Asian Journal of Pharmaceutical Research and Development Review Article a BRIEF REVIEW on APOPTOSIS

Asian Journal of Pharmaceutical Research and Development Vol. 5 (3) May–June. 2017:1-10 Asian Journal of Pharmaceutical Research and Development (An International Peer-Reviewed Journal of Pharmaceutical Research and Development) www.ajprd.com ISSN 2320-4850 Review Article A BRIEF REVIEW ON APOPTOSIS ANKIT*, RANU SHARMA, SURYA PRATAP SINGH, M. P. KHINCHI Department of Pharmacology, Kota College of Pharmacy, Kota, Rajasthan, India ABSTRACT Apoptosis is a cell death mechanism characterized by depolymerization of cytoskeleton, cell shrinkage, chromatin condensation, nuclear fragmentation and translocation of phosphatidylserine to the cell surface. This process is therefore called programmed cell death. Between 50 and 70 billion cells die each day due to apoptosis in the average human adult. Apoptosis and necrosis are considered to be distinct modes of cell death; however, apoptosis can progress to secondary necrosis if apoptotic cells are not efficiently removed by phagocytic cells. During the last decade, exceptional for the basic research, the apoptosis have attracted many attentions due to its potential application in therapying the various human diseases. In diseases caused by deficient apoptosis, such as cancer, viral latency and autoimmunity, methods of producing selective apoptosis are being sought Keywords: depolymerisation, cytoskeleton, chromatin condensation, necrosis, phagocytic cell. INTRODUCTION poptosis is a cell death mechanism The cells of a multicellular organism are characterized by depolymerization of members of a highly organized community. A cytoskeleton, cell shrinkage, The number of cells in this community is chromatin condensation, nuclear fragmentation tightly regulated—not simply by controlling and translocation of phosphatidylserine to the the rate of cell division, but also by controlling cell surface. Apoptosis arises from a number the rate of cell death. If cells are no longer of stimuli that initiate multiple signaling needed, they commit suicide by activating an pathways which lead to caspase cascade intracellular death program. This process is activation and cell death. Increases in therefore called programmed cell death.[2] apoptotic activity are hallmarks of several Unlike necrosis, apoptosis produces cell disease states including AIDS, fragments called apoptotic bodies neurodegenerative disorders, insulin- that phagocytic cells are able to engulf and dependent diabetes, myocardial infarction and quickly remove before the contents of the cell atherosclerosis. .[1] can spill out onto surrounding cells and cause damage to the neighbouring cells.[3] *Corresponding author Ankit Sharma Between 50 and 70 billion cells die each day Kota College of Pharmacy, due to apoptosis in the average human Kota, Rajasthan adult. For an average child between the ages of E mail: [email protected] Mobile – 7597306841 8 and 14, approximately 20 billion to 30 billion cells die a day.[4] Research on apoptosis has increased substantially since the early 1990s. In addition to its importance as a Ankit Sharma et al www.ajprd.com 1 Asian Journal of Pharmaceutical Research and Development Vol. 5 (3) May–June. 2017:1-10 biological phenomenon, defective apoptotic processes have been implicated in a wide variety of diseases. Excessive apoptosis example, the separation of fingers and toes in a causes atrophy, whereas an insufficient developing human embryo occurs because amount results in uncontrolled cell cells between the digits undergo apoptosis.[5] proliferation, such as cancer. Some factors like Fas receptors and caspases promote PATHWAYS apoptosis, while some members of the Bcl-2 The mechanisms of apoptosis are highly family of proteins inhibit apoptosis. Because complex and sophisticated, involving an apoptosis cannot stop once it has begun, it is a energy-dependent cascade of molecular highly regulated process. Apoptosis can be events. To date, research indicates that there initiated through one of two pathways. In are two main apoptotic pathways: the extrinsic the intrinsic pathway the cell kills itself or death receptor pathway and the intrinsic or because it senses cell stress, while in mitochondrial pathway. However, there is now the extrinsic pathway the cell kills itself evidence that the two pathways are linked and because of signals from other cells. Both that molecules in one pathway can influence pathways induce cell death by the other. There is an additional pathway that activating caspases, which are proteases, or involves T-cell mediated cytotoxicity and enzymes that degrade proteins. The two perforin-granzyme-dependent killing of the pathways both activate initiator caspases, cell. The perforin/granzyme pathway can which then activate executioner caspases, induce