«Антипролиферативное действие карнозина и его производных на опухолевые клетки нейрального происхождения ...»
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ADDIN EN.CITE.DATA [30]. Поскольку карнозин демонстрирует эффективные антиоксидантные свойства, мы предположили, что ингибирование пролиферации опухолевых клеток происходит в результате снижения уровня внутриклеточных прооксидантов под действием карнозина.
Работа выполнена в соответствии с планом НИР ФГБУ «НЦН» РАМН в рамках темы №146 «Исследование в условиях in vitro и in vivo проблем эффективности безопасности наноструктурных комплексов, обладающих нейропротекторным действием».
Цель исследования. Изучение механизма антипролиферативного действия карнозина и его производных на опухолевые клетки нейрального происхождения.
Задачи исследования:
1. Изучить характер воздействия карнозина на пролиферацию культур опухолевых клеток феохромоцитомы крысы (РС-12), карциномы горла и рта (FaDu, Cal27) и молочной железы (MB231) человека, глиобластомы человека (U-118-MG);
2. Выявить, сопровождаются ли индуцируемые карнозином изменения пролиферации опухолевых клеток колебаниями внутриклеточного уровня АФК и антиоксидантных ферментов;
3. Выяснить, являются ли индуцируемые карнозином изменения пролиферации опухолевых клеток результатом модификации прогрессии клеточного цикла;
4. Сравнить антипролиферативные свойства карнозина с действием его производных, а также синтетического трипептида пинеалона;
5. Оценить эффект совместного применения карнозина и ионизирующего излучения на гибель опухолевых клеток.
Научная новизна. Настоящая работа представляет собой оригинальное экспериментальное исследование, в котором было впервые показано избирательное подавление пролиферации клеток глиобластомы под действием карнозина. Установлено, что замедление пролиферации глиобластомы сопровождается накоплением клеток в G2 фазе клеточного цикла и активацией экспрессии циклина B1. Продемонстрировано, что параллельно с изменениями в прогрессии клеточного цикла происходит повышение активности MnСОД и понижение внутриклеточного уровня АФК. Выявлено, что метилированное производное карнозина – анзерин – подавляет пролиферацию глиобластомы эффективнее, чем карнозин. Показано, что предварительная инкубация клеток с карнозином снижает выживаемость клеток глиобластомы под действием ионизирующего излучения.
Теоретическая и практическая значимость работы. Полученные результаты существенно расширяют представления о природе антипролиферативного действия карнозина на опухолевые клетки нейрального происхождения, что важно для понимания молекулярных механизмов действия карнозина в целом. Полученные в работе данные об эффекте совместного действия карнозина и ионизирующего излучения на выживаемость клеток глиобластомы открывают перспективу для применения карнозина в комбинированной терапии опухолей головного мозга.
Основные положения, выносимые на защиту:
1. Карнозин ингибирует пролиферацию опухолевых клеток нейрального происхождения, при этом наиболее выраженный эффект проявляется на клетках глиобластомы человека U-118-MG;
2. Ингибирование пролиферации клеток глиобластомы под действием карнозина сопровождается снижением уровня АФК и увеличением активности MnСОД;
3. Изменения в антиоксидантной системе клеток глиобластомы сопровождаются накоплением клеток в G2 фазе клеточного цикла и усилением экспрессии циклина В1;
4. Метилированное производное карнозина, анзерин, ингибирует пролиферацию клеток глиобластомы эффективнее, чем карнозин;
5. Предварительная инкубация клеток с карнозином снижает выживаемость клеток глиобластомы под действием ионизирующего излучения.
Протокол диссертационного исследования «Антипролиферативное действие карнозина и его производных на опухолевые клетки нейрального происхождения» было одобрено локальным этическим комитетом ФГБУ «НЦН» РАМН. Протокол №12/13 от 11.12.2013.
Апробация работы. Диссертация апробирована и рекомендована к защите на совместном заседании научных сотрудников ФГБУ «Научный центр неврологии» РАМН 18 октября 2013 года.
Материалы диссертационной работы были представлены на V Stromboli Conference on Cancer and Ageing: “The Primeval Life-Generating Molecules. Therapeutic and Aging-Reversing Properties” (Стромболи, Италия, 2010) и The 4th Quadrennial Meeting of the World Federation of Neuro-Oncology held in conjunction with the 2013 SNO Scientific Meeting and Education Day (Сан-Франциско, США, 2013)
Публикации. По материалам диссертации опубликовано 4 научные работы, из них 1 публикация в изданиях, рекомендуемых ВАК Министерства образования и науки РФ и 2 работы в зарубежных рецензируемых журналах.
