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ISBN 978-966-698-134-2
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In monograph there are given and discussed the notifications about modern state of nitric oxide condition problem in the world neurological practice. There is given the exact description of chemical composition of interconnection, mechanisms, their participation in physical process and importance for neurogical system process function. Based on the research papers on the usage of nitric oxide it gives answers to the questions about patogenes in following diseases.
For neurologist, biologist, colleagues, medical and biological faculty students.
ISBN 978-966-698-134-2
# 616.831-005.1-005.4-085-07-032:611.018.749
56.12
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7>B MB> >48= 87 A0AB@0=5==KE M;52 =0 52=0O 53> :>;> 4·1015 B>==) A>A@54>B>G5=0 2 A2>1>4=>AB>O=88 2 0BAD5@5. 7>B G5B25@BK9 ?> @0A?@>AB@0=5==>AB8 M;5;=5G=>9 A8AB5A;5 2>4>@>40, 35;8O 8 :8A;>@>40).
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!B5?5=8 >:8A;5=8O 07>B0 B +5 (2 N2O5) 4> 3 (2 NH3). >1KG=KE CA;>28OE 2 A2>1>4=>AB>O=88 07>B >1@07C5B ;5:C;C N2, 345 0B>B0 A2O70=K B@520;5=B=KB0 >G5=L CAB>9G820.
7>B =53> ;53G5 2>74CE0; ?;>B=>ABL 1,2506 :3/45 07>B @84: ?@8 00! 2 1 @O5BAO 23,3 3 07>B0. CGH5, G545, 07>B @0AB2>@8B>@KE C3;52>4>@>40E. ">;L:> A B0:8B @5038@C5B ?@8 2KA>:>9 B5@>2. %>@>H> 87CG5=K A>548=5=8O 07>B0 A :8A;>@>4>A@54AB25==>1@07C5BAO >:8AL NO, :>B>@0O ?@8 >E;0645=88 ;53:> >:8A;O5BAO 40;55 4> 42C>:8A8 NO2. 2>74CE5 >:8A;K 07>B0 >1@07CNBAO ?@8 0BAD5@=KE @07@O40E. E 6=> ?>;CG8BL B0:65 459AB285@>4>=878@CNI8E 87;CG5=89. @8 @0AB2>@5=88 2 2>45 07>B8AB>3> N2O3 8 07>B=>3> N2O5 0=384@84>2 A>>B25BAB25==> ?>;CG0NBAO 07>B8AB0O ( NO2) 8 07>B=0O ( NO3) :8A;>BK, >1@07CNI85 A>;8 =8B@8BK 8 =8B@0BK. ! 2>4>@>4>B A>548=O5BAO B>;L:> ?@8 2KA>:>9 B5@>2, ?@8 MB>1@07C5BAO 0:A84 07>B0 , NO2
HYPERLINK "http://ru.wikipedia.org/wiki/%D0%98%D0%B7%D0%BE%D0%B1%D1%80%D0%B0%D0%B6%D0%B5%D0%BD%D0%B8%D0%B5:Nitrous-oxide-3D-vdW.png" \o "7>1@065=85:Nitrous-oxide-3D-vdW.png" INCLUDEPICTURE "http://upload.wikimedia.org/wikipedia/commons/thumb/1/1a/Nitrous-oxide-3D-vdW.png/120px-Nitrous-oxide-3D-vdW.png" \* MERGEFORMATINET
>:A84 07>B0, N2O
HYPERLINK "http://ru.wikipedia.org/wiki/%D0%98%D0%B7%D0%BE%D0%B1%D1%80%D0%B0%D0%B6%D0%B5%D0%BD%D0%B8%D0%B5:Dinitrogen-trioxide-3D-vdW.png" \o "7>1@065=85:Dinitrogen-trioxide-3D-vdW.png" INCLUDEPICTURE "http://upload.wikimedia.org/wikipedia/commons/thumb/8/89/Dinitrogen-trioxide-3D-vdW.png/120px-Dinitrogen-trioxide-3D-vdW.png" \* MERGEFORMATINET
>:A84 07>B0 , N2O3
HYPERLINK "http://ru.wikipedia.org/wiki/%D0%98%D0%B7%D0%BE%D0%B1%D1%80%D0%B0%D0%B6%D0%B5%D0%BD%D0%B8%D0%B5:Dinitrogen-pentoxide-3D-vdW.png" \o "7>1@065=85:Dinitrogen-pentoxide-3D-vdW.png" INCLUDEPICTURE "http://upload.wikimedia.org/wikipedia/commons/thumb/4/41/Dinitrogen-pentoxide-3D-vdW.png/120px-Dinitrogen-pentoxide-3D-vdW.png" \* MERGEFORMATINET
07>B=K9 0=384@84, N2O5 HYPERLINK "http://ru.wikipedia.org/wiki/%D0%98%D0%B7%D0%BE%D0%B1%D1%80%D0%B0%D0%B6%D0%B5%D0%BD%D0%B8%D0%B5:Dinitrogen-tetroxide-3D-vdW.png" \o "7>1@065=85:Dinitrogen-tetroxide-3D-vdW.png" INCLUDEPICTURE "http://upload.wikimedia.org/wikipedia/commons/thumb/e/eb/Dinitrogen-tetroxide-3D-vdW.png/120px-Dinitrogen-tetroxide-3D-vdW.png" \* MERGEFORMATINET
>:A84 07>B0, N2O4
8A. 1. !>548=5=8O 07>B0 A :8A;>@>4>B0 O2;O5BAO ?>AB>O==>9 ?@874CE0 8 459AB2C5B ?@0:B8G5A:8 :0: 8=48DD5@5=B=K9 307, 0 2 >G5=L 1>;LH8E :>=F5=B@0F8OE 2 A@>4>B8:. :8AL 07>B0 NO 2K7K205B 1KAB@>5 ?@52@0I5=85 353;>18=0 :@>28 2 18= 8 459AB2C5B =0 F5=B@0;L=CN =5@2=CN A8AB5:8AL 07>B0 NO2 (N2O4) @074@0605B 3;02=K1@07>B5: [51, 36, 1022].
"5@:A84 07>B0» (8;8 «>:8AL 07>B0») >1>7=0G05BAO 2>AAB0=>2;5==0O D>@>:8A8 07>B0 (NO) A ?5@8>4>;C@0A?040 >B 2 4> 30 A. NO ?@54AB02;O5B A>1>9 @0AB2>@845 8 68@0E 15AF25B=K9 307 A C=8:0;L=K;>38G5A:89AB20H5=88 NO ?@54AB02;O5B A>1>9 D8;L=CN ;5:C;C, A>AB>OICN 87 >4=>3> 0B>B0 8 >4=>3> 0B>@>40 8 8=, GB> ?@52@0I05B 55 2 2KA>:> @50:B82=K9 @048:0;, A2>1>4=> ?@>=8:0NI89 G5@57 18>;>38G5A:85 ;O@870F8O ;5:C;K NO >4=0 87 ?@8G8= ?;>E>9 @0AB2>@8AB8 NO 2 2>45. E84>9 NO =5 2ABC?05B, 8 NO =5 O2;O5BAO A>;5>1@07CNI8:8A;>@>4 ;53:> >:8A;O5B NO 4> A>;5>1@07CNI8E >:8A;>2 07>B0, 2 :>B>@KE 0B>B0 8;55 2KA>:85 20;5=B=>AB8 8 1>;55 2KA>:85 AB5?5=8 >:8A;5=8O. 84@0B0F8O A>;5>1@07CNI8E >:8A;>2 07>B0 ?@82>48B : >1@07>20=8N 07>B8AB>9 (HNO2) 8 07>B=>9 (HNO3) :8A;>B. !C?5@>:A840=8>= ( 2-) >:8A;O5B NO 4> ?5@>:A8=8B@8B0 (ONOO-) [121, 130, 167].
