«Антипролиферативное действие карнозина и его производных на опухолевые клетки нейрального происхождения ...»
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ADDIN EN.CITE.DATA [232, 233]. Приведенные данные указывают на возможное участие регуляторных каскадов HIF-1 и Hsp70 в антипролиферативном эффекте карнозина. В нашей лаборатории было показано, что карнозин замедляет рост уровня фосфо-ERK1/2 и JNK в гранулярных клетках мозжечка в условиях окислительного стресса, индуцированного активацией глутаматных рецепторов ADDIN EN.CITE <EndNote><Cite><Author>Rybakova</Author><Year>2012</Year><RecNum>345</RecNum><DisplayText>[234]</DisplayText><record><rec-number>345</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">345</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rybakova, Y. </author><author>Akkuratov, E.</author><author>Kulebyakin, K.</author><author>Brodskaya, O.</author><author>Dizhevskaya, A.</author><author>Boldyrev, A.</author></authors></contributors><auth-address>International Biotechnological Center of MV Lomonosov Moscow State University, Moscow, Russia. julie_ribakova@yahoo.com</auth-address><titles><title>Receptor-mediated oxidative stress in murine cerebellar neurons is accompanied by phosphorylation of MAP (ERK 1/2) kinase</title><secondary-title>Curr Aging Sci</secondary-title><alt-title>Current aging science</alt-title></titles><periodical><full-title>Curr Aging Sci</full-title><abbr-1>Current aging science</abbr-1></periodical><alt-periodical><full-title>Curr Aging Sci</full-title><abbr-1>Current aging science</abbr-1></alt-periodical><pages>225-30</pages><volume>5</volume><number>3</number><edition>2013/02/08</edition><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1874-6128 (Electronic)</isbn><accession-num>23387889</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[234]. Как было отмечено выше ERK1/2 представляет собой редокс-чувствительную МАР-киназу, регулирующую множество внутриклеточных функций, в том числе и пролиферативные процессы. Было показано, что ингибирование образования Н2О2 препятствует активации ERK1/2 и развитию пролиферативного ответа PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb25nPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [234, 236]. Повышенный уровень ERK1/2 часто встречается при онкологических заболеваниях ADDIN EN.CITE <EndNote><Cite><Author>Roberts</Author><Year>2007</Year><RecNum>388</RecNum><DisplayText>[105]</DisplayText><record><rec-number>388</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roberts, P. J.</author><author>Der, C. J.</author></authors></contributors><auth-address>Division of Pharmacotherapy and Experimental Therapeutics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.</auth-address><titles><title>Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer</title><secondary-title>Oncogene</secondary-title><alt-title>Oncogene</alt-title></titles><periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></periodical><alt-periodical><full-title>Oncogene</full-title><abbr-1>Oncogene</abbr-1></alt-periodical><pages>3291-310</pages><volume>26</volume><number>22</number><edition>2007/05/15</edition><keywords><keyword>Animals</keyword><keyword>Drug Delivery Systems/ methods</keyword><keyword>Extracellular Signal-Regulated MAP Kinases/ antagonists & inhibitors/physiology</keyword><keyword>Humans</keyword><keyword>MAP Kinase Kinase Kinases/ antagonists & inhibitors/physiology</keyword><keyword>MAP Kinase Signaling System/ drug effects/physiology</keyword><keyword>Neoplasms/ drug therapy/ enzymology/genetics</keyword><keyword>raf Kinases/ antagonists & inhibitors/genetics/physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>May 14</date></pub-dates></dates><isbn>0950-9232 (Print)
0950-9232 (Linking)</isbn><accession-num>17496923</accession-num><urls></urls><electronic-resource-num>10.1038/sj.onc.1210422</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[105]. Ингибирование роста ERK1/2 может быть одним из механизмов антипролиферативного эффекта карнозина.
