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001-es BibID:BIBFORM090173
035-os BibID:(WoS)000611866700001 (Scopus)85099753663
Első szerző:Regdon Zsolt (biokémikus, molekuláris biológus)
Cím:High-Content Screening identifies inhibitors of oxidative stress-induced parthanatos : cytoprotective and anti-inflammatory effects of ciclopirox / Regdon Zsolt, Demény Máté A., Kovács Katalin, Hajnády Zoltán, Nagy-Pénzes Máté, Bakondi Edina, Kiss Alexandra, Hegedűs Csaba, Virág László
Dátum:2021
ISSN:0007-1188
Megjegyzések:Background and purpose: Excessive oxidative stress can induce poly (ADP-ribose) polymerase-1 (PARP1)-mediated, programmed necrotic cell death, termed parthanatos. Inhibition of parthanatos may be therapeutically beneficial in a wide array of diseases associated with tissue injury and inflammation. Our goal was to identify novel molecules inhibiting parthanatos. Experimental approach: A small library of 774 pharmacologically active compounds was screened in a Sytox green uptake assay which identified 20 hits that reduced hydrogen peroxide-induced parthanatos with an efficiency comparable to the benchmark PARP inhibitor, PJ34. Key results: Of these hits, two compounds, antifungal ciclopirox (CIP) and dopaminergic agonist apomorphine (AMO) inhibited PAR polymer synthesis. These two compounds prevented the binding of PARP1 to oxidatively damaged DNA but did not directly interfere with the interaction between DNA and PARP1. Both compounds inhibited mitochondrial superoxide and H2 O2 production and suppressed DNA breakage. Since H2 O2 -induced damage is dependent on Fe2+ -catalysed hydroxyl radical production (Fenton chemistry), we determined the iron chelation activity of the two test compounds and found that CIP and, to a lesser extent, AMO act as iron chelators. We also show that the Fe2+ chelation and indirect PARP inhibitory effects of CIP translate to anti-inflammatory actions as demonstrated in a mouse dermatitis model, where CIP reduced ear swelling, inflammatory cell recruitment, and poly (ADP-ribosyl)ation. Conclusion and implications: Our findings indicate that the antimycotic drug, CIP, acts as an iron chelator and thus targets an early event in hydrogen-peroxide-induced parthanatos. CIP has the potential to be repurposed as a cytoprotective and anti-inflammatory agent.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
cell death
cytoprotection
inflammation
oxidative stress
poly (ADP-ribose) polymerase 1
regulated necrosis
Megjelenés:British Journal Of Pharmacology. - 178 : 5 (2021), p. 1095-1113. -
További szerzők:Demény Máté Ágoston (1976-) (molekuláris biológus) Kovács Katalin (1978-) (biokémikus) Hajnády Zoltán (1991-) (biomérnök, biokémikus) Nagy-Pénzes Máté (1988-) (biokémikus) Bakondi Edina (1975-) (biokémikus, vegyész) Kiss Alexandra (1991-) (klinikai laboratóriumi kutató) Hegedűs Csaba (1980-) (biokémikus, molekuláris biológus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus)
Pályázati támogatás:GINOP-2.3.2-15-2016-00048-STAYALIVE
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GINOP-2.3.2-15-2016-00020 TUMORDNS"
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OTKA K132193
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OTKA K112336
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ÚNKP-19-4-DE-299
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