>76=>ABL 8>=870F88 NO A >1@07>20=85=0 =8B@>7>=8O (NO+) C:07K205B =0 A2>9AB20 NO :0: 2>AAB0=>28B5;O. !?5:B@ 25I5AB2, 2 >B=>H5=88 :>B>@KE NO A51O ?@>O2;O5B :0: 2>AAB0=>28B5;L, =525;8:. =8B=>AOBAO ;5:C;O@=K9 :8A;>@>4 ( 2), >7>= ( 3), AC?5@>:A840=8>= ( 2-), ;5:C;O@=K9 DB>@ (F2). >76=>ABL 8>=870F88 NO A >1@07>20=85=0 =8B@>:A8;0 (NO) C:07K205B =0 A2>9AB20 NO :0: >:8A;8B5;O. >B=>H5=88 18>>@30=8G5A:8E A>548=5=89 NO A51O >1KG=> ?@>O2;O5B :0: >:8A;8B5;L.
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4=8@54C:B070, >1;040NI0O AB@C:BC@=K4AB2>, :A0=B8=>:A84070 ;>:0 A?>A>1=0 2 0M@>1=KE CA;>28OE 2>AAB0=02;820BL =8B@0BK 8 =8B@8BK A>>B25BAB25==> 2 >-A>45@60I5;L7CO 2 :0G5AB25 4>=>@0 M;5:B@>=>2 NADH. 5402=> CAB0=>2;5=>, GB> :A0=B8=>:A84070 B:0=59 ?8B0NI8E A?>A>1=0 2>AAB0=02;820BL =8B@8B 2 NO. @54?>;0305BAO, GB> MB0 @50:F8O >ACI5AB2;O5BAO 2 ;8145=>2>@5 M;5:B@>=>2 8 2K?>;=O5B 207>48;0B0B>@=CN @>;L ?@8 38?>:A88, :>340 NO-A8=B070 =5 DC=:F8>=8@C5B, 0 :>=F5=B@0F8O NADH 2 B:0=OE ?>2KH5=0 [21, 30, 190, 345, 789].
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=8 A8=B578@CNB NO 2 =51>;LH>;8G5AB25 ;81> 1070;L=>, B.5. =5?@5@K2=>, ;81> AB820==>, =51>;LH8@F8O4 459AB285@>2, :>B>@K5 2>7459AB2CNB 8;8 G5@57 @5F5?B>@K, 8;8 =5 7028AOB >B @5F5?B>@>2. @5F5?B>@7028A8AOBAO 0F5B8;E>;8=, 1@048:8=8=, =>@04@5=0;8=, 0=38>B5=78=, 0 B0:65 D0:B>@K, :>B>@K5 2KA2>1>640NBAO 87 B@>F8B>2, B.5. "$, B@>B>=8=. D0:B>@0B>@K5 =5 7028AOB >B @5F5?B>@>2, >B=>AOBAO >A=>2=K5 D878G5A:85 D0:B>@K, B.5. :>=F5=B@0F8O :8A;>@>40 2 :;5B:5 8 =0?@O65=85 A42830, A28 ?> >B=>H5=8N : M=4>B5;80;L=>N. @53C;OF88 A5@45G=>-A>AC48AB>9 A8AB5;L 83@05B :>=AB8BCB82=0O 5NOS [321, 356, 889].
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>;LH8=AB2> 8AA;54>20B5;59 AG8B05B, GB> 0:B820F8O nNOS 2 20A:C;O@=KE =59@>=0E A>?@>2>6405BAO A=865=852=O A8AB53> 0@B5@80;L=>3> 402;5=8O 8 C:@0I5=89, >1CA;>2;5==KE C3=5B5=854OI8E A80:B828@CNI8E 2;8O=89 : A5@4FC 8 A>AC40=0;L=0O 8 M=4>B5;80;L=0O NO-A8=B07K MB> :>=AB8BCB82=K5 D5@B>@KE, :0: ?@028;>, A2O70=0 A =5B>@>9 2>7@0AB05B 2 1>;55 >B40;5==K5 A@>:8 2A;54AB285 0:B820F88 M:A?@5AA88 A>>B25BAB2CNI8E 35=>2. :B82=>ABL 1070;L=>3> C@>2=O :>=AB8BCB82=KE NOS 7028A8B >B D878>;>38G5A:>3> A>AB>O=8O >@30=8720A:C;O@=8E :0B0AB@>D0E 8 @O45 4@C38E 38?>:A8G5A:8E A>AB>O=8OE >@30=87B2>48BAO 254CI0O @>;L 2 >15A?5G5=88 ?>AB>O==>3> 1078A=>3> C@>2=O NO, :>B>@K9 0AA>F88@CNB A @50;870F859 :0;L=>9 M=4>B5;80;L=>9 F8B>?@>B5:F88 8 ?>445@60=85AC48AB>3> 3>AB070 [422, 630]. !=865=85 0:B82=>AB8 MB>9 87>D>@48B : =0@0AB0=8N M=4>35==>9 =54>AB0B>G=>AB8 NO 8 O2;O5BAO >4=835=570 8H59 1>;57=8 A5@4F0 (!) 8 F5@51@>20A:C;O@=>9 ?0B>;>388. eNOS ;>:0;87>20=0 2 :;5B:0E M=4>B5;8O (-) :@>25=>A=KE A>AC4>2 8 65B 1KBL :0: 2 @0AB2>@89, B0: 8 2 9 D>@:0;87>20=0 2 ?;079 F88@>20=0 A :025>;8=>AB>O=88 55 0:B82=>ABL >G5=L =87:0. >4 2;8O=85@7028A8;8=, 1@048:8=8=, 38AB02KH0NI8E :>=F5=B@0F8N :0;LF8O 2 -, ?@>8AE>4OB 2KA2>1>645=85 eNOS 87 ?;079 ;LH8E :>;8G5AB2 (?:;L) N [615, 730].
>:0;870F8O MB>3> D5@5 2>7=8:05B 2A;54AB285 CA:>@5=8O :@>2>B>:0, GB> 8:A8G5A:8E A>AB>O=8OE >@30=87AB0 :>=F5=B@0F88 2=CB@8:;5B>G=>3> :0;LF8O, CA8;5=85 ?@>=8:=>25=8O :>B>@>3> 2 :;5B:C 2> 2@58AE>48B 2A;54AB285 0:B820F88 +-B>:0. :B820F8O 5=4>B5;80;L=>9 NOS 65B 8:>=AB@8:F88 A>AC4>2 8 ?>4 2;8O=85@0 0:B820F88 B@>F8B>2 ($") G5@57 $"-@5F5?B>@K =0 :;5B:0E M=4>B5;8O. !8=B578@>20==K9 NO 48DDC=48@C5B : 1;87;560I8@K9 70?CA:05B B0:CN F5?L ?@5>1@07>20=89: ?@>B58=:8=070 G 0:B828@C5B ?@>B58=D>AD0B07C, :>B>@0O 2> 2@5AD>@8;8@>20=8O 15;:>2 +!0-:0=0;0 >:07K205B A>459AB285 CA8;5=8N +-?@>2>48AB8 G5@57 F8B>?;07@==KE 8720==KE 38?5@?>;O@870F859 2, 0 C@>25=L !02+ 2 :;5B:0E ?0405B, GB> ?@82>48B : @0AA;01;5=8N D81@8; 8, :0: :>=5G=K9 @57C;LB0B, : 207>48;0B0F88.
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/2;OOAL A8;L=KAAB0=>28B5;5 ?@>B>=8@>20==0O D>@20BL @50:F88 >:8A;5=8O. NO- 8:CN 8 8718@0B5;L=CN @50:B>35==>ABL ?> >B=>H5=8N : 0@>4A>45@60I8D8;01@07C5B :>;L, 2 >B;8G85 >B 4>=>@>2 N , >:07K205B ?>78B82=>5 8=>B@>?=>5 459AB285 =0 :0@4 C25;8G8205B 2 =5=B@>;8@CNI53> DC=:F8N :0;LF8B>=8=>2>3> 35=0 (CGRP); CA8;8205B D8;>2. -B8 MDD5:BK =5 A2O70=K A >1@07>20=85:A8=8B@8B0 8 873> A>45@60=8O cGMP [501]. "0:65 ! 2 A>>B25BAB2CNI8E :>=F5=B@0F8OE =5?>A@54AB25==> >:8A;O5B 2>AAB0=>2;5==K9 3;CB0B8>= (GSH), A=860O 53> 2=CB@8:;5B>G=>5 A>45@60=85 [152, 255, 394].