apoptosis via either granzyme B or which then kill the cell by degrading proteins granzyme A. The extrinsic, intrinsic, and indiscriminately. granzyme B pathways converge on the same Apoptosis and necrosis are considered to be terminal, or execution pathway. This pathway distinct modes of cell death; however, is initiated by the cleavage of caspase-3 and apoptosis can progress to secondary necrosis if results in DNA fragmentation, degradation of apoptotic cells are not efficiently removed by cytoskeletal and nuclear proteins, cross-linking phagocytic cells.In contrast to necrosis, which of proteins, formation of apoptotic bodies, is a form of traumatic cell death that results expression of ligands for phagocytic cell from acute cellular injury, apoptosis is a highly receptors and finally uptake by phagocytic regulated and controlled process that confers cells. The granzyme A pathway activates a advantages during an organism's lifecycle. For parallel, caspase-independent cell death pathway via single stranded DNA damage.[6] Fig.1 Normal apoptosis process Ankit Sharma et al www.ajprd.com 2 Asian Journal of Pharmaceutical Research and Development Vol. 5 (3) May–June. 2017:1-10 Figure 2 : Apoptotic Pathway By Different Pathways Intrinsic Pathway Extrinsic Pathway Two theories of the direct initiation of The intrinsic signaling pathways that initiate apoptotic mechanisms in mammals have been apoptosis involve a diverse array of non-receptor- suggested: the TNF-induced (tumor necrosis mediated stimuli that produce intracellular signals factor) model and the Fas-Fas ligand- that act directly on targets within the cell and are mediated model, both involving receptors of mitochondrial-initiated events. The stimuli that the TNF receptor (TNFR) family[9] coupled to initiate the intrinsic pathway produce intracellular extrinsic signals. signals that may act in either a positive or negative fashion. Negative signals involve the absence of TNF path certain growth factors, hormones and cytokines that can lead to failure of suppression of death TNF-alpha is a cytokine produced mainly by programs, thereby triggering apoptosis. In other activated macrophages, and is the major words, there is the withdrawal of factors, loss of extrinsic mediator of apoptosis. Most cells in apoptotic suppression, and subsequent activation of the human body have two receptors for TNF- apoptosis. Other stimuli that act in a positive alpha: TNFR1 and TNFR2. The binding of fashion include, but are not limited to, radiation, TNF-alpha to TNFR1 has been shown to toxins, hypoxia, hyperthermia, viral infections, and initiate the pathway that leads to caspase free radicals. The mitochondria are essential to activation via the intermediate membrane multicellular life. Without them, a cell ceases proteins TNF receptor-associated death to respire aerobically and quickly dies. This fact domain (TRADD) and Fas-associated death forms the basis for some apoptotic pathways. domain protein (FADD). cIAP1/2 can inhibit Apoptotic proteins that target mitochondria affect TNF-α signaling by binding to TRAF2. FLIP [10] them in different ways. They may cause inhibits the activation of caspase-8. Binding mitochondrial swelling through the formation of of this receptor can also indirectly lead to the membrane pores, or they may increase the activation of transcription factors involved in permeability of the mitochondrial membrane and cell survival and inflammatory cause apoptotic effectors to leak out.[7][8] responses. However, signalling through TNFR1 might also induce apoptosis in a caspase-independent manner.[35]The link Ankit Sharma et al www.ajprd.com 3 Asian Journal of Pharmaceutical Research and Development Vol. 5 (3) May–June. 2017:1-10 between TNF-alpha and apoptosis shows why bypassed and there is direct induction of the an abnormal production of TNF-alpha plays a execution phase of apoptosis. fundamental role in several human diseases, especially in autoimmune diseases. Execution Pathway Fas path The extrinsic and intrinsic pathways both end at the point of the execution phase, considered the final The fas receptor (First apoptosis signal) – (also pathway of apoptosis. It is the activation of the known as Apo-1 or CD95) is a transmembrane execution caspases that begins this phase of protein of the TNF family which binds the Fas apoptosis. Execution caspases activate cytoplasmic ligand (FasL). The interaction between Fas endonuclease, which degrades nuclear material, and FasL results in the formation of the death- and proteases that degrade the nuclear and inducing signaling complex (DISC), which cytoskeletal proteins. Caspase-3, caspase-6, and contains the FADD, caspase-8 and caspase-10. caspase-7 function as effector or ―executioner‖ In some types of cells (type I), processed caspases,

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