Acute Radiation Disease,CountermeasureDevelopment

8/9/2019 Acute Radiation Disease,CountermeasureDevelopment

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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 ME D I CA L T E C H N O L O G Y A N DS Y S T E M S I N C . C A N A D A .

Acute Radiation Disease.

Countermeasure Development.


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Acute Radiation Disease. Countermeasure Development.

Complete Prote!e I"#$%$tor Co&'t$l

ProteoGuard is a complete EDTA-free protease inhibitor cocktailcontaining an optimied mi!ture of protease inhibitors"speciall#designed to protect proteins from being digested b# endogenous

proteases that can be released during protein e!traction from celll#sates.

http$%%&&&.clontech.com%'(%Products%Protein)E!pression)and)Purification%Reagents%Protease)*nhibitors+

pmc,proteoguardsite!,//0/$00120$'(gclid,C3&4EAiA/uGm5RD&32mEv-6lC7(8AD!9:;6oeh9A?t?r@k&2471R;9knf/t2BR& 6ofv:C5oCCd&)&c5


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ild and oderate doses and of radiation e!posureinduces apoptosis controlledF programmed death ofradiosensitive cells &ithout significant levels of

specific radiation-induced to!in formation and &ithout of inflammator# response.


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oderate and high doses of radiation inducesnecrosis of radiosensitive cells &ith the subse>uentformation of radiation to!ins and their induced acute

inflammator# processes. Radiation necrosis is themost substantial and most severe form of radiationinduced in3ur#F and &hen &idespreadF has gravetherapeutic implications.


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C!p!e!F or c #steine-aspartic proteases or & #steine-dependent !partate-directed prote!e! are a famil# ofc#steine proteasesthat pla# essential roles in apoptosis programmed cell deathF necrosisF and inflammation.H0I

Caspases are essential in cells for apoptosisF orprogrammed cell death such as JecrptosisF indevelopment and most other stages of adult lifeF andhave been termed Ke!ecutionerK proteins for their rolesin the cell. (ome caspases are also re>uired in theimmune s#stem for the maturation of l#mphoc#tes.

http://en.wikipedia.org/wiki/Cysteine_proteasehttp://en.wikipedia.org/wiki/Cysteine_proteasehttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Caspasehttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Developmental_biologyhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Developmental_biologyhttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Caspasehttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Cysteine_proteasehttp://en.wikipedia.org/wiki/Cysteine_proteasehttp://en.wikipedia.org/wiki/Cysteine_protease


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Caspases are regulated at a post-translational levelF ensuring thatthe# can be rapidl# activated. The# are first s#nthesied asinactive pro-caspasesF that consist of a prodomainF a smallsubunit and a large subunit. *nitiator caspases possess a longer

prodomain than the effector caspasesF &hose prodomain is ver#small. The prodomain of the initiator caspases contain domainssuch as a CARD domain e.g.F caspases-0 and caspase-L or adeath effector domain DED caspases-M and caspase-/ thatenables the caspases to interact &ith other molecules that

regulate their activation. These molecules respond to stimuli thatcause the clustering of the initiator caspases. (uch clusteringallo&s them to activate automaticall#F so that the# can proceed toactivate the effector caspases.

http://en.wikipedia.org/wiki/Translation_(genetics)http://en.wikipedia.org/wiki/CARD_domainhttp://en.wikipedia.org/wiki/Caspase_2http://en.wikipedia.org/wiki/Caspase-9http://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Caspase_8http://en.wikipedia.org/wiki/Caspase_10http://en.wikipedia.org/wiki/Caspase_10http://en.wikipedia.org/wiki/Caspase_8http://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Death_effector_domainhttp://en.wikipedia.org/wiki/Caspase-9http://en.wikipedia.org/wiki/Caspase_2http://en.wikipedia.org/wiki/CARD_domainhttp://en.wikipedia.org/wiki/Translation_(genetics)


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The caspase cascade can be activated b#$

;vervie& of signal transduction path&a#s involvedin apoptosis.

gran#me 5 released b# c#toto!ic T l#mphoc#tes and J4 cellsF &hich is kno&n to activate caspase-1and -2

death receptors like ?asF TRA*6 receptors and

TJ? receptorF &hich can activate caspase-M and -/the apoptosome regulated b# c#tochrome c and the

5cl-0 famil# F &hich activates caspase-L.

http://en.wikipedia.org/wiki/Apoptosishttp://en.wikipedia.org/wiki/Granzyme_Bhttp://en.wikipedia.org/wiki/Granzyme_Bhttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocytehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocytehttp://en.wikipedia.org/wiki/NK_cellshttp://en.wikipedia.org/wiki/Fas_ligandhttp://en.wikipedia.org/wiki/TRAILhttp://en.wikipedia.org/wiki/Tumor_necrosis_factor_receptorhttp://en.wikipedia.org/wiki/Apoptosomehttp://en.wikipedia.org/wiki/Cytochrome_chttp://en.wikipedia.org/wiki/Cytochrome_chttp://en.wikipedia.org/wiki/Bcl-2http://en.wikipedia.org/wiki/Caspase-9http://en.wikipedia.org/wiki/Caspase-9http://en.wikipedia.org/wiki/Bcl-2http://en.wikipedia.org/wiki/Cytochrome_chttp://en.wikipedia.org/wiki/Cytochrome_chttp://en.wikipedia.org/wiki/Apoptosomehttp://en.wikipedia.org/wiki/Tumor_necrosis_factor_receptorhttp://en.wikipedia.org/wiki/TRAILhttp://en.wikipedia.org/wiki/Fas_ligandhttp://en.wikipedia.org/wiki/NK_cellshttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocytehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocytehttp://en.wikipedia.org/wiki/Granzyme_Bhttp://en.wikipedia.org/wiki/Granzyme_Bhttp://en.wikipedia.org/wiki/Apoptosis


