MUDr. Ing. Mgr. Peter Celec, PhD., MPH Ústav Molekulárnej Biomedicíny Ústav Patologickej Fyziológie
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1 MUDr. Ing. Mgr. Peter Celec, PhD., MPH Ústav Molekulárnej Biomedicíny Ústav Patologickej Fyziológie
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5 Literatúra Časopisy Indexované Databáza PubMed/Medline Karentové (Current contents) Databáza ISI Web of Science Impact factor Vydavateľstvá Elsevier, Springer, Willey
6 Literatúra Systematické vyhľadávanie Vyuţívanie logických operátorov Špecifické operátory [ti], [au] Review Date range limit Type of publication
7 Literatúra Prístup do časopisov Kniţnice Open Access Biomednet Central PubMed Central Public Library of Science
8 Approach to clinical medicine Empirical medicine Expert opinion Evidence-based medicine Guidelines Individualized medicine
9 Oxidačný a karbonylový stres MUDr. Ing. Mgr. Peter Celec, PhD., MPH petercelec@gmail.com
10 Úvod Oxidačný a karbonylový stres Definície Zdroje a príčiny Dôsledky Markery Úloha v patogenéze ochorení Terapeutické ovplyvnenie
11 Definície Voľný radikál Free radical Častica s nespáreným voľným elektrónom vo valenčnej vrstve Reaktívny metabolit kyslíka/dusíka Reactive oxygen/nitrogen species ROS/RNS Vysoko reaktívna molekula
12 Kyslíkové ROS Voľné radikály Iné Superoxid. O - 2 Hydroxyl. OH Peroxid vodíka H 2 O 2 Kyselina chlórna HClO Peroxyl ROO. Ozón O 3 Alkoxyl RO. Singletový kyslík 1 O 2 Hydroperoxyl HO 2. Molekulárny kyslík O 2
13 Kyslíkové ROS
14 Kyslíkové ROS
15 Fentonova reakcia Fe 2+ + H 2 O 2 Fe OH + OH -. O 2- + Fe 3+ O 2 + Fe 2+. O 2- + H 2 O 2 O 2 +. OH + OH - Katalytický účinok iónov prechodných kovov
16 Dusíkové RNS Voľné radikály Iné Oxid dusnatý. NO Nitrozyl NO + Oxid dusičitý. NO 2 Kyselina dusitá HNO 2 Oxid dusitý N 2 O 3 Peroxynitrit ONOO - Alkylperoxynitrit ROONO
17 Endogénne zdroje ROS reakcie Autooxidácia (Fentonova reakcia) Hemoglobín, myoglobín, redukované tioly, cytochróm C, katecholamíny Respiračné vzplanutie NADPH oxidáza Iná enzymatická produkcia Prostaglandín syntáza, lipoxygenáza, myeloperoxidáza, xantín oxidáza
18 Endogénne zdroje ROS organely Mitochondrie Terminálna oxidácia & Oxidačná fosforylácia Elektrónový transportný systém cytochróm oxidáza Superoxidový aniónový radikál Hyperoxia / hypoxia
19 Endogénne zdroje ROS organely Endoplazmatické retikulum Oxidačno-redukčné reakcie Metabolizmus xenobiotík Cytochróm P450 Mikrozómy Peroxizómy Metabolizmus mastných kyselín Peroxid vodíka
20 Exogénne zdroje ROS Lieky Nitrofurantoín, antracyklíny, metotrexát, sulfasalazín Ţiarenie RTG, rádioterapia, UV Fajčenie Ozón
21 Zdroje RNS NO syntázy Endoteliálna Inducibilná Neuronálna Reakcie. NO a. O 2 - Znečistený vzduch
22 Fyziologické funkcie ROS Detoxifikácia xenobiotík Monoxygenázy, cytochrómoxidázy Imunitná odpoveď & Fagocytóza Myeloperoxidázy NADPH oxidáza Signálne cesty
23 Fyziologické funkcie RNS Zatiaľ známe len pre. NO Vazodilatácia Parakrinná komunikácia Neuromediátor Nitrozylácia
24 Poškodenie spôsobené ROS Lipidy Lipoperoxidácia XNA Poškodenie báz mutácie Proteíny Karbonylácia proteínov Cross-linking
25 Antioxidanty rozdelenia Antioxidačný status Inhibícia produkcie Vychytávanie, zhášanie Korekčné mechanizmy
26 Antioxidanty rozdelenia Endogénne Exogénne Nízkomolekulové (neenzymatické) Vysokomolekulové (enzymatické)
27 Vysokomolekulové antioxidanty Enzymatické antioxidanty Superoxid dizmutáza SOD Kataláza CAT Glutatión peroxidáza/reduktáza
28 Vysokomolekulové antioxidanty Superoxid dizmutáza Mitochondriálna MnSOD Cytoplazmatická CuZn Extracelulárna CuZn
29 SOD U všetkých aeróbnych organizmov Aj u prokaryotov. O O H + H 2 O 2 + O 2
30 CAT U všetkých aeróbnych eukaryotov v cytoplazme Dizmutácia peroxidu vodíka 2 H 2 O 2 2 H 2 O + O 2
31 Glutatiónový systém Glutatión (GSH) Glu-Cys-Gly -SH skupina na cysteíne Nízkomolekulový antioxidant Vychytávač voľných radikálov 2 GSH +. O 2- GSSG + H 2 O Najdôleţitejší cytoplazmatický antioxidant
32 Glutatiónový systém Len u zvierat Glutatión peroxidáza Obsahuje selenocysteín Redukuje peroxid vodíka pomocou glutatiónu 2 GSH + H 2 O 2 GSSG + 2 H 2 O Glutatión reduktáza GSSG + NADPH + H + 2 GSH + NADP +
33 Antioxidačná metabolická dráha
34 Nízkomolekulové antioxidanty Glutatión Vitamín C, E Karotenoidy Koenzým Q 10 Taníny, Flavonoidy... Prolín
35 Rovnováha Oxidanty Antioxidanty
36 Oxidačný stres Nerovnováha medzi produkciou voľných radikálov a antioxidačnými mechanizmami Súčasť patogenézy......všetkého
37 Markery oxidačného stresu EPR Poškodenie lipidov Malondialdehyd, 4-OH-2-nonenal, 8-izoprostán Poškodenie DNA 8-OH-guanín Poškodenie proteínov Dityrozín, karbonylované proteíny
38 Diabetes mellitus
39 Karbonylový stres Koncové produkty pokročilej glykácie Advanced glycation end products AGEs
40 Karbonylový stres Diabetická hyperglykémia (glykovaný hemoglobín) Alkohol Zlyhávanie obličiek Melanoidíny Oxidačný stres
41 Synergizmus
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43 Downov syndróm Trizómia 21 21q22.11 gén pre SOD 150% génová dávka Zvýšený oxidačný stres Prečo?
44 Antioxidačná metabolická dráha
45 Ateroskleróza
46 Starnutie Zníţený antioxidačný status Lipoperoxidácia Tvorba lipofuscínu stareckého pigmentu Cross-linking proteínov Indukcia chronického zápalu Kumulácia poškodení DNA Zníţenie efektivity mitochondrií
47 Ako spomaliť čas?
48
49 Výhľad do budúcnosti Nové antioxidanty Kombinované prístupy Antioxidačná génová terapia Aminoguanidín a AGE-breakers Klinické štúdie...
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