Исследование противоопухолевого эффекта производных карнозина (анзерина, гомокарнозина и D-карнозина) выявило, что только анзерин способен ингибировать рост трансформированных клеток. Также было обнаружено, при равных концентрациях (20 мМ) -аланин не оказывал какого либо влияния на опухолевые клетки, в то время как гистидин убивал все клетки (нормальные и опухолевые) ADDIN EN.CITE <EndNote><Cite><Author>Holliday</Author><Year>1996</Year><RecNum>73</RecNum><DisplayText>[23]</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holliday, R.</author><author>McFarland, G. A.</author></authors></contributors><auth-address>CSIRO Division of Biomolecular Engineering, Sydney Laboratory, NSW, Australia.</auth-address><titles><title>Inhibition of the growth of transformed and neoplastic cells by the dipeptide carnosine</title><secondary-title>Br J Cancer</secondary-title><alt-title>British journal of cancer</alt-title></titles><periodical><full-title>Br J Cancer</full-title><abbr-1>British journal of cancer</abbr-1></periodical><alt-periodical><full-title>Br J Cancer</full-title><abbr-1>British journal of cancer</abbr-1></alt-periodical><pages>966-71</pages><volume>73</volume><number>8</number><edition>1996/04/01</edition><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents/ pharmacology</keyword><keyword>Carnosine/ pharmacology</keyword><keyword>Cell Line, Transformed</keyword><keyword>Culture Media</keyword><keyword>Glycolysis/drug effects</keyword><keyword>HeLa Cells</keyword><keyword>Humans</keyword><keyword>Pyruvates/metabolism</keyword><keyword>Pyruvic Acid</keyword><keyword>Simian virus 40</keyword><keyword>Tumor Cells, Cultured</keyword></keywords><dates><year>1996</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0007-0920 (Print)
0007-0920 (Linking)</isbn><accession-num>8611433</accession-num><urls></urls><custom2>PMC2075811</custom2><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[23]. Полученные данные явно указывают на определяющую роль гистидина в проявлении противоопухолевого эффекта карнозина.
1.3.4. Пинеалон. Общая характеристика и свойстваВ настоящее время установлена роль регуляторных короткоцепочечных пептидов в формировании адаптационного ответа организма на стресс и нарушения гомеостаза ADDIN EN.CITE <EndNote><Cite><Author>Ashmarin</Author><Year>2005</Year><RecNum>435</RecNum><DisplayText>[237]</DisplayText><record><rec-number>435</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">435</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ashmarin, I. P.</author><author>Samonina, G. E. </author><author>Lyapina, L. A.</author><author>Kamenskii, A. A.</author><author>Levitskaya, N. G.</author><author>Grivennikov, I. A.</author><author>Dolotov, O. V.</author><author>Andreeva, L. A.</author><author>Myasoedov, N. F.</author></authors></contributors><auth-address>Chair of Animal and Human Physiology, M.V. Lomonosov Moscow State University, Vorobjevy Gory 1, Building 12, Moscow 119899, Russia.</auth-address><titles><title>Natural and hybrid ("chimeric") stable regulatory glyproline peptides</title><secondary-title>Pathophysiology</secondary-title><alt-title>Pathophysiology : the official journal of the International Society for Pathophysiology / ISP</alt-title></titles><periodical><full-title>Pathophysiology</full-title><abbr-1>Pathophysiology : the official journal of the International Society for Pathophysiology / ISP</abbr-1></periodical><alt-periodical><full-title>Pathophysiology</full-title><abbr-1>Pathophysiology : the official journal of the International Society for Pathophysiology / ISP</abbr-1></alt-periodical><pages>179-185</pages><volume>11</volume><number>4</number><edition>2005/04/20</edition><dates><year>2005</year><pub-dates><date>May</date></pub-dates></dates><isbn>0928-4680 (Print)
0928-4680 (Linking)</isbn><accession-num>15837162</accession-num><urls></urls><electronic-resource-num>10.1016/j.pathophys.2004.10.001</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[237]. Будучи эндогенными компонентами живой клетки, пептидные биорегуляторы обладают разнообразным биологическим действием, они эффективны в низких дозах, не вызывают побочных эффектов ADDIN EN.CITE <EndNote><Cite><Author>Gomazkov</Author><Year>2003</Year><RecNum>436</RecNum><DisplayText>[238]</DisplayText><record><rec-number>436</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">436</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gomazkov, O. A.</author></authors></contributors><auth-address>Oreckhovich Institute of Biomedical Chemistry of RAMS, Moscow.