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Ser$"e prote!e! or !er$"e e"opept$!e!are en#mes that cleave peptide bonds in proteinsF in &hich serine serves as thenucleophilic amino acid atthe en#meNs active site.HI The# are foundubi>uitousl# in both eukar#otes and prokar#otes.(erine proteases fall into t&o broad categories basedon their structure$ ch#motr#psin-like tr#psin-like orsubtilisin-like.H0I *n humansF the# are responsible forco-ordinating various ph#siological functionsFincluding digestionF immune responseF bloodcoagulation and reproduction

http://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Peptide_bondhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Serinehttp://en.wikipedia.org/wiki/Nucleophilichttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Active_sitehttp://en.wikipedia.org/wiki/Serine_proteasehttp://en.wikipedia.org/wiki/Eukaryoteshttp://en.wikipedia.org/wiki/Prokaryoteshttp://en.wikipedia.org/wiki/Chymotrypsinhttp://en.wikipedia.org/wiki/Subtilisinhttp://en.wikipedia.org/wiki/Serine_proteasehttp://en.wikipedia.org/wiki/Serine_proteasehttp://en.wikipedia.org/wiki/Subtilisinhttp://en.wikipedia.org/wiki/Chymotrypsinhttp://en.wikipedia.org/wiki/Prokaryoteshttp://en.wikipedia.org/wiki/Eukaryoteshttp://en.wikipedia.org/wiki/Serine_proteasehttp://en.wikipedia.org/wiki/Active_sitehttp://en.wikipedia.org/wiki/Amino_acidhttp://en.wikipedia.org/wiki/Nucleophilichttp://en.wikipedia.org/wiki/Serinehttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Peptide_bondhttp://en.wikipedia.org/wiki/Enzyme


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The ER;P( protease classification s#stem counts :superfamilies as of 0/1 each containing man# families.Each superfamil# uses the catal#tic triad or d#ad in adifferent protein fold and so represent convergent evolution

of the catal#tic mechanism. The ma3orit# belong to the (famil# of the PA clan superfamil# of proteases.

?or superfamiliesF P , superfamil# containing a mi!ture ofnucleophile class familiesF ( , purel# serine proteases.

superfamil#. ithin each superfamil#F families aredesignated b# their catal#tic nucleophile ( , serineproteases.

http://en.wikipedia.org/wiki/MEROPShttp://en.wikipedia.org/wiki/Protein_superfamilyhttp://en.wikipedia.org/wiki/Protein_familyhttp://en.wikipedia.org/wiki/Catalytic_triadhttp://en.wikipedia.org/wiki/Protein_foldhttp://en.wikipedia.org/wiki/Convergent_evolutionhttp://en.wikipedia.org/wiki/Catalytic_mechanismhttp://en.wikipedia.org/wiki/PA_clanhttp://en.wikipedia.org/wiki/Protein_superfamilyhttp://en.wikipedia.org/wiki/Nucleophilehttp://en.wikipedia.org/wiki/Protein_familyhttp://en.wikipedia.org/wiki/Protein_familyhttp://en.wikipedia.org/wiki/Nucleophilehttp://en.wikipedia.org/wiki/Protein_superfamilyhttp://en.wikipedia.org/wiki/PA_clanhttp://en.wikipedia.org/wiki/Catalytic_mechanismhttp://en.wikipedia.org/wiki/Convergent_evolutionhttp://en.wikipedia.org/wiki/Protein_foldhttp://en.wikipedia.org/wiki/Catalytic_triadhttp://en.wikipedia.org/wiki/Protein_familyhttp://en.wikipedia.org/wiki/Protein_superfamilyhttp://en.wikipedia.org/wiki/MEROPS


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E!perimental treatment of Acute Radiation(#ndromes. *nhibition of activated serine proteases.

The usual doses of gabe!ate

mesilate ?;7F nafamostat mesilate ?'Tand ulinastatin 'T* for Acute Radiation

(#ndromes are

0//-:// mg%da#F /-:/ mg%da# and


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(ince severe Acute Radiation (#ndromes is often

complicated b# disseminated intravascular

coagulation and shockF it is recommended that

these reagents be given in doses approved for

in severe acute pancreatitis.

?;7$ 1/-/ mg%kg%da#O ?'T$ 0.-.M mg%kg%da#O 'T*

Acute Radiation Disease,CountermeasureDevelopment

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