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What is Apoptosis Library?
Apoptosis, often referred to as programmed cell death, is a crucial biological process that occurs naturally in multicellular organisms. It plays a key role in various physiological processes, including development, maintaining homeostasis, and eliminating damaged or potentially harmful cells.
Molecular Mechanisms Of Apoptosis Library
Apoptosis occurs in a well-choreographed sequence of morphological events. The dying cell thus undergoes nuclear and cytoplasmic condensation with blebbing of the plasma membrane, and eventually breaks up into membrane-enclosed particles termed apoptotic bodies containing intact organelles, as well as portions of the nucleus. These apoptotic bodies are then rapidly recognized, ingested and degraded by professional phagocytes or neighbouring cells. As apoptosis typically does not induce inflammation or tissue scarring, it is well suited for a role in normal cell turnover during embryogenesis and in adult tissues. Necrosis, on the other hand, is a pathological or accidental mode of cell death, characterized by irreversible swelling of the cytoplasm and distortion of organelles, including mitochondria. Eventually there is loss of membrane integrity resulting in cell rupture and release of noxious cellular contents. Typically, a number of contiguous cells are affected, and exudative inflammation develops in the surrounding tissue.
Necrosis occurs when cells are subjected to toxic stimuli such as hyperthermia, metabolic poisons and direct cell trauma. Moreover, in some pathological conditions a combination of cell death by necrosis and apoptosis may occur. For instance, ischaemic damage is frequently characterized by a core of acutely damaged necrotic cells and a penumbra of cells that undergo delayed apoptotic death. The ‘decision’ of the cell to die by necrosis or apoptosis is thought to depend largely on the severity of the insult. In addition, previous studies have shown that the intracellular ATP concentration is a crucial factor that influences the mode of cell death . Other forms of cell death have been described in recent years, including autophagy (self-digestion), paraptosis, necroptosis and oncosis. However, less is known concerning the molecular regulation and significance of these modes of cell death, and the present discussion will therefore be restricted to apoptosis.
Several important biochemical markers of apoptosis have been identified, including nuclear DNA fragmentation, activation of aspartate-specific proteases known as caspases and cell surface externalization of phosphatidylserine (PS) residues. Apoptosis may therefore be viewed, in biochemical terms, as a mediated form of cell death. However, detailed biochemical analyses are sometimes difficult to perform in the clinico-pathological setting, and the assessment of apoptosis is therefore frequently restricted to morphological inspection of tissue sections. In this context, the importance of quantification is worth noting. The speed of apoptosis and the rapidity of clearance of apoptotic cell corpses in vivo (a few hours at most) mean that identification of only a few apoptotic bodies in a tissue section can represent a considerable degree of cumulative cell loss; in other words, numerically small differences in apoptotic indices can be of great biological (and medical) importance. Furthermore, in order to ascribe changes in tissue or tumour size to alterations in the rate of apoptosis, a parallel quantitative assessment of cell proliferation is required.
Apoptosis, or programmed cell death, eliminates damaged, infected or redundant cells. Apoptosis is associated with distinct morphological changes, including cell shrinkage, chromatin condensation, loss of nuclear membrane integrity, plasma membrane blebbing, and the formation of apoptotic bodies. Other types of cell death include necrosis, which occurs after cellular injury and is less regulated than apoptosis. Understanding if cell death is a result of apoptosis is important for understanding developmental pathways, the mechanism of action of small molecule and large molecule (biologics) drugs, and related functions of the immune system.
Apoptosis assays typically detect biochemical and cellular events that indicate activation of an apoptotic pathway. The activation of an effector (e.g., caspase-3) leads to common apoptotic events such as exposure of phosphatidylserine on the outer surface of the plasma membrane (typically measured through annexin V binding), cleavage of cellular homeostatic and repair enzymes (e.g., poly [ADP-ribose] polymerase [PARP] measured by antibody techniques) and internucleosomal DNA fragmentation (typically measured through TUNEL assays). Caspase-3 activation is considered full commitment to apoptotic cell death. Exactly which events occur will depend on the apoptotic pathway activated.