</auth-address><titles><title>[Regulatory molecular mechanisms of the neurochemical processes. History and the present time]</title><secondary-title>Usp Fiziol Nauk</secondary-title><alt-title>Uspekhi fiziologicheskikh nauk</alt-title></titles><periodical><full-title>Usp Fiziol Nauk</full-title><abbr-1>Uspekhi fiziologicheskikh nauk</abbr-1></periodical><alt-periodical><full-title>Usp Fiziol Nauk</full-title><abbr-1>Uspekhi fiziologicheskikh nauk</abbr-1></alt-periodical><pages>42-54</pages><volume>34</volume><number>3</number><edition>2003/08/29</edition><keywords><keyword>Aging</keyword><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Growth Substances/physiology</keyword><keyword>History, 20th Century</keyword><keyword>History, 21st Century</keyword><keyword>Humans</keyword><keyword>Nervous System Diseases/physiopathology</keyword><keyword>Neurobiology/history/ trends</keyword><keyword>Neurochemistry/history/ trends</keyword><keyword>Neurons/chemistry/pathology/ physiology</keyword><keyword>Neurotransmitter Agents/physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul-Sep</date></pub-dates></dates><orig-pub>Molekuliarnye mekhanizmy reguliatsii neirokhimicheskikh protsessov. Istoria i sovremennyi vzgliad.</orig-pub><isbn>0301-1798 (Print)
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ZE5vdGU+
ADDIN EN.CITE.DATA [239-243].
Пинеалон представляет собой синтетический трипептид состоящий из трех аминокислот глутаминовой кислоты, аспарагиновой кислоты и аргинина (Glu-Asp-Arg), синтезированный на основе анализа экстракта коры головного мозга крупного рогатого скота (Рис. 1.6). Последовательность Glu-Asp-Arg была выбрана как наиболее часто встречающаяся в "активных участках" наиболее функционально-значимых в своей группе полипептидов, содержащихся в животных экстрактах.
Пинеалон демонстрирует эффективные антиоксидантные свойства. Пинеалон усиливал устойчивость экспериментальных животных к пренатальной и острой сублетальной гипобарической гипоксии. Введение пинеалона крысам чувствительным к гипоксии усиливало активность антиоксидантных ферментов – СОД и GPx. В культуре гранулярных клеток мозжечка пинеалон снижал уровень АФК и клеточную гибель, индуцированные активацией глутаматных рецепторов NMDA-класса PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3ppbmE8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [244, 245]. На модели пренатальной гипергомоцистеинемии было показано, что инъекции пинеалона самкам улучшают когнитивные способности потомства и способствуют развитию устойчивости к окислительному стрессу ADDIN EN.CITE <EndNote><Cite><Author>Arutjunyan</Author><Year>2012</Year><RecNum>294</RecNum><DisplayText>[246]</DisplayText><record><rec-number>294</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">294</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arutjunyan, A.</author><author>Kozina, L.</author><author>Stvolinskiy, S.</author><author>Bulygina, Y.</author><author>Mashkina, A.</author><author>Khavinson, V.</author></authors></contributors><titles><title>Pinealon protects the rat offspring from prenatal hyperhomocysteinemia</title><secondary-title>Int J Clin Exp Med</secondary-title><alt-title>International journal of clinical and experimental medicine</alt-title></titles><periodical><full-title>Int J Clin Exp Med</full-title><abbr-1>International journal of clinical and experimental medicine</abbr-1></periodical><alt-periodical><full-title>Int J Clin Exp Med</full-title><abbr-1>International journal of clinical and experimental medicine</abbr-1></alt-periodical><pages>179-85</pages><volume>5</volume><number>2</number><edition>2012/05/09</edition><dates><year>2012</year></dates><isbn>1940-5901 (Electronic)
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ADDIN EN.CITE.DATA [247]. Недавно были получены данные о возможном участии пинеалона в эпигенетической регуляции. Пинеалон проникал в ядро клетки, а также взаимодействовал с некоторыми промоторными последовательностями, в частности с одноцепочечной oligo(dGC). Интересно, что предпочтительным местом связывания пинеалона была последовательность CNG, которая также является местом метилирования ДНК PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWRvcmV5ZXZhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh
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ADDIN EN.CITE.DATA [248, 249]. Исходя из способностей пинеалона модулировать внутриклеточный уровень АФК и связываться с ДНК можно предположить, что пинеалон также способен участвовать в регуляции пролиферации.