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$>@B>@>9 N 2KA2>1>6405BAO 87 :;5B>: 8 >ACI5AB2;O5B D878>;>38G5A:85 DC=:F88, 0:B82=> 48A:CB8@C5BAO. 0?@8;L M=4>B5;89@5;0:A8@CNI53> D0:B>@0 (EDRF) «2K42830NBAO»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×1010 -1A-1. KA>:>5 A@>4AB2> NO : 2- >3@0=8G8205B 53> ?@O5 459AB285 8 >?@545;O5B @07=>>1@07=K5 B>:A8G5A:85 ?@>O2;5=8O, >?>A@54>20==K5 >1@07>20=8515==> 1;03>?@8OB=K5 CA;>28O 4;O A8=B570 N O- A>740NBAO 2 :;5B>G=KE :>9 0:B82=>ABLN NOS 8 B0:8E D5@2, >B25BAB25==KE 70 >1@07>20=85 2-, :0: :A0=B8=>:A84070, NAD(P)H->:A84>@54C:B070, F8:;>>:A835=070, ;8?>:A835=070 8 F8B>E@>F5AA5 DC=:F8>=8@>20=8O M;5:B@>=B@0=A?>@B=>9 F5?8 E>=4@89 8 0CB>>:8A;5=8O =5:>B>@KE ;8B>2. >I=KG=8:>20==K5 D038 8 =59B@>D8;K [962].
>A=>2=KAB02;ONI89 70I8BK >B=>AOBAO SOD, 2 G0AB=>AB8 55 E>=4@80;L=0O 8 F8B>?;07D>@= 8 G520O :8A;>B0. =>@@30=87=F5=B@0F88 SOD =0 420 ?>@O4:0 ?@52KH0NB :>=F5=B@0F88 N . -B> A>7405B ?@5?OBAB285 4;O >1@07>20=85 N O-, =5AB@O =0 B>, GB> 2>76=>ABL :>=B0:B0 2- A D5@ 48DDC788 G=K 2KH5, G5@>ABL CAB@0=5=8O 2- 2 AC?5@>:A8448A9 @50:F88 (2×109 -1A-1). =B5@5A=>, GB> SOD 2 ?@8ACBAB288 2KA>:8E :>=F5=B@0F89 2 2 8 NO 65B >1@07>2K20BL N O-. >A;54=89 B0:65 A?>A>15= 8=3818@>20BL Cu-Zn-SOD 8 Mn-SOD G5@57 =8B@>20=85 55 34-3> B8@>78=>2>3> >AB0B:0 [163, 604]. @8 D878>;>38G5A:8E CA;>28OE 0=B8>:A840=B=0O A8AB5 :>;8G5AB20 A8=B578@C53> 2-. ">;L:> =51>;LH0O G0ABL N @0AE>4C5BAO =0 A8=B57 RNOS, 0 >AB0;L=0O ;>:0;L=>, 2 ?@545;0E 48DDC788, 2ABC?05B 2 ?@O5 2708459AB285 A B538G5A:8=4@80;L=>9 8 ;>:0;87CNI59AO 2 M=4>?;07@F5AA5 CG0AB2CNB NADH 8;8 NADPH 8 D;02>?@>B58=K. @57C;LB0B5 =8B@8B@54C:B07=KE @50:F89 =5 B>;L:> A=8605BAO :>=F5=B@0F8O B>:A8G=>3> RNOS, => 8 C4;8=O5BAO B0: =07K2055 2@52>;L=> AB018;L=K548=5=85 :@8AB0;;K 3CB E@0=8BLAO 3>403> @07;>65=8O), A?>A>15= 48DDC=48@>20BL =0 7=0G8B5;L=K5 @0AAB>O=8O 2 :;5B:0E 8 ?@5>4>;520BL :;5B>G=K5 4=>9 A@545 ?@8 >:8A;5=88 ?@>B>=8@C5BAO 8 1KAB@> @07@CH05BAO A >1@07>20=85:>;> 70 % 0=8>=0 =8B@0B0 8 30 % @048:0;>2 (384@>:A8;L=>3> 8 48>:A840 07>B0), :>B>@K5 2> 3>1CA;>2;820NB 53> >:8A;8B5;L=K5 8 =8B@CNI85 A2>9AB20: 2- + " NO ! ONOO- + + ! HOONO ! NO3- + + + + " + " NO2. >MB>:A8G5A:85 MDD5:BK N O- >A>15==> 2K@065=K 2 >@30=8728OE 0F84>70, 2 8H520=KE B:0=OE, 0 B0:65 D03>A>20==KE D03>F8B0@=KE :;5B>:. ">:A8G5A:>5 459AB285 N O- 7028A8B >B :>=F5=B@0F88. @8 =87:8E :>=F5=B@0F8OE ?@>O2;O5BAO 53> @53C;OB>@=K5 8 ?@>B5:B>@=K5 A2>9AB20 2 >B=>H5=88 DC=:F88 D5@2;5=> 53> CG0AB85 2 ?@>F5AA0E A83=0;L=>9 B@0=A4C:F88. >MB>1@07>20=85 N O- 65B >BG0AB8 =59B@0;87>20BL ?@O5 B>:A8G5A:>5 459AB285 " NO 8;8 2- [17, 69].
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! >1@07>20=857>B8>;>2 2 7=0G8B5;L=>9 @=>5 8 F8B>?@>B5:B>@=>5 459AB285 =87:8E :>=F5=B@0F89 N O- [170, 671].
2C>:8AL C3;5@>40 CA?5H=> :>=:C@8@C5B 70 N O- A B8>;0B58=0;>38G5A:8E CA;>28OE, :>340 53> ?@>B>=8@>20=85 8 @07@CH5=85 ?@>8AE>48B >G5=L . -B> >1CA;>2;5=> 2KA>:>9 :>=F5=B@0F859 ! 2 2 B:0=OE. A;54AB285 2708459AB28O ! 2 8 N O- >1@07C5BAO =8B@>7>?5@>:A8:0@1>=0B=K9 0=8>= (ONOOCOO-), :>B>@K9 2 >B=>H5=88 @O40 15;:>2 O2;O5BAO 1>;55 I=KB:>682CI81@07>20=85=0 =8B@0B0, 0 B0:65 35 % 25AL2 48>:A840 07>B0 (" NO2) 8 :0@1>=0B=>3> 0=8>=0 (! 3" -) [72, 375, 856]. " NO2 65B B0:65 >1@07>2K20BLAO 2 @50:F88 N A ;5:C;O@=K@>4>:8E :>=F5=B@0F8OE 2 384@>D>1=>:@C65=88 (2 1AB2CNI5:>9 @0AB2>@8AB8 8AE>4=KE @5035=B>2. > MB0 @50:F8O 0CB>>:8A;5=8O N , >G5284=>, 2=>A8B =51>;LH>9 2:;04 2 A8=B57 " NO2, ?>A:>;L:C 2 40;L=59H548B : >1@07>20=8N N2O3 ;5:C;K =081>;55 >B25BAB25==>9 70 ?@>F5AAK >1@07>20=8O S- 8 N-=8B@>7>A>548=5=89 [76, 964]. In vivo, ?>-2848;55 2K@065= ?CBL >1@07>20=8O " NO2 87 =8B@8B0=8>=0 2A;54AB285 >4=>M;5:B@>==>3> >:8A;5=8O A CG0AB854OI53>AO 2 B5E 8;8 8=KE :>:A>D>@20=85 " NO2 ?@>8AE>48B ?@8 2>A?0;8B5;L=KE ?@>F5AA0E A CG0AB85F8B0@=KE 35:A8407 (?5@>:A8407K, M>78=>D8;L=>9 ?5@>:A8407K), 0 B0:65 2 2 8 " . AB>G=8:>@30=87 D0:B>@0 65B 1KBL N , :>B>@K9 >:8A;O5BAO >:A8- 8;8 18=>:8A;5==K:A84=K9 0=8>= 2 @50:F88 A :8A;>@>4>72>;O5B " NO2 2ABC?0BL 2 @50:F88 ?5@>:A840F88 8 =8B@8@>20=8O ;8?84>2, 0 B0:65 >:8A;5=8O 0:8A;>B, ?@58 F8AB58=0, B@8?B>D0=0 8 >A>15==> B8@>78=0 2 384@>D>1=>:@C65=88 :;5B>G=KE 2. 0;8G85 70@O40 2 ! 3" - >3@0=8G8205B 53> 459AB285 2 2>4=>9 A@545, 345 MB>B 0=8>==K9 @048:0; ;53:> >:8A;O5B 3;CB0B8>=, 0:8A;>B=K5 >AB0B:8 15;:>2 8 3C0=8=>2>5 >A=>20=85 =C:;5>784>2, =C:;5>B84>2 8 =C:;58=>2KE :8A;>B. 4=>2@55 >1@07>20=85 " NO2 8 ! 3" - A>7405B CA;>285 4;O 8E :>20==>3>, 2>7459AB28O =0 20=85 8 >:8A;5=85, 2A;54AB285 :>B>@>3> 2>76=> A8=5@38G5A:>5 CA8;5=85 8E ?>2@5640NI53> 459AB28O [73, 82, 902].