Typically, more than one method is necessary to confirm that cell death is occurring via apoptosis. Markers of apoptosis such as caspase activity may be expressed only transiently. Therefore, to determine if apoptosis is the primary mechanism of cell death, understanding the kinetics of the cell death process in your model system is critical. Real-time, live-cell assays monitor apoptotic events over time. Multiple methods may also be used to assess the timing of events within the apoptotic pathway.
Apoptosis, a form of programmed cell death, is a natural process for removal of diseased, damaged or unwanted cells such as those with potentially harmful mutations, aberrant substratum, or alterations in cell-cycle control. It plays a central role in proper embryonic development, immune system function, and hormone-dependent atrophy. The activation or inhibition of apoptosis has therapeutic value in cancer or HIV and neurodegenerative diseases.
Apoptosis can be triggered by two known pathways: the intrinsic pathway (also called the mitochondrial pathway) and the extrinsic pathway. The intrinsic pathway, as its name implies, is activated by intracellular stimuli such as irreparable genetic damage, hypoxia, extremely high concentrations cytosolic Ca2+ and severe oxidative stress. This pathway is closely regulated by a group of proteins belonging to the Bcl-2 family and is the result of increased mitochondrial permeability and the release of pro-apoptotic molecules such as cytochrome c into the cytoplasm. The other pathway, extrinsic pathway is initiated when extracellular ligands binding to cell-surface death receptors.
An understanding of the mechanism of apoptosis is important as it plays a pivotal role in the pathogenesis of many diseases. In some cases, the problem is due to too much apoptosis, such as in the case of degenerative diseases while in others, too little apoptosis is the culprit. Despite being the cause of problem, apoptosis plays an important role in the treatment of cancer as it is a popular target of many treatment strategies.
Further complicating the analysis of cell death is the fact that Apoptosis Library is a common response to cell stress. Cells monitor many aspects of their physiology. Any drug or agent that is capable of killing a cell will cause physiological changes when given at sub-lethal doses or in the period before the cell is biochemically inert. When detected by the cell, these changes often elicit some kind of stress response.
Some responses, such as production of heat shock proteins, may serve to protect the cell, whereas others, such as activation of the apoptotic process, may hasten its demise. The ability of drugs and toxins with known lethal biochemical activities to nevertheless provoke an apoptotic death response has caused a great deal of confusion in the field.
Not only drugs can induce an apoptotic response, but by disturbing cell physiology, so can loss of gene expression, overexpression of genes and expression of mutant genes. The oncogene c- myc , for example, can stimulate apoptosis both when it is overexpressed or when its expression is suddenly reduced. The regulation of apoptosis is not an intrinsic function of the great majority of drugs and genes, but if the goal of a drug is to cause death of cancer cells, its ability to cause cell suicide indirectly might be just as important as its direct cytotoxic activity.
Under physiological conditions, the occurrence of apoptosis in tissues is typically a rare event. Thus, only a small number of apoptotic cells can be seen at any time point. Studies with cytosolic extracts of cells, which have been induced to undergo apoptosis in a synchronous manner, have shown that apoptosis can be divided into biochemically and morphologically distinct phases. In the first, pro-apoptotic stimuli trigger activation of the central molecular machinery of apoptosis (initiation phase). In the second, committed or effector phase, the molecular executioner machinery becomes fully activated as shown by the ability of the cytosolic extracts of committed cells to induce apoptotic changes in nuclei. Only after this, in the third, or degradation phase, do the hallmarks of apoptosis become evident. These include morphologic changes and DNA fragmentation.