20955635Рисунок 1.6. Химическая структура молекулы пинеалона.
Подводя итог всему выше сказанному, можно заключить, что антипролиферативный эффект карнозина известен давно, однако его молекулярный механизм до сих пор непонятен. Понимание механизма действия карнозина помогло бы расширить область применения природного дипептида карнозин на практике, например в терапии опухолевых заболеваний. На сегодняшний день накоплено множество сведений об участии про- и антиоксидантов в регуляции процессов клеточной пролиферации. Поскольку, карнозин демонстрирует эффективные антиоксидантные свойства, было сделано предположение о том, что ингибирующий эффект карнозина на пролиферацию опухолевых клеток является следствием его антиоксидантной активности. Сравнительный анализ действия карнозина и его производных на пролиферацию опухолевых клеток помог бы определить функциональную нагрузку отдельных частей молекулы при антипролиферативном эффекте и пути улучшения эффективности антипролиферативных свойств карнозина.
ГЛАВА 2. МЕТОДЫ ИССЛЕДОВАНИЯ2.
1. Культуры клетокВ работе были использованы следующие клеточные линии: феохромоцитома крысы (РС-12); карцинома горла и рта (FaDu, Cal27) и молочной железы (MB231) человека; глиобластома человека (U-118-MG). Клетки PC-12 культивировали в среде RPMI 1640 с 25 мМ HEPES и 24 мМ бикарбоната натрия (ПанЭко, Россия), с добавлением 2 мМ глутамина (ПанЭко, Россия), 20 мкг/мл гентамицина (ПанЭко, Россия) и 10% эмбриональной телячьей сыворотки (ПанЭко, Россия). Клетки FaDu и Cal27 культивировали в среде DMEM (Gibco, США) с добавлением 10% эмбриональной телячьей сыворотки (HyClone, США) и 100 ед/мл ПенСтреп (Gibco, США). Клетки MB231 инкубировали в среде RPMI 1640 (Gibco, США) с добавлением 10% эмбриональной телячьей сыворотки (HyClone, США) и 100 ед/мл ПенСтреп (Gibco, США). Клетки U-118-MG культивировали в смеси DMEM:F12 (1:1) (Gibco, США) с добавлением 15 мМ HEPES (Gibco, США), 1 мМ пирувата натрия (Gibco, США), 10 мкг/мл инсулина (Sigma Aldrich, США), 5 нг/мл фактора роста фибробластов (Sigma Aldrich, США), 15% эмбриональной телячьей сыворотки (HyClone, США) и 100 ед/мл ПенСтреп (Gibco, США). Клетки содержали в СО2-инкубаторе (ShelLab, США) в присутствии 5% СО2, 98% влажности и 37С.