06=K:A8G5A:>3> 459AB28O N O- 2 >@30=8720=85 B8@>78=0 (A2>1>4=>3> 8 2 A>AB025 15;:>2) A >1@07>20=85B8@>78=0. !CI5AB2C5B 2KA>:0O :>@@5;OF8O ABLN >1@07>20=8O N O- 8 3-=8B@>B8@>78=0. ! CG5B>3>, GB> N O- in vivo =5 >1=0@C68205BAO, C@>25=L 3-=8B@>B8@>78=0, >?@545;O5ILN 0=0;8B8G5A:8E 8 8@30=87ABL >1@07>20=8O N O-. > MB> =5 A>2A5@@5:B=>, ?>A:>;L:C >1@07>20=85 A2>1>4=>3> 8 A2O70==>3> A 15;:0B8@>78=0 A:>@55 2A53> >B@0605B 459AB285 8 4@C38E RNOS. >7@0AB0=85 C@>2=O 3-=8B@>B8@>78=0 =01;N405BAO ?@8 E@>=8G5A:8E 2>A?0;5=8OE, 0B5@>A:;5@>75, =59@>4535=5@0B82=KE ?@>F5AA0E, A5@45G=>-A>AC48ABKE 8 >AB@KE ;53>G=KE ?>@065=8OE, F8B>B>:A8G5A:>18>B8:>2 [22, 189, 815].
K720==>5 N O- =8B@8@>20=85 B8@>78=0 A CG0AB858AE>48B 1;03>40@O >1@07>20=8N @048:0;>2 " NO2 8 B8@>78=0. 1@07>20=85 @048:0;>2 B8@>78=0 CA:>@O5BAO ! 3" - 8 D>@A;54=89 >1@07C5B ONOO-, 8=4CF8@CNI89 =8B@8@>20=85 B8@>78=0. 4=0:> 2A5 1>;LH5 M:A?5@8:070B5;LAB2 ?>;CG05B 38?>B570, ?> :>B>@>9 20==0O SOD ?@>O2;O5B ?5@>:A8407=K5 A2>9AB20 8 :0B0;878@C5B ?@52@0I5=85 2 2 2 " , ?>2@5640NI89 =59@>=K C 1>;L=KE !!. ONOO- G5@57 =8B@8@>20=85 A?>A>15= A=860BL 0:B82=>ABL !u-, Zn- 8 Mn-SOD. 8H5=LN =8B@8@>20=8O Mn-SOD A;C68B B8@>78=>2K9 >AB0B>: 34 [86, 92, 444].
N2O3 >1@07C5BAO 2 >@30=87>:A840F88 N 2 ?@8ACBAB288 ;5:C;O@=>3> :8A;>@>40:
;03>40@O A2>59 384@>D>1=>AB8 NO 8 2 3CB =0:0?;820BLAO 2 ;8?84=>5 G5=L 2KA>:8E :>=F5=B@0F8OE, A?>A>1=KE CA:>@8BL MBC @50:F8N 2 BKAOG8 @07. N2O3, O2;OOAL 8AB>G=8:>=0 =8B@>7>=8O (:0: ?>:070=> 2KH5), >1;0405B A8;L=>9 A?>A>1=>ABLN : =8B@>78@>20=8N.
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hmRSNO) 2 >@30=877>3;CB0B8>= (GSNO) 8 S-=8B@>7>3>F8AB58= (HcySNO). =CB@8:;5B>G=K5 :>=F5=B@0F88 3;CB0B8>=0 ( 2KH5, G5;5:C;O@=KE SH-A>45@60I8E ;830=4>2, 8 ?>MB>= O2;O5BAO ?@589 78@>20=8O. =0G8B5;L=> 1>;LH0O ?> A@02=5=8N A S-=8B@>7>F8AB58=>ABL GSNO >15A?5G8205B 5A=>2=CN @>;L 2 45?>=8@>20=88 N 8 53> B@0=A?>@B8@>2:5 : A5=A>@=K38G5A:8E MDD5:B>2 hmRSNO 8 N 2 >B=>H5=88 B>=CA0 A>AC4>2, =59@>F8B>2, 8 3>4=0 8 A2O70=0 A> A?>A>1=>ABLN hmRSNO 2KA2>1>640BL NO. > 18>0:B82=>ABL hmRSNO 8A>15==>AB8, GB> >?@545;ONBAO 8E AB018;L=>ABLN 8 4@C389AB201CA;>2;5==K=0;L=>9 3@C??>9 -S-N=O. "0:, ?>:070=0 2>76=>ABL CG0AB8O CysSNO, => =5 NO, 2 ?5@540G5 A83=0;>2 20A:C;O@=K=0B45;L=>3> B@0:B0 (NTS) G5@57 A2O7K20=85 A A>>B25BAB2CNI8@0 3>3;0A=> =5:>B>@K;>65=8O9 2 8 ³-3;CB0ACI5AB2;O5B 45=8B@>78@>20=85 hmRSNO, GB> ?@82>48B : =0:>?;5=8N 2 384@>D>1=>9 G0AB8 :8A;5=8N 2 N2O3, :>B>@K9 70B578@C5B B8>;K, =0E>4OI85AO 2 F8B>7>;5 2>7;5 2=CB@5==59 ?>25@E=>AB8 ?;079 G=K9 GSNO 2 S-=8B@>7>F8AB58=8;3;8F8=. KA2>1>6405 N CG0AB2C5B 2 =8B@>78@>20=88 2=CB@8:;5B>G=KE B8>;>2 :0: C:070=> 2KH5. &8AB8= A ?>ILN 0:8A;>B=>3> B@0=A?>@B5@0 ?5@5=>A8BAO 2 :;5B:C, 345 2>AAB0=02;8205BAO 2 F8AB58=, :>B>@K9, 2KA2>1>482H8AL 87 :;5B:8 8 @5038@CO A GSNO, >1@07C5B CysNO. >A;54=89 G5@57 4@C3CN B@0=A?>@B8@CNICN 0:8A;>BK A8AB5=8:05B 2 :;5B:C, 345 CG0AB2C5B 2 B@0=A=8B@>78@>20=88 3;CB0B8>=0 8 4@C38E =87:>- 8 2KA>:>;5:C;O@=KE SH-A>45@60I8E ?5@2>5 M:A?5@85 >1>A=>20=85 7>A>548=5=89 2 :;5B:8 (0 2>76=> 8 87 =8E) 157 A>?CBAB2CNI53> 2KA2>1>645=8O NO. !?>A>1=>ABL @07;8G=KE B8?>2 :;5B>: B@0=A?>@B8@>20BL hmRSNO =5>48=0:>20. "5 87 =8E, C :>B>@KE >=0 2K@065=0 A;01>, 3CB, >G5284=>, 1>;55 CA?5H=> ?@>B82>AB>OBL =8B@>70B82=>1CA;>2;5==>>B25BAB2CNI8E :;5B:0E ?@8 2>A?0;8B5;L=KE 8 4@C38E ?@>F5AA0E [100, 607, 1002].