Личный вклад автора. Автором лично выполнено культивирование клеточных линий и исследования клеточной пролиферации, проведено измерение уровня АФК, доли мертвых клеток, а также анализ клеточного цикла, определена активность и экспрессия антиоксидантных ферментов. Выполнена последующая аналитическая обработка и обобщение полученных результатов, сформулированы выводы и подготовлены публикации.
Структура и объем диссертации. Диссертация состоит из введения, обзора литературы, описания материалов и методов исследования, изложения результатов, их обсуждения, выводов и списка литературы. Работа содержит 120 стр. машинописного текста, 1 таблицу и 29 рисунков. Список литературы включает 271 источник (18 отечественных и 253 зарубежных).
ГЛАВА 1. ОБЗОР ЛИТЕРАТУРЫРАЗДЕЛ 1.
1. Редокс-статус клетки определяется соотношением внутриклеточных про- и антиоксидантов1.1.1. Активные формы кислорода и их значение в жизни клеткиНаиболее распространенные и реакционноспособные прооксиданты в клетке – активные формы кислорода (АФК). АФК представляют собой продукты частичного восстановления кислорода, содержащие один или несколько неспаренных электронов, и относятся к классу свободных радикалов ADDIN EN.CITE <EndNote><Cite><Author>Cadenas</Author><Year>1985</Year><RecNum>210</RecNum><DisplayText>[31]</DisplayText><record><rec-number>210</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">210</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cadenas, E.</author><author>Sies, H.</author></authors></contributors><titles><title>Oxidative stress: excited oxygen species and enzyme activity</title><secondary-title>Adv Enzyme Regul</secondary-title><alt-title>Advances in enzyme regulation</alt-title></titles><periodical><full-title>Adv Enzyme Regul</full-title><abbr-1>Advances in enzyme regulation</abbr-1></periodical><alt-periodical><full-title>Adv Enzyme Regul</full-title><abbr-1>Advances in enzyme regulation</abbr-1></alt-periodical><pages>217-37</pages><volume>23</volume><edition>1985/01/01</edition><keywords><keyword>Aldehydes/metabolism/pharmacology</keyword><keyword>Animals</keyword><keyword>Azoles/pharmacology</keyword><keyword>Cell Survival/drug effects</keyword><keyword>Electron Transport</keyword><keyword>Ethanol/pharmacology</keyword><keyword>Free Radicals</keyword><keyword>Lipid Metabolism</keyword><keyword>Organoselenium Compounds</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxygen/ metabolism</keyword><keyword>Pargyline/pharmacology</keyword><keyword>Peroxides/metabolism</keyword><keyword>Quinones/metabolism</keyword><keyword>Selenium/pharmacology</keyword></keywords><dates><year>1985</year></dates><isbn>0065-2571 (Print)
0065-2571 (Linking)</isbn><accession-num>3907304</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31].
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ADDIN EN.CITE.DATA [34], монооксигеназа, NO-синтаза ADDIN EN.CITE <EndNote><Cite><Author>Bedard</Author><Year>2007</Year><RecNum>458</RecNum><DisplayText>[35]</DisplayText><record><rec-number>458</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">458</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bedard, K.</author><author>Krause, K. H.</author></authors></contributors><auth-address>Biology of Ageing Laboratories, University of Geneva, Geneva, Switzerland.</auth-address><titles><title>The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology</title><secondary-title>Physiol Rev</secondary-title><alt-title>Physiological reviews</alt-title></titles><periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></periodical><alt-periodical><full-title>Physiol Rev</full-title><abbr-1>Physiological reviews</abbr-1></alt-periodical><pages>245-313</pages><volume>87</volume><number>1</number><edition>2007/01/24</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>NADPH Oxidase/ physiology</keyword><keyword>Reactive Oxygen Species</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0031-9333 (Print)
0031-9333 (Linking)</isbn><accession-num>17237347</accession-num><urls></urls><electronic-resource-num>10.1152/physrev.00044.2005</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[35] и др), метаболизме ксенобиотиков, активации дыхательного взрыва в лейкоцитах, под воздействием цитокинов, ионизирующего и УФ-излучения ADDIN EN.CITE <EndNote><Cite><Author>Thannickal</Author><Year>2000</Year><RecNum>412</RecNum><DisplayText>[36]</DisplayText><record><rec-number>412</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">412</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thannickal, Victor J.</author><author>Fanburg, Barry L.</author></authors></contributors><titles><title>Reactive oxygen species in cell signaling</title><secondary-title>American Journal of Physiology - Lung Cellular and Molecular Physiology</secondary-title></titles><periodical><full-title>American Journal of Physiology - Lung Cellular and Molecular Physiology</full-title></periodical><pages>L1005-L1028</pages><volume>279</volume><number>6</number><dates><year>2000</year><pub-dates><date>2000-12-01 08:00:00</date></pub-dates></dates><urls><related-urls><url>http://ajplung.physiology.org/ajplung/279/6/L1005.full.pdf</url></related-urls></urls></record></Cite></EndNote>[36]. Образование АФК происходит в несколько стадий. Одноэлектронное восстановление кислорода приводит к формированию супероксидного аниона (или супероксида, О2•-), который сам по себе не является окислителем, а наоборот, по свойствам напоминает слабое основание.