2.2. Исследуемые соединенияКарнозин (чистота 99%) был любезно предоставлен «Hamari Chem., Ltd», Осака, Япония. Гомокарнозин (чистота 99%) и анзерин (чистота 99%) были приобретены, соответственно, в «Hamari Chem., Ltd» и «Yaizu Suisankagaku Industry Co.,Ltd.» (чистота 99%). N-ацетилкарнозин был синтезирован рутинным путем в Лаборатории клинической и экспериментальной нейрохимии ФГБУ «НЦН» РАМН (чистота 98,7%, определена с помощью HPLC). L-гистидин--аланин был синтезирован рутинным путем в Исследовательском Институте Химического Разнообразия (чистота 98%, определена с помощью HPLC). Пинеалон был предоставлен Научно-производственным центром ревитализации и здоровья.
2.3. Исследование клеточной пролиферации2.3.1. Время удвоения популяцииВремя удвоения популяции (Тd) – это период времени, за который происходит увеличение количества клеток в два раза. Для вычисления Тd клетки высаживали в чашки Петри в небольших разведениях. Каждые два дня клетки снимали с помощью трипсина (Gibco, США), считали их количество с помощью Z1 Coulter Counter (Beckman Coulter, США) и строили кривые роста (Рис. 2.1). Время удвоения популяции (Тd) рассчитывали на экспоненциальном участке роста по формуле:
Тd=0.693t/ln(Nt/N0),
где t – время (дни), N0 – начальное количество клеток, Nt – количество клеток ко дню t. Nt вычисляли по уравнению экспоненциальной линии тренда (Рис. 2.1).
1778011430Рисунок 2.1. Пример кривой роста с экспоненциальной линией тренда и уравнением линии тренда для вычисления времени удвоения популяции. x – время (д), y – количество клеток ко дню х.
2.3.2. Эффективность посева и выживаемость клетокВыживаемость клеток определяли по их способности формировать колонии. Клетки рассеивали в низких разведениях в 60 мм чашки Петри, по истечении 10 дней клетки фиксировали 2-4 мин в 70% этаноле, разведенном на фосфатном буфере, окрашивали 10 мин с помощью раствора содержащего 0.05% бриллиантового синего G-250, 50% метанола, 5% уксусной кислоты, 45% воды. Далее подсчитывали количество колоний состоящих из 50 и более клеток и вычисляли процент клеток образовавших колонии, эффективность посева (ЭП), по формуле:
ЭП = (количество колоний/количество посаженных клеток) х 100.
Выживаемость рассчитывали как процентное соотношение ЭП в клетках, обработанных карнозином или подвергнутых действию ионизирующего излучения, к ЭП клеток в контроле.
2.4. Проточная цитометрия
В данной работе все измерения проводили на проточном цитометре FACSCalibur (BD, США), оснащенном ионным аргоновым лазером с длинной волны 488 нм и двумя светофильтрами: 585/42 нм для красной флуоресценции (PI) и 530/30 нм для зеленой флуоресценции (ФИТЦ, DCF).
2.4.1. Измерение уровня АФК
Уровень внутриклеточных АФК измеряли с помощью флуоресцентного красителя 2,7-дихлордигидрофлуоресцеин-диацетата (DCFН2-DA) (Рис. 2.2).
Рисунок 2.2.
Реакция превращения DCFH2-DA в DCF (из ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>2010</Year><RecNum>238</RecNum><DisplayText>[250]</DisplayText><record><rec-number>238</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">238</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, X.</author><author>Zhong, Z.</author><author>Xu, Z.</author><author>Chen, L.</author><author>Wang, Y.</author></authors></contributors><auth-address>Institute of Chinese Medical Sciences, University of Macau, Macau, PR China.</auth-address><titles><title>2',7'-Dichlorodihydrofluorescein as a fluorescent probe for reactive oxygen species measurement: Forty years of application and controversy</title><secondary-title>Free Radic Res</secondary-title><alt-title>Free radical research</alt-title></titles><periodical><full-title>Free Radic Res</full-title><abbr-1>Free radical research</abbr-1></periodical><alt-periodical><full-title>Free Radic Res</full-title><abbr-1>Free radical research</abbr-1></alt-periodical><pages>587-604</pages><volume>44</volume><number>6</number><edition>2010/04/08</edition><keywords><keyword>Animals</keyword><keyword>Fluoresceins/ chemistry/ diagnostic use/metabolism</keyword><keyword>Fluorescent Dyes/ chemistry/ diagnostic use/metabolism</keyword><keyword>Humans</keyword><keyword>Reactive Oxygen Species/ analysis</keyword></keywords><dates><year>2010</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1029-2470 (Electronic)
1029-2470 (Linking)</isbn><accession-num>20370560</accession-num><urls></urls><electronic-resource-num>10.3109/10715761003709802</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[250] с изменениями). См. пояснения в тексте.
