Влияние белков вируса гепатита C на регуляцию окислительного стресса и метаболизм биогенных полиаминов

выводы.

1. Белки NS5A, NS4B, El, Е2, а также белок капсида вируса гепатита С вызывают окислительный стресс в клетках в клетках гепатомы человека Huh7- наиболее активным регулятором которого является белок капсида. N-концевой домен белка капсида активирует экспрессию NADPH-оксидаз 1 и 4, что приводит к усилению продукции супероксид-радикала, тогда как его С-концевой домен вызывает активацию экспрессии цитохрома Р450 2Е1 (CYP 2Е1) и оксидоредуктина (Erola) — источников супероксид-радикала и пероксида водорода, соответственно.

2. Белки El, Е2, NS4B, NS5A и белок капсида активируют систему защиты клетки (Nrf2/AREKacKa/<) от активных форм кислорода (АФК) в клетках Huh7 по нескольким независимым механизмам. Все эти белки вызывают усиленную экспрессию «ферментов Пфазы защиты» путем фосфорилирования фактора транскрипции №Опротеинкиназой С (РКС) по АФК-зависимому механизму. Белок капсида и белок NS5A способны также активировать фактор Nrf2 по механизму, не зависящему от концентрации АФК, при участии фосфоинозитид-3-киназы (PI3K) и казеинкиназы 2 (СК2). В случае белков El, Е2 и NS4B активация Nrf2 по АФК-независимому механизму предположительно опосредовано протеинкиназой PERK. Наиболее активным регулятором № 12/А11Екаскада является белок капсида, N-концевой домен которого отвечает за индукцию АФК-независимого, а С-концевой — АФК-зависимого механизмов защиты.

3. В клетках гепатомы человека Huh7 окислительный стресс, вызванный химическими агентами, приводит к повышению уровней биогенных полиаминов спермина и спермидина вследствие усиления экспрессии орнитиндекарбоксилазы (ODC) и спермидин/спермин-Nацетилтрансферазы (SSAT), опосредованного факторами транскрипции Nrf2 и NF-kB. Окислительный стресс, вызванный белком капсида и белком NSSABHpyca гепатита С, также вызывает активацию транскрипции генов ОБСи SSAT, что, однако, сопровождается снижением активности кодируемых ими ферментов и падением уровня полиаминов в клетке.

4. Клетки Huh7, несущие полноразмерный репликон ВГС, обладают сниженным уровнем биогенных полиаминов и активностей ферментов их метаболизма, а повышение концентрации спермина и спермидина приводит к ингибированию репликации ВГС и снижению уровня геномной РНК вируса.

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277. Мнехотелосьбыпоблагодарить своего научного руководителя Иванова Александра Владимировича за чуткое руководство и огромную помощь в подготовке диссертационной работы.