Abstract
Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.
Highlights
General enhancement of Poly (ADP-ribose) polymerase-1 (PARP-1) activity is associated with the development of tumor, cardiovascular and neurodegenerative diseases, and pharmacological inhibition of PARP-1 is a promising strategy for their therapy
PARP-1 is involved in pathogenesis of oncological diseaseswas in asuggested complex way responsible for accelerated aging during chronic inflammatory diseases described in several excellent comprehensive reviews [49,50,51,52]
Flavones do not contain the nicotinamide-like moiety that is characteristic for most PARP-1 inhibitors, and the flavone-based pharmacophore model was designed for TNK inhibitors [134,135]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. PARP-1-dependent cell death occur afterofPARP-1 hyperactivation due to an up-regulating expression of various suchcompounds as tumor necrosis energy crisis caused by the depletion of inflammatory cellular reservesmediators of macroergic [32,33]. PARP-1 was shown to be acetylated at lysine residues (K498, K505, K508, K521, K524) by the p300/CREB-binding protein complex (CREB - cAMP-response element binding protein) and phosphorylated at Y829 by mitogen-activated protein kinases (MAPKs) in response to pro-inflammatory stimuli [37,38] Modified in this way, PARP-1 stimulates transcription of NF-κB-dependent genes of inflammatory mediators (Figure 3) [37,38,39,40]. An important role of PARP-1 in the development of inflammatory diseases was confirmed by experiments with PARP-1 knockout mice These mice are better protected during stress andand activating production of inflammatory cytokines by the cells anmultiple innate from diabetic septic complications associated with inflammation suchofas immunity system [41]. The N-terminal fragment remains associated with DNA injuries blocking
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