5:>78F8O hmRSNO in vivo, >ACI5AB2;O5@18=>2>9 :8A;>BK, :8A;>@>40 8 AC?5@>:A840, ?@82>48B : >1@07>20=8N @07;8G=KE ;8B>2, 2:;NG0O NO, N2O, NO2-, NH4+, NH2OH, 48AC;LD84K, AC;LD8=02K5 8 AC;LD>=>2K5 :8A;>BK. 5@5=>A NO+ >B 1>;55 AB018;L=KE S-=8B@>7>B8>;>2 (GSNO, S-=8B@>7>?@>B58=>2) : F8AB58=C, S-=8B@>7>F8AB58=8;3;8F8=C) >1;53G05B 40;L=59H55 2KA2>1>645=85 87 =8E NO. KA2>1>645=85 ?>A;54=53> 87 hmRSNO A >1@07>20=85>B25BAB2CNI8E 48AC;LD84>2 65B ACI5AB25==> CA:>@OBLAO 8>=0B>@KE >15A?5G8205BAO 2>AAB0=>2;5=85=01>4=KE B8>;>2 (RS-). >76=>, GB> 2708459AB285 hmRSNO 2 >@30=87=048B : >1@07>20=8N 48=8B@>78;L=KE :>2, :>B>@K5 A;C60B 8AB>G=8:>7459AB2853> >1;CG5=8O 8;8 ?>2KH5==>9 B58AE>48B @0AI5?;5=85 hmRSNO A 2KA2>1>645=85B>:A8G=KE :>=F5=B@0F89 >:A840 07>B0. 5:>78F8O S-=8B@>7>B8>;>2 CA:>@O5BAO 2- 8 65B 70:>=G8BLAO >1@07>20=85:A8=8B@8B0 [103, 386, 781, 808, 1019].
5@5=>A NO+ >B S-=8B@>7>B8>;>2 : 4@C3835==K;078@>20=85) O2;O5BAO >A=>2=K72>;O5B 2>2;5GL 2 =8B@>78@>20=85 @07;8G=K5 A>45@60I85 B8>;K ;5:C;K (=0E>4OI85AO 2 :;5B:0E, =0 8E ?>25@E=>AB8 8 2> 2=5:;5B>G=>AB@0=AB25), GB> A?>A>1AB2C5B ;8G5A:>9 :>1@078B 18>;>38G5A:>5 459AB285 NO 2 >@30=8778@>20=8O ?>4>1=> @50:F8OAD>@8;8@>20=8O 8;8 0F5B8;8@>20=8O >ACI5AB2;O5B >1@0B8ABB@0=A;OF8>==CN 48D8:0F8N 15;:>2. @8 S-B@0=A=8B@>78@>20=88 15;:>2 =C:;5>D8;L=>9 0B0:5 ?>425@30NBAO @50:F8>==>A?>A>1=K5 SH-3@C??K F8AB58=0, :>B>@K5 >15A?5G820NB B5A=CN A2O7L F8=:0, 65;570 8 :>D5@2 A 15;:0==KE :0=0;>2, G-15;:>2, D0:B>@>2 B@0=A:@8?F88, 0 B0:65 @01>B0 @B0 M;5:B@>=>2 8 D>@20=85 A83=0;L=>9 B@0=A4C:F88. 7 38E @50:B>35==KE SH-3@C?? 15;:>2 ?>425@30NBAO S-B@0=A=8B@>78@>20=8N B>;L:> =5:>B>@K5, ;>:0;878@CNI85AO 2 CG0AB:0E A >?@545;5==>9 ?5@28G=>9 AB@C:BC@>9 21;878 NOS-A8=B07 8 =87:>;5:C;O@=KE B8>;>2, ?@8 A>>B25BAB2CNI5:A-A>AB>O=88 :;5B>: [109].
:@>2O=>78@>20=8O CG0AB2CNB 2 @53C;OF88 B>=CA0 8 ?@>;8D5@0F88 :;5B>: A>AC4>2, A:>@>AB8 03@530F88 B@>F8B>2 8 ;59:>F8B0@=>9 0435788, 0 B0:65 2 >ACI5AB2;5=88 ?0@0:@8==>9 8 M=4>:@8==>9 DC=:F88 N . >A;54=NN A2O7K20NB A >1@07>20=857>0;L1C7>353;>18=0 (HbSNO), :>B>@K5 3CB ?5@5=>A8BL N B>:>28 =0 1>;LH85 @0AcB>O=8O [10, 111, 205]. 384@>D>1=KE CG0AB:0E 0;L1C 0CB>>:8A;5=8O N 2 N2O3, :>B>@K9 @0AE>4C5BAO =0 S-=8B@>78@>20=85 A>1AB25==KE Cys-34- 8 Trp-214-ocB0B:>2 8 =87:>;5:C;O@=KE B8>;>2 ?;0728. >1@07>20=88 AlbSNO G5@57 S-B@0=A=8B@>78@>20=85 3CB CG0AB2>20BL CySNO, GSNO, S-=8B@>7>-±-;8?>520O :8A;>B0, HcySNO 8 4@C385 hmRSNO [2, 113, 381].
!K2>@>B>G=K9 0;L1C;5:C;O@=KE B8>;>2 7=0G8B5;L=> C25;8G8205B 38?>B5=782=>5 8 8=3818@CNI55 03@530F8N B@>F8B>2 459AB285 N , GB> >1CA;>2;8205BAO >1@07>20=85, 2>76=>, CA8;8205BAO ?>4 2;8O=85@10B0 8 F5@C;>?;07;CG5==K5 =0 B@>F8B0E 8 F8B0E, A2845B5;LAB2CNB 2 ?>;L7C B>3>, GB> D878>;>38G5A:0O 0:B82=>ABL GSNO 8 AlbSNO >?>A@54C5BAO @50:F8O78@>20=8O A B8>;0;>65==K25@E=>AB8 ?;079 N 65B @5038@>20BL A ²-93-F8AB58=>18=0, >1@07CO HbSNO. @54?>;0305BAO, GB> HbSNO >1@07C5BAO 2 CA;>28OE 2KA>:>3> ?0@F80;L=>3> 402;5=8O 2 2 ;53:8E, >BBC40 :@>2>B>:>AB02;O5BAO : 38?>:A8G=K6405B N , A?>A>1AB2CO B5F8B>2 8 2 2> 2A5 CG0AB:8 B:0=8. @3C;L7C MB>9 38?>B57K AG8B0;>AL =0;8G85 2KA>:>9 :>=F5=B@0F88 HbSNO 2 M@8B@>F8B0E 0@B5@80;L=>9 :@>28 (2,5 3> 0@B5@8>25=>7=>3> :>=F5=B@0F8>==>3> 3@0485=B0 ?> MB>:070B5;N. 4=0:> 2 =0AB>OI55 2@5;L S-=8B@>78@>20=8O 0;L1C18=0 2 >15A?5G5=88 M=4>:@8==>9 DC=:F88 N ?@8 D878>;>38G5A:8E CA;>28OE ?>425@305BAO A5@L57=K2KE GC2AB28B5;L=KE 4>2 >?@545;5=8O S-=8B@>7>B8>;>2, CG8BK20NI8E 8E 2KA>:CN ;018;L=>ABL, ?>:070=> :@09=5 =87:>5 A>45@60=85 AlbSNO 2 ?;0728 (>:>;> 5 =;L/;), :>B>@>5 : B> =5 87==>@30=87:A840 07>B0. @8G8=0 B0:>9 =87:>9 :>=F5=B@0F88 AlbSNO =5 OA=0. #@>2=8 HbSNO 2 M@8B@>F8B0E =5 ?@52KH0NB 40 =;L/; 8 84=K5 25;8G8=K 2 :@>28 0@B5@89 8 25=. 87:>5 A>45@60=85 Hb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lbSNO 8 HbSNO 2>7@0AB05B B0:65 C@>25=L HbFe-NO, hmRSNO, N-=8B@>7>02, =8B@>B8@>78=0 (2 15;:0E) 8 =8B@8B0. >O28;8AL =>2K5 D0:BK, C:07K20NI85 =0 206=>ABL =8B@8B0 :0: D>@=8@>20=8O 8 B@0=A?>@B8@>2:8 N 2 :@>28. 8B@8B ?> A@02=5=8N A AlbSNO 8 HbSNO 1>;55 AB018;L=K9, 53> :>=F5=B@0F88 2 :@>28 A>AB02;ONB 0,5-1,0 =8 =0 ?>@O4>: 2KH5. 8B@8B 2 ?@8ACBAB288 457>:A835=8@>20==KE M@8B@>F8B>2 2>AAB0=02;8205BAO 2 N 8 2K7K205B @5;0:A0F8N A>AC4>2. >=F5=B@0F88 =8B@8B0 2 >@30=87ABL B:0=59 (ACI5AB25==K9 2:;04 2 =55 2=>AOB 352K5 15;:8 8 :A0=B8=>:A84>@54C:B070) 8 M@8B@>F8B>2, 7=0G8B5;L=> 2>7@0AB0NB ?@8 38?>:A88. MB8E CA;>28OE @>;L =8B@8B0 2 35=5@0F88 N , =5>1E>483> 4;O C;CGH5=8O :@>2>A=0165=8O B:0=59, ?@54AB02;O5BAO 8A:;NG8B5;L=> 206=>9 [122].