DCFН2-DA представляет собой липофильное соединение, легко проникающее через мембрану живых клеток. Внутриклеточные эстеразы отщепляют ацетильные группы от DCFН2-DA, превращая его в 2,7-дихлордигидрофлуоресцеин (DCFН2), для которого мембрана живой клетки уже непроницаема. Под действием внутриклеточных АФК (в основном Н2О2) происходит окисление DCFН2 с образованием флуоресцирующего продукта 2,7-дихлорфлуоресцеина (DCF, ex=504 нм, em=529) ADDIN EN.CITE <EndNote><Cite><Author>Chen</Author><Year>2010</Year><RecNum>238</RecNum><DisplayText>[250]</DisplayText><record><rec-number>238</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">238</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chen, X.</author><author>Zhong, Z.</author><author>Xu, Z.</author><author>Chen, L.</author><author>Wang, Y.</author></authors></contributors><auth-address>Institute of Chinese Medical Sciences, University of Macau, Macau, PR China.</auth-address><titles><title>2',7'-Dichlorodihydrofluorescein as a fluorescent probe for reactive oxygen species measurement: Forty years of application and controversy</title><secondary-title>Free Radic Res</secondary-title><alt-title>Free radical research</alt-title></titles><periodical><full-title>Free Radic Res</full-title><abbr-1>Free radical research</abbr-1></periodical><alt-periodical><full-title>Free Radic Res</full-title><abbr-1>Free radical research</abbr-1></alt-periodical><pages>587-604</pages><volume>44</volume><number>6</number><edition>2010/04/08</edition><keywords><keyword>Animals</keyword><keyword>Fluoresceins/ chemistry/ diagnostic use/metabolism</keyword><keyword>Fluorescent Dyes/ chemistry/ diagnostic use/metabolism</keyword><keyword>Humans</keyword><keyword>Reactive Oxygen Species/ analysis</keyword></keywords><dates><year>2010</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1029-2470 (Electronic)
1029-2470 (Linking)</isbn><accession-num>20370560</accession-num><urls></urls><electronic-resource-num>10.3109/10715761003709802</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[250]. Для измерения уровня АФК клетки инкубировали с 100 мкМ DCFН2-DA (Biotium, США) в течение 30 мин в темноте (37оС) и затем анализировали на проточном цитометре. Данные обрабатывали в программе CellQuest Pro (BD, США) и рассчитывали среднее значение интенсивности флуоресценции.
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ADDIN EN.CITE.DATA [251, 252]. После связывания с нуклеиновой кислотой флуоресценция PI усиливается в 20 - 30 раз и максимум испускания смещается на 15 нм в УФ-сторону (максимум поглощения (ex) 535 нм, максимум испускания (em) – 617 нм) ADDIN EN.CITE <EndNote><Cite><Author>Arndt-Jovin</Author><Year>1989</Year><RecNum>237</RecNum><DisplayText>[253]</DisplayText><record><rec-number>237</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">237</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arndt-Jovin, D. J.</author><author>Jovin, T. M.</author></authors></contributors><auth-address>Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Gottingen, Federal Republic of Germany.</auth-address><titles><title>Fluorescence labeling and microscopy of DNA</title><secondary-title>Methods Cell Biol</secondary-title><alt-title>Methods in cell biology</alt-title></titles><periodical><full-title>Methods Cell Biol</full-title><abbr-1>Methods in cell biology</abbr-1></periodical><alt-periodical><full-title>Methods Cell Biol</full-title><abbr-1>Methods in cell biology</abbr-1></alt-periodical><pages>417-48</pages><volume>30</volume><edition>1989/01/01</edition><keywords><keyword>DNA/ ultrastructure</keyword><keyword>Fluorescent Antibody Technique</keyword><keyword>Fluorescent Dyes</keyword><keyword>Microscopy, Fluorescence/ methods</keyword><keyword>Staining and Labeling</keyword></keywords><dates><year>1989</year></dates><isbn>0091-679X (Print)
0091-679X (Linking)</isbn><accession-num>2467179</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[253].