О2 + 1е- + (H+) О2•- (НО2•)
НО2•- + 1е- + H+ Н2О2
Н2О2 + 1е- + Н+ Н2О + НО•
НО• + 1е- + H+ Н2О
В результате воздействия ионизирующего или УФ-излучения, некоторых химических соединений (ксенобиотики и др.), а также при старении и опухолевой трансформации происходит повышение внутриклеточного уровня АФК, что приводит к окислительному повреждению макромолекул (ДНК, белки, липиды), нарушению их структуры, функции и в итоге к гибели клетки. В то же время, на сегодняшний день накоплено множество данных о том, что в небольших количествах АФК играют важную роль в жизни клетки PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxsaXdlbGw8L0F1dGhvcj48WWVhcj4xOTkyPC9ZZWFy
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ADDIN EN.CITE.DATA [28]. Сравнительный анализ образования АФК в нормальных и опухолевых клетках выявил, что уровень АФК в опухолевых клетках значительно выше по сравнению с нормальными клетками того же вида ADDIN EN.CITE <EndNote><Cite><Author>Burdon</Author><Year>1995</Year><RecNum>272</RecNum><DisplayText>[29]</DisplayText><record><rec-number>272</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">272</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burdon, R. H.</author></authors></contributors><auth-address>Department of Bioscience and Biotechnology, University of Strathclyde, Glasgow, Scotland, UK.</auth-address><titles><title>Superoxide and hydrogen peroxide in relation to mammalian cell proliferation</title><secondary-title>Free Radic Biol Med</secondary-title><alt-title>Free radical biology & medicine</alt-title></titles><periodical><full-title>Free Radic Biol Med</full-title><abbr-1>Free radical biology & medicine</abbr-1></periodical><alt-periodical><full-title>Free Radic Biol Med</full-title><abbr-1>Free radical biology & medicine</abbr-1></alt-periodical><pages>775-94</pages><volume>18</volume><number>4</number><edition>1995/04/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Death</keyword><keyword>Cell Division/ drug effects</keyword><keyword>Cells, Cultured</keyword><keyword>Cricetinae</keyword><keyword>Free Radicals</keyword><keyword>Glutathione/pharmacology</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/ metabolism</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Mice</keyword><keyword>Platelet-Derived Growth Factor/pharmacology</keyword><keyword>Rats</keyword><keyword>Superoxides/ metabolism</keyword></keywords><dates><year>1995</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0891-5849 (Print)
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ADDIN EN.CITE.DATA [28].
1.1.2. Основные представители антиоксидантной системы клетки и их роль в поддержании редокс-статусаКонцентрация внутриклеточных прооксидантов регулируется антиоксидантной системой клетки, которая включает как низкомолекулярные вещества (витамин Е, С, -каротин, глутатион, НАДФН, пируват, тиоредоксин и др.), так и ферменты (супероксиддисмутаза, глутатионпероксидаза, каталаза, тиоредоксин пероксидаза и др.). Таким образом, в норме в клетке постоянно поддерживается равновесие между скоростью образования прооксидантов и их устранением с помощью системы антиоксидантов. Это равновесие называется окислительно-восстановительным балансом или редокс-статусом ADDIN EN.CITE <EndNote><Cite><Author>Schafer</Author><Year>2001</Year><RecNum>187</RecNum><DisplayText>[47]</DisplayText><record><rec-number>187</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">187</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schafer, F. Q.</author><author>Buettner, G. R.</author></authors></contributors><auth-address>Free Radical Research Institute & ESR Facility, The University of Iowa, Iowa City, IA 52242-1101, USA. fraya-schafer@uiowa.edu</auth-address><titles><title>Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple</title><secondary-title>Free Radic Biol Med</secondary-title><alt-title>Free radical biology & medicine</alt-title></titles><periodical><full-title>Free Radic Biol Med</full-title><abbr-1>Free radical biology & medicine</abbr-1></periodical><alt-periodical><full-title>Free Radic Biol Med</full-title><abbr-1>Free radical biology & medicine</abbr-1></alt-periodical><pages>1191-212</pages><volume>30</volume><number>11</number><edition>2001/05/23</edition><keywords><keyword>Cell Cycle/physiology</keyword><keyword>Cell Division/ physiology</keyword><keyword>Glutathione/ metabolism</keyword><keyword>Glutathione Disulfide/ metabolism</keyword><keyword>Humans</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress</keyword><keyword>Signal Transduction/physiology</keyword><keyword>Sulfhydryl Compounds/metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun 1</date></pub-dates></dates><isbn>0891-5849 (Print)
0891-5849 (Linking)</isbn><accession-num>11368918</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[47].
