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Radiation Toxicity: Apoptosis and\or Necrosis.
1. D M I T R I P O P O V . P H D , R A D I O B I O L O G Y .
M D ( R U S S I A )
A D V A N C E D M E D I C A L T E C H N O L O G Y A N D
S Y S T E M S I N C . C A N A D A .
I N T E R V A C C I N E @ G M A I L . C O M
Radiation Toxicity: Apoptosis
andor Necrosis.
2. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Accumulating evidences suggest that induction of
apoptosis alone is insufficient to account for the
therapeutic effect of radiotherapy.
ï‚— Tumour Biol. 2010 Aug;31(4):363-72. doi:
10.1007/s13277-010-0042-8. Epub 2010 May 20.
ï‚— Radiation-induced cell death mechanisms.
ï‚— Eriksson D1, Stigbrand T.
3. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Moderate and high doses of radiation induces
necrosis of radiosensitive cells with the subsequent
formation of radiation toxins and their induced acute
inflammatory processes. Radiation necrosis is the
most substantial and most severe form of radiation
induced injury, and when widespread, has grave
therapeutic implications.
4. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Mild and Moderate doses and of radiation exposure
induces apoptosis (controlled, programmed death of
radiosensitive cells) without significant levels of
specific radiation-induced toxin formation and
without of inflammatory response.
5. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— The type of Cell Death depend on doses of Radiation,
Type of Radiation and Radiosensitivity of irradiated
cells.
ï‚— Radiosensitivity of irradiated cells depend on
mitotic rate, metabolic rate.
6. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Radiation induced Apoptosis and Necrosis as
response of eukaryotic cells to influence of
different types of radiation remain contraversion.
Radiation induced cell death by triggering
apoptosis pathways was described in many articles
and supported by many scientists.
7. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— However, some scientists and some institutions
described processes developing in irradiated
eukaryotic cells as necrosis and some scientists
describing a variety of complex mechanism and
mentioned that radiation-induced cell death could
developing under different mechanisms of
pathogenesis which include and apoptosis and
necrosis.
8. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Activation of cysteine proteases, cleavage of PARP -
poly (ADP-ribosyl) activation of nuclear proteins
causes the inner mitochondrial membrane to become
permeable for ions and other small molecules
during both types of cell death- apoptosis and
necrosis. Many mechanisms of cell necrosis
and cell apoptosis are identical – for example,
degradation of the Nuclear matrix is a Common
Element during Radiation-Induced Apoptosis and
Necrosis.
9. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— During apoptosis, the activation of a family of
cysteine proteases, or caspases, results in proteolytic
cleavage of numerous substrates.
Poly (ADP-ribose) polymerase (PARP), a nuclear
enzyme involved in DNA repair, is a well-known
substrate for caspase-3 cleavage during apoptosis.
10. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptotic death requires the controlled degradation
of the cell. Proteases play a crucial role in this
programmed cell death or apoptosis. However,
proteases can play important role in development
non-programmed cell death or necrosis.
ï‚— Possible, that cell apoptosis and cell necrosis share
pathways for cell death up to some point of this
pathways and after this point developing different
mechanisms of death with different biological
sequaele.
11. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Data from different sources described that the
differences between apoptosis and necrosis
ï‚— are much less numerous than previously studies
suggested.
ï‚— Joseph Dynlacht and his research group of scientists
studied the outcome of human promyelocytic leukemia
(HL60) cells irradiated with 10 or 50 Gy of X-rays and
determined the mode of leukemic cell death.
ï‚— Different doses of X-rays induced different modes of cell
death – cells irradiated with 10 Gy died by apoptosis;
cells irradiated with 50Gy died predominantly by
necrosis.
12. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— The Cell Death Nomenclature Committee
recommends the use of the appropriate diagnosis:
Apoptotic Necrosis.
13. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptosis is described as a normally active,
programmed process of cell death devoid of
inflammation and toxins.
14. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Necrosis possesses the characteristics of accidental
or externally-induced cell death from the influence
of different environmental factors and
triggering development of inflammation and
elaborating of toxins, release of proinflammatory
active and toxic cellular contents into the
intracellular and extracellular fluids
and into the lymphatic systems and blood
circulation
15. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptosis : Inflammation never present. Toxic
substances never present. Morphologically cells
shrinks, become denser, condensation occur, original
name – shrinkage necrosis. Mitochondria’s
structure and functions are not affected. Karyorhexis
– pyknotic nuclear fragments. DNA broken into
segments. Caspase activation always present. Genetic
control initiate apoptosis. The Budding
phenomenon. Cell membrane not affected.
17. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Karyolysis, Pyknosis, Karyorhesis. Nuclear
swelling, Chromatin granular, Chromatin
flocculation, Types of radiation induced
damage of DNA: Breaks of the strand,
alteration to bases, destruction of sugar,
cross-links and formation of dimmers.
18. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Caspase depended initiation of developing
of necrosis possible. Caspase-8 initiation
possible with apoptosis and necrosis.
19. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptosis can be induced through the activation of
death receptors including Fas, TNFαR, DR3, DR4,
and DR5 by their respective ligands. Death receptor
ligands characteristically initiate signaling via
receptor oligomerization, which in turn results in the
recruitment of specialized adaptor proteins and
activation of caspase cascades - See more at:
http://www.cellsignal.com/contents/science-
pathway-research-apoptosis/death-receptor-
signaling-pathway/pathways-apoptosis-deathÑŽ .
20. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Activated caspase-8 stimulates apoptosis via two
parallel cascades: it can directly cleave and activate
caspase-3, or alternatively, it can cleave Bid, a pro-
apoptotic Bcl-2 family protein. Truncated Bid (tBid)
translocates to mitochondria, inducing cytochrome c
release, which sequentially activates caspase-9 and -
3. TNF-α and DR-3L can deliver pro- or
antiapoptotic signals - See more at:
http://www.cellsignal.com/contents/science-
pathway-research-apoptosis/death-receptor-
signaling-pathway/pathways-apoptosis-death .
21. Radiation Toxicity: Apoptosis andor Necrosis.
 TNFαR and DR3 promote apoptosis via the adaptor
proteins TRADD/ FADD and the activation of
caspase-8. Interaction of TNF-α with TNFαR may
activate the NF-κB pathway via NIK/IKK. The
activation of NF-κB induces the expression of pro-
survival genes including Bcl-2 and FLIP, the latter
can directly inhibit the activation of caspase-8. - See
more at:
http://www.cellsignal.com/contents/science-
pathway-research-apoptosis/death-receptor-
signaling-pathway/pathways-apoptosis-death
22. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— In the absence of caspase activation, stimulation of
death receptors can lead to the activation of an
alternative programmed cell death pathway termed
necroptosis by forming complex IIb. - See more at:
http://www.cellsignal.com/contents/science-
pathway-research-apoptosis/death-receptor-
signaling-pathway/pathways-apoptosis-
death#sthash.gORBJNss.dpuf
23. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptosis and necroptosis are distinct types of
regulated cell death.
24. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Apoptosis is characterized by condensed cytosol,
marginalized chromatin and nuclear fragmentation.
Apoptosis requires caspases for its execution. This
cell death pathway can be induced by caspase
activation downstream of growth factor deprivation,
DNA damage or ligands of the death receptor family,
such as tumour necrosis factor (TNF), FAS and TNF-
related apoptosis-inducing ligand (TRAIL).
ï‚— http://www.nature.com/nrm/journal/v14/n11/box/
nrm3683_BX1.html
25. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Necroptosis is characterized by early plasma
membrane permeabilization, translucent cytosol and
swollen mitochondria. Necroptotic cells can be
observed when cells are stimulated by pro-death
signals, such as ligands of the death receptor family
(including TNF, FAS or TRAIL), in the absence of
caspase activation or in vivo after ischaemic injuries.
ï‚— http://www.nature.com/nrm/journal/v14/n11/box/
nrm3683_BX1.html
26. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Receptor-interacting protein 1 (RIP1) kinase is
required to mediate necroptosis signalling through
the activation of RIP3, a downstream mediator of
necroptosis.
ï‚— http://www.nature.com/nrm/journal/v14/n11/box/
nrm3683_BX1.html
ï‚— http://www.intechopen.com/books/current-topics-
in-ionizing-radiation-research/radiation-toxins-
molecular-mechanisms-of-toxicity-and-
radiomimetic-properties-
27. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— Necrostatin 1 was isolated in a cell-based high-
throughput chemical screen for inhibitors of caspase-
independent necrosis6. Although the original necrostatin
1 isolated from the screen, methyl-thiohydantoin-Trp
(MTH-Trp), can inhibit indoleamine 2,3-dioxygenase
(IDO) activity as well as receptor-interacting protein 1
(RIP1) activity, an improved analogue of necrostatin 1, 7-
Cl-O-Nec-1 (5-(7-chloro-1H- indol-3-yl)methyl)-3-
methylimidazolidine-2,4-dione), has no IDO inhibitory
activity.
ï‚— http://www.nature.com/nrm/journal/v14/n11/box/nrm
3683_BX1.html
28. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— 7-Cl-O-Nec-1 demonstrates exclusive selectivity towards
RIP1, as it inhibits RIP1 kinase 1,000 times more
potently than 485 other human kinases, including several
other members of the RIP family, and it binds to RIP1
with high affinity (with a dissociation constant (Kd) of ~3
nM)3. 7-Cl-O-Nec-1 also targets RIP1 kinase
specifically in vivo, as its ability to inhibit cell death is
entirely dependent on the expression of RIP1.
ï‚— Degterev, A. et al. Identification of RIP1 kinase as a
specific cellular target of necrostatins.Nature Chem.
Biol. 4, 313–321 (2008).
Demonstrates that RIP1 kinase is the target of
necrostatin 1.
29. Radiation Toxicity: Apoptosis andor Necrosis.
ï‚— At the present time post radiation necroptosis can be
considered as an alternative form of programmed
cell death whose activation induces important
biological consequences including immune reactions
and induced inflammation.
ï‚— Post Radiation Apoptosis vs Post Radiation
Necroptosis.