Рисунок 2.3.
Флуоресцентные красители использованные в работе. (А) Йодид пропидия (PI). (Б) 5-бромдезоксиуридин (БДУ).
Для определения доли мертвых клеток клетки инкубировали с 1 мкМ PI (Invitrogen, Germany) в течение 3 мин в темноте при комнатной температуре (tкомн) и затем анализировали на проточном цитометре. Данные обрабатывали в программе Cell Quest Pro (BD, США) и рассчитывали среднее значение интенсивности флуоресценции в Microsoft Exel (Microsoft, США).
2.4.3. Анализ клеточного циклаРаспределение клеток по фазам клеточного цикла измеряли по интенсивности свечения PI (Рис. 2.3.А). PI связывается с ДНК пропорционально его количеству, то есть, чем выше содержание ДНК, тем интенсивнее флуоресценция PI. Количество ДНК в разных фазах клеточного цикла неодинаково. G0 и G1 фазы характеризуются диплоидным набором хромосом – 2n, где n – это количество хромосом, а 2 обозначает, что каждая хромосома содержит только две хроматиды. Во время S фазы происходит удвоение хроматид в каждой хромосоме, которое завершается к началу G2 фазы, поэтому набор хромосом клеток в G2 фазе составляет 4n. Клетки, содержащие >2n, но <4n хромосом, относятся к S фазе (Рис. 2.4). Иногда G1 пику предшествует sub-G1 пик, который отражает количество апоптотических клеток. Фрагментация ДНК под действием эндонуклеаз при апоптозе приводит к образованию большого количества коротких ДНК фрагментов. Часть ДНК фрагментов теряется при подготовке проб, приводя к снижению внутриклеточного количества ДНК, которое в апоптотических клетках составляет <2n, что отражается в появлении sub-G1 пика.
209551270Рисунок 2.4. Пример анализа клеточного цикла согласно содержанию ДНК. См. пояснения в тексте.
Для анализа клеточного цикла клетки фиксировали в 70% этаноле в течение 12 ч при - 4оС. Фиксированные клетки отмывали от этанола и инкубировали 30 мин с 1 мг/мл РНКазы (Invitrogen, Германия), затем 60 мин с 35 мкг/мл PI (Invitrogen, Германия) в темноте при tкомн. Данные обрабатывали с помощью программы ModFit LTTM (BD, США).
2.4.4. Двухпараметрический анализ клеточного циклаДля двухпараметрического анализа клеточного цикла был использован маркер клеток в S фазе – 5-бромдезоксиуридин (БДУ) (Рис. 2.3.Б) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZW5vbjwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [170, 254]. БДУ представляет собой аналог нуклеотида тимидина и включается в ДНК во время репликации, то есть в S фазе. Клетки инкубировали 30 мин с 5-бромдезоксиуридином (БДУ) (37оС) и фиксировали в 70% этаноле в течение 12 ч при - 4оС. Фиксированные клетки инкубировали 30 мин в 0.4 мг/мл пепсина, приготовленном на 2 N HCl, и нейтрализовали в 0.1 M боратном буфере. Пробы центрифугировали (1500 об/мин, 5 мин при 4оС), осадок инкубировали 1 ч с мышиными антителами к БДУ (1:10, BD, США) и 1 ч с антимышиными козьими флуоресцеин изотиоцианат (ФИТЦ)-коньюгированными антителами (1:10, BD, США). Далее клетки инкубировали с РНКазой и PI (см. предыдущий пункт). Данные обрабатывали в программе FlowJo v8.8.7.
