Pathologic apoptosis

Abnormalities in cell death regulation can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurodegenerative diseases such as Parkinson s disease, Alzheimer s disease, Huntington s disease, and amyotrophic lateral sclerosis. Some conditions feature insufficient apoptosis, whereas others feature excessive apoptosis. 

Cancer is an example where the normal mechanisms of cell cycle regulation are dysfunctional, with an overproliferation of cells and/or decreased removal of cells. In fact, suppression of apoptosis during carcinogenesis is thought to play a central role in the development and progression of some cancers. There are a variety of molecular mechanisms that tumor cells use to suppress apoptosis. 

Alterations of various cell signaling pathways can result in dysregulation of apoptosis and lead to cancer. The p53 tumor suppressor gene is a transcription factor that regulates the cell cycle and is the most widely mutated gene in human 

In addition to cancer, too little apoptosis can also result in diseases such as autoimmune lymphoproliferative syndrome (ALPS). This occurs when there is insufficient apoptosis of auto-aggressive T cells, resulting in multiple autoimmune diseases. An overproliferation of B cells occurs as well, resulting in excess immunoglobulin production, leading to autoimmunity. Some of the common diseases of ALPS include hemolytic anemia, immune-mediated thrombocytopenia, and autoimmune neutropenia. The different types of this condition are caused by different mutations. Type 1A results from a mutation in the death domain of the Fas receptor, Type IB results from a mutation in Fas ligand, and Type 2 results from a mutation in caspase 10, reducing its activity. 

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Tan pathology Apoptosis Neurotransmission deficits APP production inhibitors A 3-Selective regulators Phosphatase activators GSK-3 inhibitors Cdk5 inhibitors P38 inhibitors JNK inhibitors Caspase inhibitors Neurotrophic agents Phenserine tartrate Posiphen Reticulons Chaperones/SLF-CR Axonyx Axonyx/National Institutes of Health Howard Hughes Medical Institute... 

Blomgren, K., Zhu, C., Wang, X., et al., 2001, Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia a mechanism of pathological apoptosis , J. Biol. Chem., 276, 10191-10198... 

Cyclosporine binds to cyclophilin within T cells. The CsA-cyclophilin complex then binds to calcinenrin and inhibits calcinenrin s activity reqnired for the dephosphorylation of regnlatory proteins necessary for the transcription and prodnction of proinflammatory cytokines (IL-2, IL-4, IFN-y, and tnmor necrosis factor-a) from T-helper cells. CsA prevents pathologic apoptosis of the tear-secreting epithelia by preventing the ability of the mitochondrial permeability transition pore to open, a reqnired step in the apoptotic process. 

HDAC inhibition holds particular promise in anticancer therapy, where the concerted effects on multiple pathways involved in growth inhibition, differentiation and apoptosis may prove to be advantageous in the treatment of a heterogeneous pathology such as tiunor formation and growth. 

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

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