>@30=874OB 2A5 1>;LH5 425@30578@>20=8N. !@548 =8E A;54C5B >B@K ?;0735=0 8 B@0=A:@8?F88, @07;8G=K5 @5F5?B>@K, G-15;:8 (2:;NG0O H-ras) 8 D5@0;L45384-3-D>AD0B45384@>35=07K, ?@>B507K, ?@>B58=:8=07K, D>AD0B07K 8 4@. [203, 439, 626, 899].
8B@>70B82=K9 8 >:A840B82=K9 AB@5AA 2 >@30=871=0@C68205BAO >4=>2@5. @8 MB>78@>20=85 15;:>2 A>G5B05BAO A 8E S-B8>;8@>20=851@07>20=852 15;:>2 8 SH-3@C?028OE >:A840B82=>3> AB@5AA0 >A=>2=K20=8O 15;:>2 A;C60B 8E >:8A;5==K5 8=B5@:-S" 8 15;>:-SOH), 0 B0:65 CysSH 8 GSH. AB>I5=85 :;5B>G=>3> D>=40 GSH ?@82>48B : >:8A;5=8N 15;:>2 8 8E =5>1@0B82@5645=8N. GSNO 8 53> >:8A;5==K5 ?@>872>4=K5 ?@8 4>102;5=88 : :;5B:0;8@>20BL 15;:8 8 >1@07>2K20BL =87:>;5:C;O@=K5 48AC;LD84K. 081>;LHCN @50:B>35==>ABL ?@8 MB>O2;O5B 3;CB0B8>=48AC;LD84-S->:A84 (GS(O)SG). >4 2;8O=85B>@K5 15;:8 2 B>9 8;8 8=>9 425@30NBAO :0: S-=8B@>78@>20=8N, B0: 8 S-B8>;8@>20=8N. AB820==KE =59B@>D8;0E 8 D030E =01;N405BAO CA8;5=85 S-B8>;8@>20=8O 0:B8=0 8 3;8F5@0;L45384-3-D>AD0B45384@>35=07K. @8 8H5 2>7@0AB05B :>;8G5AB2> S-B8>;8@>20==KE 15;:>2, B0:8E :0: @5F5?B>@ LDL, " -A8=B070, 15;>: B5?;>2>3> H>:0, >:A8:8A;>B=0O >:A84070, B@8>7>D>AD0B-87>7459AB288 GSNO =0 F8AB58=>2K5 ?@>B507K >1@07CNBAO A48B : A=865=8N 8E 0:B82=>AB8. S-B8>;8@>20=85 15;:>2 >1@0B8 ?>4 2;8O=85AAB0=02;820NI8E 035=B>2. >MB> ?>;030BL, GB> MB0 @50:F8O ?>4>1=> S-=8B@>78@>20=8N, 65B ;81> @07=>>1@078BL A83=0;L=K5 8 ;8G5A:85 DC=:F88 15;:>2, ;81> =0@CH0BL 8E 8 B5:A8G5A:>5 459AB285 N [25, 617, 986, 993, 1005].
$878>;>38G5A:85 A2>9AB20 >:A840 07>B0
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>:070=>, GB> NO CA8;8205B A8=B57 cGMP ?CB51=0 4C;8@>20BL @01>BC cGMP-7028A82 , A=860O 8E 0:B82=>ABL, ;81> 0:B828@>20BL G-:8=07K (cGMP-7028A8B58=:8=07K) [21, 30, 197]. :B820F8O ?>A;54=8E ?@82>48B, =0?@8AD>@8;8@>20=8N D>AD>;0 0:B82=>ABL !02+-=0A>A0 M=4>?;073> @5B8:C;C=8@>20=8O !02+ 2 ?>A;54=5F8B0E G5;>25:0 B0:65 ?>:070=> NO/A! -7028A85 8=3818@>20=85 D>AD>;8?07K ! 8, 2>76=>, =5?>A@54AB25==>5 D>AD>@8;8@>20=85 @5F5?B>@0 8=>78B>;-3-D>AD0B0, GB> ?@82>48B : 53> 45A5=A818;870F88. @>3>, G-:8=07K 0:B828@CNB ?@>B58=D>AD0B07C, 45D>AD>@8;8@CNICN +-:0=0;K 8 0:B828@CNICN 8E. ?8A0==K5 ?@>F5AAK =0?@02;5=K =0 A=865=85 C@>2=O A2>1>4=>3> !02+ 2 F8B>?;07: [77].
4=>2@5 A MB8:070=> 0:B828@CNI55 459AB285 NO G5@57 cGMP-7028A8=8AB0 @80=>48=>2KE @5F5?B>@>2 CA8;8205B 2KE>4 !02+ 87 - . "0:81@07>4=>3> !02+ 2 F8B>7>;5 [7]. 4=81JOA=5=89 MB>3> D5=>@30=>A?5F8D8G=>ABL, 2 G0AB=>AB8, A2O70==0O A =5>48=0:>2K15==>AB8 2=CB@8:;5B>G=>3> ;876=> B0:65 ?@54?>;>68BL, GB> A;>6=>5 8 =5>4=>7=0G=>5 459AB285 NO >15A?5G8205B B>=:CN =5>1E>482=O F8B>7>;L=>3> !02+ 2> 2@5AB@0=AB25 4;O 2K?>;=5=8O :;5B>G=KE DC=:F89.
AE>4O 87 2KA>:>9 @50:F8>==>9 A?>A>1=>AB8 NO, 4>?CA:05BAO 2>76=>ABL ?@O9 48D8:0F88 8 ?@>872>4=K2 2 :;5B:0E ?>465;C4>G=>9 65;57K, =5A5;5:B82=KE :0B8>==KE :0=0;>2 68@>2>9 B:0=8, 0 B0:65 A>?@O65==KE A NMDA-@5F5?B>@>2 2 =5@2=>9 B:0=8 [287].
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
2KA>:>9 :>=F5=B@0F88 =8B@>?@CAA84 8 SNAP (100-200 2>48ABL, 0 2 =87:>9 (10 ABL :0=0;>2. @57C;LB0B5 A45;0= 2K2>4, GB> 1;>:8@CNI89 MDD5:B NO =0 +-?@>2>48ABL A2O70= A >1@07>20=85:A8=8B@8B0 [218].
5@>OB=>, 7=0G8B5;L=CN @>;L 2 >?8A0==KE MDD5:B0E 83@05B :>=F5=B@0F8O NO, GB> >1CA;>2;8205B in vivo 4C;OF8N 8>==>3> 3>AB070 @07=K872>4=K==>3> 3>AB070 >:A84>B0 >ACI5AB2;O5BAO B0:65 ?>A@54AB2>AB8 G-15;:>2. @>45=AB@8@>20=0 NO-7028A82 8 p21ras [130].
NO 65B >ACI5AB2;OBL A2>5 459AB285 2 >@30=87B :>=F5=B@0F88 ;81> :0: @, :>=B@>;8@CNI89 18>E8@30=>2 8 A8AB5;>38G5A:8E :>=F5=B@0F8OE), ;81> :0: B>:A8G5A:89 035=B (?@8 ?>2KH5==KE :>=F5=B@0F8OE) [41, 930].
