Nrf2 Activation by SK-119 Attenuates Oxidative Stress, UVB, and LPS-Induced Damage.
Adult
Apoptosis
Benzylidene Compounds
/ pharmacology
Caspase 3
/ metabolism
Cells, Cultured
Cytokines
/ metabolism
DNA Damage
/ drug effects
Female
Humans
Lipopolysaccharides
/ pharmacology
Middle Aged
NF-E2-Related Factor 2
/ metabolism
Oxidative Stress
/ drug effects
Pyrrolidines
/ pharmacology
Signal Transduction
/ drug effects
Skin
/ drug effects
Ultraviolet Rays
/ adverse effects
LPS-induced damage
Nrf2 activator
SK-119
UVB
Journal
Skin pharmacology and physiology
ISSN: 1660-5535
Titre abrégé: Skin Pharmacol Physiol
Pays: Switzerland
ID NLM: 101188418
Informations de publication
Date de publication:
2019
2019
Historique:
received:
02
10
2018
accepted:
05
03
2019
pubmed:
13
5
2019
medline:
10
1
2020
entrez:
13
5
2019
Statut:
ppublish
Résumé
The Nrf2 signaling pathway plays a pivotal role in neutralizing excess reactive oxygen species formation and therefore enhancing the endogenous cellular protection mechanism. Thus, activating this pathway may provide therapeutic options against oxidative stress-related disorders. We have recently applied a computer-aided drug design approach to the design and synthesis of novel Nrf2 enhancers. The current study was aimed at investigating the potential beneficial impact of (E)-5-oxo-1-(4-((2,4,6-trihydroxybenzylidene)amino)phenyl)pyrrolidine-3-carboxylic acid (SK-119) in skin oxidative damage models. SK-119, tested initially in PC-12 cells, attenuated oxidative stress-induced cytotoxicity concomitantly with Nrf2 activation. The potential impact of this compound was evaluated in skin-based disease models both in vitro (HaCaT cells) and ex vivo (human skin organ culture). The data clearly showed the marked anti-inflammatory and photoprotection properties of the compound; SK-119-treated cells or tissues displayed a reduction in cytokine secretion induced by lipopolysaccharides (LPS) in a manner comparable with dexamethasone. In addition, topical application of SK-119 was able to block UVB-induced oxidative stress and attenuated caspase-mediated apoptosis, DNA adduct formation, and the concomitant cellular damage. These results indicate that SK-119 is an Nrf2 activator that can be used as a prototype molecule for the development of novel treatments of dermatological disorders related to oxidative stress.
Sections du résumé
BACKGROUND/AIMS
OBJECTIVE
The Nrf2 signaling pathway plays a pivotal role in neutralizing excess reactive oxygen species formation and therefore enhancing the endogenous cellular protection mechanism. Thus, activating this pathway may provide therapeutic options against oxidative stress-related disorders. We have recently applied a computer-aided drug design approach to the design and synthesis of novel Nrf2 enhancers. The current study was aimed at investigating the potential beneficial impact of (E)-5-oxo-1-(4-((2,4,6-trihydroxybenzylidene)amino)phenyl)pyrrolidine-3-carboxylic acid (SK-119) in skin oxidative damage models.
METHODS
METHODS
SK-119, tested initially in PC-12 cells, attenuated oxidative stress-induced cytotoxicity concomitantly with Nrf2 activation. The potential impact of this compound was evaluated in skin-based disease models both in vitro (HaCaT cells) and ex vivo (human skin organ culture).
RESULTS
RESULTS
The data clearly showed the marked anti-inflammatory and photoprotection properties of the compound; SK-119-treated cells or tissues displayed a reduction in cytokine secretion induced by lipopolysaccharides (LPS) in a manner comparable with dexamethasone. In addition, topical application of SK-119 was able to block UVB-induced oxidative stress and attenuated caspase-mediated apoptosis, DNA adduct formation, and the concomitant cellular damage.
CONCLUSION
CONCLUSIONS
These results indicate that SK-119 is an Nrf2 activator that can be used as a prototype molecule for the development of novel treatments of dermatological disorders related to oxidative stress.
Identifiants
pubmed: 31079103
pii: 000499432
doi: 10.1159/000499432
doi:
Substances chimiques
Benzylidene Compounds
0
Cytokines
0
Lipopolysaccharides
0
NF-E2-Related Factor 2
0
Pyrrolidines
0
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
173-181Informations de copyright
© 2019 S. Karger AG, Basel.