الفهرس 
Mechanism of apoptosisOnly 14 pages are availabe for public view
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Abstract
Proliferation and cell death are the two sides of the
same coin, rimmed by cellular homeostasis. The
regulatory networks controlling the life and death
decisions on the cellular level are more complex than we
previously thought. The strict regulation of responses to
external stimuli maintains tuned the signalling cascades,
while unbalance is involved in a number of pathological
conditions, ranging from neurodegeneration to
neoplastic transformation.
Apoptosis is a well-conserved physiological
pathway whose basic tenets appear common to all
metazoans. Key components regulate the commitment
step and/or participate in effecting cell demise.
Two main trails lead to apoptosis: the death receptor
or extrinsic pathway and the mitochondrial or intrinsic
pathway. The later is a rapid and strong way to execute
the process. Breaches of mitochondria integrity result in
the release of proapoptotic factors like cytochrome c.
Tough this research area is rapidly developing many
issues remain shrouded in uncertainties. The relationship
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between both mitochondrial membranes is uncertain and
controversial. Large pores are involved, though their
possible interplay is unclear. Recently the work on
mitochondrial cristae remodeling has elucidated a novel
checkpoint for apoptosis, which may determine
sensitivity to apoptosis in vivo, during adult animal life.
Apoptosis, an essential physiological process that is
required for the normal development and maintenance
of tissue homeostasis, is mediated by active intrinsic
mechanisms, although extrinsic factors can also
contribute.
Aerobic metabolism induces the production of
reactive oxygen species (ROS), which are able to induce
oxidative stress that promotes cellular apoptosis. The
mechanisms of ROS-induced modifications in ion
transport pathways involves oxidation of sulphydryl
groups located in the ion transport proteins, peroxidation
of membrane phospholipids, inhibition of membranebound
regulatory enzymes and modification of the
oxidative phosphorylation and ATP levels.
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Alterations in the ion transport mechanisms lead to
changes in a second messenger system, primary Ca2+
homeostasis. Ca2+ disregulation induces mitochondrial
depolarization, which further augments the abnormal
electrical activity and disturbs signal transduction,
causing cell dysfunction and apoptosis. Control of ROS
levels in cells is important, because cellular dysfunction
triggered by ROS is a major factor contributing to the
development of many diseases. Available evidences
show that ROS can induce increases in cytosolic free
Ca2+ concentration ([Ca2+]c) by release of the divalent
cation from internal stores and impairment of Ca2+
clearance systems. In fact, [Ca2+]c increase is a constant
feature of pathological states associated with oxidative
stress and apoptosis.
In the central nervous system both neurons and
astrocytes play crucial roles. On a cellular level, brain
activity involves continuous interactions within complex
cellular circuits established between neural cells and
glia. Despite it was initially considered that neurons
were the major cell type in cerebral function, nowadays
astrocytes are considered to contribute to cerebral
function too. Astrocytes support normal neuronal
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activity, including synaptic function, by regulating the
extracellular environment with respect to ions and
neurotransmitters.
In both cell types Ca2+ signalling plays a pivotal
role. Normal Ca2+ homeostasis is required for cell
activity, in either in neurons and astrocytes, and must be
precisely regulated. On the other hand, mitochondria are
the major cellular source for ATP, and are also central
for Ca2+ homeostasis. Deregulation of cell cycle has
devastating effects on the integrity of cells, and has been
closely associated with the development of pathologies
which can lead to dysfunction and cell death.
Programmed cell death or apoptosis can be activated
and/or initiated by different mechanisms involving cell
membrane receptor activation, Ca2+ signal impairment,
mitochondrial uncoupling or oxidative stress, and
involves in its majority, caspase-mediated cleavage
cascade.
An alteration of normal neuronal/glial physiology
and apoptotic processes could represent the basis of
neurodegenerative processes. In this chapter we will pay
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attention on to the recent findings in neuronal-astrocyte
connection and its relationship to apoptosis.
Acute neuronal injury models provide an interesting
platform for an
investigation into the range and diversity of cell
death mechanisms within a single insult. Acute toxicity
models range from excitotoxic and inflammatory states
to activation-delayed programmed cell death.
Furthermore, the diversity of cell types and subtypes
present within the neuronal system leads to differential
sensitivity to cell death stimuli.
The role of apoptosis during neuronal development,
as well as the possible role of nonapoptotic cell death in
the nervous system is well known. There is an
importnant relevance of different cell death mechanisms
in several neurodegenerative diseases and this can be
potentially neuroprotective targets for treatment of these
diseases.
There is too much evidence of apoptotic death in
several neurodegenerative diseases. There is also
evidence for the involvement of caspase-independent
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cell death in neurodegenerative disorders, focusing on
the proteolytic mechanism of calpains and cathepsins.
Neurodegenerative diseases, includingAlzheimer’s
disease, Parkinson’s disease, and Huntington’s disease,
are a group of age-dependent, progressive disorders that
exhibit prominent neuronal death. Alzheimer’s disease
and Parkinson’s disease are mainly sporadic, whereas
Huntington’s disease is entirely genetic. Studies on
human postmortem brains highlighted the possible
involvement of apoptosis and autophagy in neuron death
in the diseases. Studies using genetically engineered
mouse models confirmed contributions of key apoptosis
genes in disease progression in these experimental
systems. In addition, mouse models confirmed that
neurotoxins may accelerate and exacerbate disease
progression. A better understanding of neuron death
mechanisms in these diseases will help design better
treatment strategies.
Recent advances in apoptosis research have paved
the way for targeting apoptosis for therapy, using
different strategies and pharmacological manipulation.
But, there are some technical limitations for techniques
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such as gene therapy, antisense strategies. It needs to be
determined to what extent toxicity of normal tissue will
limit the application of apoptosis-based therapies in
clinical trials. Perhaps, apoptosis-based treatment will
need to be tailor made for each patient and one should
also take into consideration the emergence of resistance
to treatment. Therefore, a combination of current
conventional treatment and apoptosis-targeted events
seems a more likely successful scenario