@8 MB>B>:A8G5A:89 8;8 F8B>?@>B5:B>@=K9 MDD5:BK 7028AOB >B AC 459AB28O 38E 2=5H=8E AB82 8 AB0BCA0 :;5B>:. 081>;55 @0A?@>AB@0=5==K;>38G5A:8E CA;>28OE ?@>O2;5=85B>:A8G5A:>3> 459AB28O O2;O5BAO 0?>?B>7 [821].
-DD5:B >:A840 07>B0 =0 A>AC48ABK9 B>=CA 1K; 2?5@2K5 ?@>45=AB@8@>20= 1>;55 20 ;5B =0704 8 A B5E ?>@ 4>2>;L=> E>@>H> 87CG5=. :A84 07>B0, 2K@010BK205B5;8515A?5G8205B @0AA;01;5=85 3;04:8E F8B>2 8 ?>A;54CNICN 207>48;0B0F8N. $0@;>38G5A:>5 8=3818@>20=85 40==>3> ?@>F5AA0 ?@82>48B : ?>2KH5=8N B>=CA0 A>AC4>2, GB> C1548B5;L=> 45=AB@8@C5B @>;L =54>AB0B:0 MB>3> A>548=5=8O 2 35=575 MAA5=F80;L=>9 38?5@B5=788, !, F5@51@>20A:C;O@=KE 701>;520=89 8 8E >A;>6=5=89 [201, 1013].
NO O2;O5BAO >4=8;55 I=KE 207>48;0B0B>@>2. @>=8:0O 87 - 2 3;04:>AC48AB>9 AB5=:8, >= 0:B828@C5B @0AB2>@8 2545B : ?>2KH5=8N C@>2=O F $, 0:B820F88 F $-7028A8B58=:8=07 (PKG), A=865=8N :>=F5=B@0F88 :0;LF8O, @0AA;01;5=8N A>AC4>2 [223, 667].
8B>35 A=8605BAO B>=CA 0@B5@80;L=KE 8 2 1>;LH59 AB5?5=8 25=>7=KE A>AC4>2 ?> ;LH>2>>1@0I5=8O, CAB=03@C7:0 =0 A5@4F5, 0 B0:65 402;5=85 =0?>;=5=8O 65;C4>G:>2. !;54C5B 70 :>@>=0@>48;0B8@CNI55 459AB285 =0?@02;5=> 2 >A=>2=> 10AA59=0, >A>15==> =0 AB5=>78@>20==K5 53> CG0AB:8, ?0B>;>38G5A:8 87A:;5@>B8G5A:8F5AA>BACBAB2C5B A8=4@>1:@04K20=8O. @>3>, >:A84 07>B0 A?>A>15= AB820BL ;815@0F8N M=4>B5;80;L=>3> ?@>AB0F8:;8=0 8 C3=5B0BL A8=B57 B@>:A0=0 2, GB> ?>B5=F8@C5B 2>7>48;0B0F8N.
@>3>, >= >?>A@54C5B A>AC4>@0AH8@ONI85 MDD5:BK M=4>B5;897028A848;0B0B>@>2 (0F5B8;E>;8=0, 1@048:8=8=0, 38AB0@78B >1@07>20=85 M=4>B5;80;L=>3> A>AC4>AC6820NI53> D0:B>@0 M=4>B5;8=0-1 8 2KA2>1>645=85 =>@04@5=0;8=0 >:>=G0=8O2, ?@5?OBAB2C5B >ACI5AB2;5=8N G@572 4@C38E 207>:>=AB@8:B>@>2 (0=38>B5=78=0, B@>:A0=0 2). ;03>40@O MB>AC48AB>3> B>=CA0 8 :@>2>B>:0 (2 B>3>), C@>2=O , A8AB59 8 @538>=0;L=>9 3548=03> D0:B>@0 @>AB0 [65], => B>@78B ?@>;8D5@0F8N [437] 8 : (B58=B8D8N A>AC4>2 [19], C;LH8E :>=F5=B@0F8OE) 8;8 C25;8G8205B (2 1>;LH8E :>=F5=B@0F8OE) 0?>?B>7 [108, 111], ?>402;O5B A8=B57 2=5:;5B>G=>3> 445@6820O 2A59 AB5=:8.
:A84 07>B0 4>7>7028A8 B>@78B ?@>;8D5@0F8N 3;04:8E F8B>2, :>B>@0O =01;N405BAO ?@8 ?@>3@5AA8@>20=88 0B5@>A:;5@>B8G5A:8E 87AC4>2, C;CGH05BAO :>@>=0@=0O 3548=02>B>: 2 25=>7=>B0 A?>A>15= AB820BL 0=38>35=57, GB> ?>B5=F80;L=> 206=> 2 CA;>28OE 8H52KE :0B0AB@>D [644].
NO >:07K205B I=>5 ?@>B82>2>A?0;8B5;L=>5 8 0=B8B@>35==>5 459AB285: B>@78B B@0=A:@8?F8N ?@>B82>2>A?0;8B5;L=>3> O45@=>3> D0:B>@0 (NF-kB) [173, 184], 1;>:8@C5B AB82 =>F8B>2 [16], CD8;>2 8 =>F8B>2, ?@52@0I5=85 ?>A;54=8E 2 D038 [157], B>@78B 03@530F8N 8 043578N B@>F8B>2, M:A?@5AA8N 0:B828@CNI53> B@>F8BK D0:B>@0 [18, 444], @>AB D>@AO B@>20=85 NO-A8=B07K C 74>@>2KE 4>1@>2>;LF52 4>AB>25@=> C25;8G8205B 2@528 8 CEC4H05B 4@C385 ?>:070B5;8 :>03C;>3@0AC48AB>9 AB5=:8 2E>48B E>;5AB5@8=, >1;040NI89 87>;8@CNI89AB20 @0AB2>@ONB @50:F8>==>-A?>A>1=K5 ;5:C;K NO 8 70I8I0NB 8E >B 384@>D8;L=KE A>548=5=89. >MB> >1@07>20=85 A?8@0;L=KE ?>;8;5AB5@8=>2>:07K20NB ACI5AB25==>5 2;8O=85 =0 @07;8G=K5 725=LO A8AB5402;OO >1@07>20=85 NO, GB> 2 7=0G8B5;L=>9 AB5?5=8 65B >?>A@54>20BL 2K7K205AC4>2, 254CI85 : @0728B8N 0B5@>A:;5@>70.
!=865=85 :>=F5=B@0F88 ;8?>?@>B584>2 2KA>:>9 ?;>B=>AB8 ( ) A?>A>1AB2C5B >:8A;5=8N ;8?84>2 8 48ADC=:F88 M=4>B5;8O. 5>1E>48 >B9 A2O78, GB> ±-B>:>D5@>; 3;02=0O 0=B8>:A840=B=0O A>AB02;ONI0O 28B0?@>B58=0 8=:>@?>@8@>20=85 2 A>AC48AB>9 AB5=:5 ?@5?OBAB2C5B @0728B8N 48ADC=:F88 M=4>B5;8O =0 @0==59 AB0488 0B5@>A:;5@>70. >:070=>, GB> ?5@5=>AOI89 ?;07AD>;8?84K 15;>: (PLTP) A?>A>1AB2C5B ?5@5=>AC ±-B>:>D5@>;0 87 2 -. -B>B ?5@5=>A ?@54>B2@0I05B 48ADC=:F8N M=4>B5;8O 0=B8>:A840=B=>9 70I8B>9 A2O70==KE A AD>;8?84>2 8 A>E@0=5=85AC48ABKE -. ?>445@6820NB =>@5 DC=:F8>=8@>20=85 M=4>B5;8O (0=B80B5@>A:;5@>B8G5A:89 MDD5:B) 8 A2>8@7OI8E@0=5=8N DC=:F89 A>AC48AB>3> M=4>B5;8O A?>A>1AB2C5B AB8B5;80;L=>3> NO. 5;> 2 B> >:8A;5==K5 ;8H0NB :025>;K (A?5F80;878@>20==K5 Q->1@07=K5 CG0AB:8 4;8=>9 50-100 =; 8 =0@CH05B ?@>F5AA 55 0:B820F88, ?>402;OO >1@07>20=85 NO. , =0>1>@>B, ?>445@6820NB =>@5 A>45@60=85 %! 2 :025>;0E (A?>A>1AB2CO ?>3;>I5=8N 53> MD8@>2), B52KH0O >1@07>20=85 NO [424].