2.5. ИммуноблоттингДля выделения белков клетки разрушали с помощью ультразвука в лизирующем буфере, содержащем фосфатный буфер (pH 7.8,) ингибитор фосфатаз (PhosSTOP, Roche, США), коктейль ингибиторов протеаз (Sigma, США), 2% NP-40 и ДНКазу (0,01 ед/мкл, Zimo Research Corp., США). Лизаты центрифугировали, для Иммуноблоттинга использовали супернатант.
Белки разделяли в 12% полиакриламидном геле в присутствии додецилсульфата натрия по Леммли ADDIN EN.CITE <EndNote><Cite><Author>Laemmli</Author><Year>1970</Year><RecNum>239</RecNum><DisplayText>[255]</DisplayText><record><rec-number>239</rec-number><foreign-keys><key app="EN" db-id="w2wfxafe6va9z5eev2l55aa8sxsa599eev2s">239</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laemmli, U. K.</author></authors></contributors><titles><title>Cleavage of structural proteins during the assembly of the head of bacteriophage T4</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>680-5</pages><volume>227</volume><number>5259</number><edition>1970/08/15</edition><keywords><keyword>Autoradiography</keyword><keyword>Carbon Isotopes</keyword><keyword>Coliphages/ metabolism</keyword><keyword>Electrophoresis, Disc</keyword><keyword>Genes</keyword><keyword>Genetics, Microbial</keyword><keyword>Kinetics</keyword><keyword>Viral Proteins/ metabolism</keyword></keywords><dates><year>1970</year><pub-dates><date>Aug 15</date></pub-dates></dates><isbn>0028-0836 (Print)
0028-0836 (Linking)</isbn><accession-num>5432063</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[255] и переносили с помощью полусухого электротранспорта на нитроцеллюлозную мембрану (BioRad, США). Места неспецифического связывания 1 ч блокировали в 5% молоке. Мембраны инкубировали с антителами против MnСОД (1:1000, Millipore, США), циклина B1 (1:1000, BD, США), НАДФН (1:500, BD, США) и актина (1:1000, Millipore, США). В качестве вторичных антител были использованы: меченные пероксидазой хрена антимышиные овечьи антитела (1:5000, GE Healthcare, США) и антикроличьи ослиные антитела (1:10,000, GE Healthcare, США). Иммунореактивные полоски визуализировали с помощью набора Pierce ECL 2 Western Blotting Substrate (Thermo Scientific, США) согласно инструкции разработчика и детектировали хемилюминисценцию с помощью Typhoon FLA 7000 (General Electric, США). Насыщенность полос анализировали в программе ImageJ (NIH, США). Уровень актина и НАДФН использовали для коррекции загрузки белка.
2.6. Определение активности MnСОДБелки выделяли по методу, описанному в предыдущем разделе (2.5), и разделяли с помощью электрофореза в 12,5% полиакриламидном геле без додецилсульфата по методу предложенному Weydert et al. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZXlkZXJ0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ADDIN EN.CITE.DATA [66, 256]. Гель инкубировали 20 мин при tкомн в окрашивающей смеси, содержащей 2,43 мМ нитросиний тетразолий, 2,8105 M рибофлавин и 28 мМ ТЕМЕД, и проявляли на свету до появления прозрачных полос. Метод основан на том, что на свету рибофлавин образует супероксид, который превращает нитросиний тетразолий из желтого в темно синий, что окрашивает гель. Поскольку MnСОД катализирует реакцию дисмутации супероксида, то MnСОД-содержащие полоски становятся прозрачными. Проявленный гель сканировали с помощью Epson Perfection 4990 PHOTO (Epson, США) и анализировали насыщенность полос в программе ImageJ (NIH, США).
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