Самым распространенным низкомолекулярным антиоксидантом клетки является цистеин-содержащий трипептид - глутатион (Gly-Cys-Glu, GSH), его концентрация в цитоплазме может достигать 11 мМ ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>1996</Year><RecNum>220</RecNum><DisplayText>[48]</DisplayText><record><rec-number>220</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">220</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, C. V.</author><author>Jones, D. P.</author><author>Guenthner, T. M.</author><author>Lash, L. H.</author><author>Lauterburg, B. H.</author></authors></contributors><auth-address>Department of Pediatrics, Baylor College of Medicine, Houston 77030, USA.</auth-address><titles><title>Compartmentation of glutathione: implications for the study of toxicity and disease</title><secondary-title>Toxicol Appl Pharmacol</secondary-title><alt-title>Toxicology and applied pharmacology</alt-title></titles><periodical><full-title>Toxicol Appl Pharmacol</full-title><abbr-1>Toxicology and applied pharmacology</abbr-1></periodical><alt-periodical><full-title>Toxicol Appl Pharmacol</full-title><abbr-1>Toxicology and applied pharmacology</abbr-1></alt-periodical><pages>1-12</pages><volume>140</volume><number>1</number><edition>1996/09/01</edition><keywords><keyword>Acquired Immunodeficiency Syndrome/metabolism</keyword><keyword>Animals</keyword><keyword>Cell Compartmentation/ physiology</keyword><keyword>Glutathione/deficiency/ physiology</keyword><keyword>Humans</keyword><keyword>Mitochondria/ metabolism</keyword><keyword>Toxicology</keyword></keywords><dates><year>1996</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0041-008X (Print)
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ADDIN EN.CITE.DATA [47, 49].
Одним из основных антиоксидантных ферментов клетки является супероксиддисмутаза (СОД), катализирующая реакцию дисмутации супероксида: О2-• + О2-• O2 + H2O2. Несмотря на то, что дисмутация О2-• происходит быстро и сама по себе, СОД делает реакцию практически молниеносной (k=2х109 M-1•s-1) ADDIN EN.CITE <EndNote><Cite><Author>McCord</Author><Year>1969</Year><RecNum>207</RecNum><DisplayText>[50]</DisplayText><record><rec-number>207</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCord, J. M.</author><author>Fridovich, I.</author></authors></contributors><titles><title>Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>6049-55</pages><volume>244</volume><number>22</number><edition>1969/11/25</edition><keywords><keyword>Adrenochrome</keyword><keyword>Alkanes</keyword><keyword>Animals</keyword><keyword>Blood Proteins</keyword><keyword>Cattle</keyword><keyword>Centrifugation</keyword><keyword>Copper</keyword><keyword>Cytochromes</keyword><keyword>Epinephrine</keyword><keyword>Erythrocytes/enzymology</keyword><keyword>Free Radicals</keyword><keyword>Hydrogen Peroxide</keyword><keyword>Oxidoreductases/blood/isolation & purification</keyword><keyword>Oxygen</keyword><keyword>Radiochemistry</keyword><keyword>Spectrophotometry</keyword><keyword>Xanthine Oxidase</keyword></keywords><dates><year>1969</year><pub-dates><date>Nov 25</date></pub-dates></dates><isbn>0021-9258 (Print)
0021-9258 (Linking)</isbn><accession-num>5389100</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[50]. Cуществует три изоформы СОД: митохондриальная (MnСОД) ADDIN EN.CITE <EndNote><Cite><Author>McCord</Author><Year>1969</Year><RecNum>207</RecNum><DisplayText>[50]</DisplayText><record><rec-number>207</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McCord, J. M.</author><author>Fridovich, I.</author></authors></contributors><titles><title>Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>6049-55</pages><volume>244</volume><number>22</number><edition>1969/11/25</edition><keywords><keyword>Adrenochrome</keyword><keyword>Alkanes</keyword><keyword>Animals</keyword><keyword>Blood Proteins</keyword><keyword>Cattle</keyword><keyword>Centrifugation</keyword><keyword>Copper</keyword><keyword>Cytochromes</keyword><keyword>Epinephrine</keyword><keyword>Erythrocytes/enzymology</keyword><keyword>Free Radicals</keyword><keyword>Hydrogen Peroxide</keyword><keyword>Oxidoreductases/blood/isolation & purification</keyword><keyword>Oxygen</keyword><keyword>Radiochemistry</keyword><keyword>Spectrophotometry</keyword><keyword>Xanthine Oxidase</keyword></keywords><dates><year>1969</year><pub-dates><date>Nov 25</date></pub-dates></dates><isbn>0021-9258 (Print)
