Crocetin antagonizes parthanatos in ischemic stroke via inhibiting NOX2 and preserving mitochondrial hexokinase-I

Parthanatos is one of the major pathways of programmed cell death in ischemic stroke characterized by DNA damage, poly (ADP-ribose) polymerases (PARP) activation, and poly (ADP-ribose) (PAR) formation. Here we demonstrate that crocetin, a natural potent antioxidant compound from Crocus sativus , ant...

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Bibliographic Details
Published in:Cell death & disease 2023-01, Vol.14 (1), p.50-50, Article 50
Main Authors: Wu, Hao, Li, Ying, Zhang, Qian, Wang, Hanxun, Xiu, Wenyu, Xu, Pu, Deng, Yujie, Huang, Wanxu, Wang, Dan Ohtan
Format: Article
Language:English
Subjects:
13/1
13/109
13/31
14/19
14/34
38/77
631/154/555
631/378/1934
631/45/612/1254
631/80/2023/2022
631/80/458/2389
Antibodies
Apoptosis
Biochemistry
Biomedical and Life Sciences
Brain damage
Cell Biology
Cell Culture
Cell death
CYBB protein
DNA damage
Drug development
Drug dosages
Hexokinase
Hexokinase - metabolism
Humans
Immunology
Ischemia
Ischemic Stroke - metabolism
Laboratories
Life Sciences
Mitochondria - metabolism
Mitochondrial DNA
NAD(P)H oxidase
NADPH Oxidase 2 - metabolism
Parthanatos
Pharmaceuticals
Poly (ADP-Ribose) Polymerase-1 - metabolism
Poly(ADP-ribose) Polymerases - metabolism
Reactive oxygen species
Ribose - metabolism
Stroke
Ubiquitin-protein ligase
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Summary:Parthanatos is one of the major pathways of programmed cell death in ischemic stroke characterized by DNA damage, poly (ADP-ribose) polymerases (PARP) activation, and poly (ADP-ribose) (PAR) formation. Here we demonstrate that crocetin, a natural potent antioxidant compound from Crocus sativus , antagonizes parthanatos in ischemic stroke. We reveal that mechanistically, crocetin inhibits NADPH oxidase 2 (NOX2) activation to reduce reactive oxygen species (ROS) and PAR production at the early stage of parthanatos. Meanwhile we demonstrate that PARylated hexokinase-I (HK-I) is a novel substrate of E3 ligase RNF146 and that crocetin interacts with HK-I to suppress RNF146-mediated HK-I degradation at the later stage of parthanatos, preventing mitochondrial dysfunction and DNA damage that ultimately trigger the irreversible cell death. Our study supports further development of crocetin as a potential drug candidate for preventing and/or treating ischemic stroke.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-05581-x