to its cell-surface death receptor, such as Fas. Binding of homotrimeric death ligands to their receptors leads to recruitment of cytosolic factors such as FADD (Fas-associated death domain) and caspase-8, forming an oligomeric death-inducing signaling complex (DISC). Formation of DISC leads to the activa­tion of the initiator caspase-8, which then cleaves and activates the effector procaspase-3. This pathway can crosstalk to the intrinsic cell death process through caspase-8-mediated cleavage of Bid, which then triggers the release of mitochondrial proteins [6-11].