0021-9258 (Linking)</isbn><accession-num>5389100</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[50], цитоплазматическая (CuZnСОД) ADDIN EN.CITE <EndNote><Cite><Author>Fridovich</Author><Year>1989</Year><RecNum>208</RecNum><DisplayText>[51]</DisplayText><record><rec-number>208</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">208</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fridovich, I.</author></authors></contributors><auth-address>Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710.</auth-address><titles><title>Superoxide dismutases. An adaptation to a paramagnetic gas</title><secondary-title>J Biol Chem</secondary-title><alt-title>The Journal of biological chemistry</alt-title></titles><periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></periodical><alt-periodical><full-title>J Biol Chem</full-title><abbr-1>The Journal of biological chemistry</abbr-1></alt-periodical><pages>7761-4</pages><volume>264</volume><number>14</number><edition>1989/05/15</edition><keywords><keyword>Catalysis</keyword><keyword>Chemical Phenomena</keyword><keyword>Chemistry</keyword><keyword>Free Radicals</keyword><keyword>Inflammation</keyword><keyword>Magnetics</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxygen/metabolism</keyword><keyword>Oxygen Consumption</keyword><keyword>Phagocytosis</keyword><keyword>Reperfusion Injury</keyword><keyword>Superoxide Dismutase/ physiology</keyword><keyword>Superoxides/metabolism</keyword></keywords><dates><year>1989</year><pub-dates><date>May 15</date></pub-dates></dates><isbn>0021-9258 (Print)
0021-9258 (Linking)</isbn><accession-num>2542241</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[51] и внеклеточная, на поверхности клеточных мембран, (ЕС(CuZn)СОД) ADDIN EN.CITE <EndNote><Cite><Author>Folz</Author><Year>1994</Year><RecNum>209</RecNum><DisplayText>[52]</DisplayText><record><rec-number>209</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Folz, R. J.</author><author>Crapo, J. D.</author></authors></contributors><auth-address>Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.</auth-address><titles><title>Extracellular superoxide dismutase (SOD3): tissue-specific expression, genomic characterization, and computer-assisted sequence analysis of the human EC SOD gene</title><secondary-title>Genomics</secondary-title><alt-title>Genomics</alt-title></titles><periodical><full-title>Genomics</full-title><abbr-1>Genomics</abbr-1></periodical><alt-periodical><full-title>Genomics</full-title><abbr-1>Genomics</abbr-1></alt-periodical><pages>162-71</pages><volume>22</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Base Sequence</keyword><keyword>Chromosome Mapping</keyword><keyword>DNA/genetics</keyword><keyword>DNA Primers/genetics</keyword><keyword>Exons</keyword><keyword>Extracellular Space/enzymology</keyword><keyword>Gene Expression Regulation, Enzymologic</keyword><keyword>Humans</keyword><keyword>Introns</keyword><keyword>Molecular Sequence Data</keyword><keyword>RNA, Messenger/genetics/metabolism</keyword><keyword>Repetitive Sequences, Nucleic Acid</keyword><keyword>Superoxide Dismutase/ genetics</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0888-7543 (Print)
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ADDIN EN.CITE.DATA [53, 54]. Ингибирование экспрессии других изоформ СОД, каталазы или глутатионпероксидазы было совместимо с жизнью. Частичное ингибирование активности MnСОД (Sod2+/-) приводило к нарушению функционирования митохондрий и усилению их окислительного повреждения, а также увеличению риска развития опухолей PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gUmVtbWVuPC9BdXRob3I+PFllYXI+MjAwMzwvWWVh
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