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"0:81@07>4OI53>AO 2 >:@C65=88 @07;8G=>3> @>40 >:A840=B>2, >:8A;5=85 B>@78BAO (0=B80B5@>A:;5@>B8G5A:89 MDD5:B NO). 4=0:> 2 A;CG05 7=0G8B5;L=>3> ?>2KH5=8O >1@07>20=8O >:A840=B>2 NO 405B =0G0;> 2B>@8G=K548=5=8OB>@K5 C25;8G820NB C@>25=L >:8A;5==KE ;8?84>2 2 B5840E [654].
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A2>N >G5@54L NO O2;O5BAO =59@>4C;OB>@>?@5AA8=0 [117, 448]. =0 >ACI5AB2;O5BAO G5@57 8=3818@>20=85 DC=:F88 207>?@5AA8=0 8 >:A8B>F8=0 [409, 560]. "0:, 8=3818@>20=85 (70=0;L=>3> A8=B570 >:A840 07>B0) NO-A8=B07K CA8;8205B >A2>1>645=85 >:A8B>F8=0 8 207>?@5AA8=0 2> 2@5ABL NO-A8=B07K 2 38?>B0;0=0E [501]. 2545=85 65 :@KA0:>2K5 65;C4>G:8 730 4>=>@0 >:A840 07>B0 S-=8B@>7>-N-0F5B8;?5=8-F8;;048;> : ?>2KH5=8N :>=F5=B@0F88 207>?@5AA8=0 2 ?;0728 [592]. !8AB55 22545=85 :@>;8:03> 4>=>@0 NO :0: =8B@>?@CAA84 =0B@8O ?>2KH0;> A>45@60=85 207>?@5AA8=0 2 :@>28 [650].
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B5G5=85 1>;55 10 ;5B ?@>4>;60NBAO 8AA;54>20=8O ?> 2KOA=5=8N @@>40 8 A2>1>4=>@048:0;L=>9 45AB@C:F88 ;5:C; 2 ?0B>35=575 AB@5AA-8=4CF8@>20==>9 ?0B>;>388. K;8 ?@>2545=K 8AA;54>20=8O 2 45;L=KE >?KB0E, :>B>@K5 ?>72>;8;8 2KO28BL >?@545;5==K5 70:>=>AB8 D>@20=8O :0@1>=8;L=KE 3@C?? 15;:>2 2 7028A8AB8 >B :>=F5=B@0F88 2 A@545 A2>1>4=KE @048:0;>2 :8A;>@>40. :070;>AL, GB> 2 =5:>B>@KE 15;:0E, =0?@8F87@0AB0=88 2 A@545 $ A>45@60=85 :0@1>=8;L=KE 3@C?? =5 B>;L:> =5 C25;8G8205BAO, => 8 ACI5AB25==> C O2;5=85 A2O70=> =5 A >A>1>9 CAB>9G82>ABLN MB8E 15;:>2 : >:8A;5=8N, 0, =0>1>@>B, A 1>;55 A5@L57=K7459AB28O $, GB> 1K;> ?@>45=AB@8@>20=> 2 >?KB0E ?> B@8?B>D0=>2>9 8 18B8@>78=>2>9 D;C>@5AF5=F88. N1K5 15;:8, 2 B>@>B>G=K5, ?@>O2;ONB A2>8 18>;>38G5A:85 A2>9AB20, B>;L:> A>E@0=OO A2>N =0B82=CN AB@C:BC@C. 0@CH5=85 55 2A;54AB285 @07;8G=KE E8A>1=>AB8 >1@07>2K20BL 8@B=K5 DC=:F88. 07;8G=K5 15;:8 8 >B45;L=K5 4>2 3CB ?@>O2;OBL @07;8G=CN GC2AB28B5;L=>ABL : >:8A;5=8N, :0: MB> 1K;> ?>:070=> 2 8AA;54>20=88 Lee Y.J. 8 Shacter E. (1995) =0 45;8 D81@8=>35=0. :8A;O;8AL B5 53> CG0AB:8, :>B>@K5 1K;8 2 1>;LH59 AB5?5=8 3;8:>78;8@>20=K. Misato Kashiba-Iwatsuki. et al. (1997) AG8B0NB, GB> >:8A;8B5;L=0O 48D8:0F8O 0;L1C:A84>B0 2K?>;=O5B 206=CN @53C;OB>@=CN @>;L 2 A2O7K20=88 8 B@0=A?>@B5 >@30=8G5A:8E 8>=>2 8 8>=>2 BO65;KE 2. 0H8 >?KBK, A 8A?>;L7>20=8520=8O A3CAB:0 ?@8 8=:C10F88 B@>B0 C G5;>25:0 >1;0405B H8@>:8@53C;OB>@=>3> 459AB28O [33]. !59G0A B@C4=> =0720BL DC=:F8N >@30=87B>@>9 NO =5 ?@8=8 2708459AB28O, CG0AB2CNI8445@6:5 3>AB0B8G5A:8E ?0@02 >@30=87@20=88 1070;L=>3> B>=CA0 A>AC4>2, C;CGH5=8O @5>;>38G5A:8E A2>9AB2 :@>28 ?CB5F5AA>2 03@530F88 55 D>@=8F05AB8 A>AC48AB>9 AB5=:8, >1;0405B A2>1>4=>@048:0;L=K9AB2040@O ;5205B :;5B>G=K5 2 8 B:0=59 >@30=87@>B:>682CI0O ;5:C;0, 2@5;C687=8 :>B>@>9 =5 ?@52KH05B 30 A5:C=4, ?>A;5 G53> >=0 ?@5>1@07C5BAO 2 =8B@8BK [10]. NO 2K@010BK205BAO @07;8G=K@30=87B5;8>F8B0F8B0B5;85AB02;O5B 1,7 =F5=B@0F8O 3070 2 ?;0725=L NO 4;O :;5B>: M=4>B5;8O >F5=8205BAO 2 4 ?;L/ ?5@5E>40 2 =8B@0BK 8 =8B@8BK A2>1>4=K9 @048:0; NO 8@>B:89 ?5@8>4 ?>;C687=8 (5-30 A5:C=4), GB> >1JOA=O5B B@C4=>AB8 53> 2KO2;5=8O 2 18>;>38G5A:8E 684:>ABOE [20].
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5G=>5 2KA2>1>645=85 =59@>B@0=A2 3;CB028OE F8@:C;OB>@=>9 38?>:A88 2545B : CA8;5==>:A840 07>B0 8 4@C38E A2>1>4=KE @048:0;>2 ?@82>4OI8E : 3815;8 =59@>=>2. 8AA;54>20=88 [16] >?@545;O;8 C@>25=L =8B@>7>353;>18=0 (NOHb) 8 AC?5@>:A8435=5@8@CNI59 0:B82=>AB8 (!) 2 :@>28 =0 D>=5 B@048F8>==>9 B5@0?88 8 A ?@8;L=KE A ;0B5@0;L=>9 2=CB@873>2>9 359, >1J528 >B 50 A;55, 48A;>:0F859 A@548==KE AB@C:BC@ 730 8 ?@87=0:0G=>-B5=B>@80;L=>3> 8 (8;8) 0:A80;L=>3> 2:;8=5=8O AB2>;0 730. A5;L=K@O4:5 ?@>2545=> >?5@0B82=>5 2. > 2B>@>9 3@C??5 ?@8?@545;O;AO ?> 4C .. !B5?C@> 8 A>02B. (1997), ! ?> 4C Misra et Fridovich (1972).
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1;>:0B>@K :0;LF852KE :0=0;>2: F8==0@878=, D;N=0@878=, =848?8=, >:07K20NI85 207>48;0B8@CNI89 MDD5:B 1;03>40@O CG=>3> A>45@60=8O :0;LF8O 2 3;04:>AC48AB>9 AB5=:8. > =5:>B>@K@K :0;LF852KE :0=0;>2 >:07K20NB =081>;55 2K@065==K9 MDD5:B =0 A>AC4K 25@B51@0;L=>-1078;O@=>3> 10AA59=0 [3, 11];
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