CM1, a Chrysin Derivative, Protects from Endotoxin-Induced Lethal Shock by Regulating the Excessive Activation of Inflammatory Responses

Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated tha...

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Published in:Nutrients 2024-02, Vol.16 (5), p.641
Main Authors: Lee, Jae-Hyung, Ko, Young-Bok, Choi, Yong-Min, Kim, Jinju, Cho, Hwan-Doo, Choi, Hyeonil, Song, Ha-Yeon, Han, Jeong-Moo, Cha, Guang-Ho, Lee, Young-Ha, Kim, Jin-Man, Kim, Woo-Sik, Byun, Eui-Baek, Yuk, Jae-Min
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Cell cycle
Cytokines
Disease susceptibility
Dosimetry
Health aspects
Infection
Inflammation
Kinases
Macrophages
Membranes
Polyphenols
Proteins
Sepsis
Tumor necrosis factor-TNF
Ubiquitin
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Summary:Sepsis, a leading cause of death worldwide, is a harmful inflammatory condition that is primarily caused by an endotoxin released by Gram-negative bacteria. Effective targeted therapeutic strategies for sepsis are lacking. In this study, using an in vitro and in vivo mouse model, we demonstrated that CM1, a derivative of the natural polyphenol chrysin, exerts an anti-inflammatory effect by inducing the expression of the ubiquitin-editing protein TNFAIP3 and the NAD-dependent deacetylase sirtuin 1 (SIRT1). Interestingly, CM1 attenuated the Toll-like receptor 4 (TLR4)-induced production of inflammatory cytokines by inhibiting the extracellular-signal-regulated kinase (ERK)/MAPK and nuclear factor kappa B (NF-κB) signalling pathways. In addition, CM1 induced the expression of TNFAIP3 and SIRT1 on TLR4-stimulated primary macrophages; however, the anti-inflammatory effect of CM1 was abolished by the siRNA-mediated silencing of or by the genetic or pharmacologic inhibition of SIRT1. Importantly, intravenous administration of CM1 resulted in decreased susceptibility to endotoxin-induced sepsis, thereby attenuating the production of pro-inflammatory cytokines and neutrophil infiltration into the lung compared to control mice. Collectively, these findings demonstrate that CM1 has therapeutic potential for diverse inflammatory diseases, including sepsis.
ISSN:2072-6643
2072-6643
DOI:10.3390/nu16050641