The asynchronous nature of apoptotic death in cell populations is mainly due to the highly variable duration of the initiaton phase. In cell culture videomicroscopy studies the dynamic morphologic changes at the light microscopic level always take place in less than 2 h. The point of no return occurs several hours before the appearance of morphologic features. In vivo, the duration of an apoptotic cell death has been estimated to be between 6 and 24 h, although it may vary depending on the cell type. As a result of the short time scale of apoptosis, only few cells undergoing apoptosis are present at a single time point and the quantitative significance of apoptosis may easily be underestimated.
Clinical Relevance Of Apoptosis Library
In the developing organism there is a specialised form of cell death previously called apoptosis but now known as ‘programmed cell death’ (PCD). During embryonic development of the nervous system a surplus of cells is produced. PCD eliminates those neurons whose axons fail to reach the target. It occurs with the withdrawal of trophic substances, such as nerve growth factor, or with a loss of synaptic contact or afferent input. Cytokines (e.g. TNF-α) and ROS may trigger PCD.
Oxidative stress, glutamate excitotoxicity and calcium influx can induce apoptosis in the mature central nervous system. Excessive production of ROS causes ‘oxidative stress’, damaging lipid membranes, proteins, nucleic acids and extracellular matrix glycosaminoglycans. At low levels of ROS or depletion of antioxidants (e.g. superoxide dismutase, catalase, glutathione peroxidase) apoptosis occurs. At high levels ROS produce more damage and cause necrosis.
Glutamate receptor-mediated neuronal injury is an important cause of ‘excitotoxic‘ neuronal death following ischaemia, trauma, epileptic seizures or neurodegeneration. Glutamate produces either necrosis associated with influx of Na+, Cl− and water leading to cell swelling or delayed neuronal death (DND) which appears to be apoptotic, occurring several hours after exposure and associated with calcium influx via channels linked to glutamate receptors.
Calcium is an important second messenger, instrumental in inducing apoptosis by stimulating neurotransmitter release, gene induction and the activation of enzymes (proteases, phosphatases, protein kinases, endonucleases, phospholipases and nitric oxide synthase). Phospholipase A2 produces superoxide anion, and nitric oxide synthase produces nitric oxide, both of which can cause oxidative stress leading to apoptosis.
Increased apoptosis caused by excessive intracellular Ca2+ has been implicated in cerebral ischaemia, traumatic brain injury, epilepsy and neurodegenerative disease. Cerebral ischaemia results in both necrosis and DND. Cells undergoing DND as a result of less severe insult are seen on the periphery of the infarct within the penumbra. There is accumulating evidence that apoptosis plays a role in DND. Gene transfer using herpes simplex viruses containing a Bcl-2 vector may offer neuroprotection against ischaemia. In traumatic brain injury apoptosis occurs in ≈ 10% of dying neurons, peaking 24–48 h after injury. With severe trauma, the proportion of necrotic cell death increases and antiapoptotic agents may minimise cell death following trauma.
Enhanced apoptosis is implicated in several neurodegenerative diseases. In Alzheimer’s disease accumulation of β-amyloid peptide in plaques in the brain and cerebral vasculature causes apoptosis of cortical neurones, possibly via nitric oxide (NO). Parkinson's disease is associated with the loss of dopaminergic neurones in the substantia nigra, and dopamine is thought to cause apoptosis in exposed neurons.
Some forms of familial amyotrophic lateral sclerosis may be caused by a mutant gene coding for the antioxidant superoxide dismutase resulting in motor neuron loss via apoptosis. Future therapy may involve the use of growth factors or inhibitors of macromolecular synthesis to block apoptosis.
Defective apoptosis caused by mutant apoptotic genes may contribute to the development of neural tumours. Mutated p53 is seen in astrocytic tumours. Protein kinase C inhibitors (e.g. hypericin and calphostin) can cause apoptosis in glioma cell lines. Gene transfer techniques have also been used to introduce Bcl-xs into neuroblastoma cells and ICE retrovirus into gliosarcoma cells with induction of apoptosis in these tumours.
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