5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo.
5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo.
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DOI：
10.1186/s11658-022-00381-1
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发表时间：
2022-09-30
影响因子：
8.3
通讯作者：
中科院分区：
文献类型：
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作者：
Influenza-related acute lung injury (ALI) is a life-threatening condition that results mostly from uncontrolled replication of influenza virus (IV) and severe proinflammatory responses. The methoxy flavonoid compound 5-methoxyflavone (5-MF) is believed to have superior biological activity in the treatment of cancer. However, the effects and underlying mechanism of 5-MF on IV-mediated ALI are still unclear. Here, we showed that 5-MF significantly improved the survival of mice with lethal IV infection and ameliorated IV-mediated lung edema, lung histological changes, and inflammatory cell lung recruitment. We found that 5-MF has antiviral activity against influenza A virus (IAV), which was probably associated with increased expression of radical S-adenosyl methionine domain containing 2 (RSAD2) and suppression of endosomal acidification. Moreover, IV-infected A549 cells with 5-MF treatment markedly reduced proinflammatory mediator expression (IL-6, CXCL8, TNF-α, CXCL10, CCL2, CCL3, CCL4, GM-CSF, COX-2, and PGE2) and prevented P-IKBα, P-P65, and P-P38 activation. Interestingly, we demonstrated that 5-MF treatment could trigger activation of AMP-activated protein kinase (AMPK)α in IV-infected A549 cells, as evidenced by activation of the AMPKα downstream molecule P53. Importantly, the addition of AMPKα blocker compound C dramatically abolished 5-MF-mediated increased levels of RSAD2, the inhibitory effects on H1N1 virus-elicited endosomal acidification, and the suppression expression of proinflammatory mediators (IL-6, TNF-α, CXCL10, COX-2 and PGE2), as well as the inactivation of P-IKBα, P-P65, and P-P38 MAPK signaling pathways. Furthermore, inhibition of AMPKα abrogated the protective effects of 5-MF on H1N1 virus-mediated lung injury and excessive inflammation in vivo. Taken together, these results indicate that 5-MF alleviated IV-mediated ALI and suppressed excessive inflammatory responses through activation of AMPKα signaling. The online version contains supplementary material available at 10.1186/s11658-022-00381-1.
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影响因子：
4.6
作者：
Kiso, Maki;Takano, Ryo;Sakabe, Saori;Katsura, Hiroaki;Shinya, Kyoko;Uraki, Ryuta;Watanabe, Shinji;Saito, Hiroshi;Toba, Masamichi;Kohda, Noriyuki;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
DOI：
10.3390/antiox9100973
发表时间：
2020-10-11
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
L Suraweera T;Rupasinghe HPV;Dellaire G;Xu Z
通讯作者：
Xu Z
影响因子：
3.9
作者：
Gowans GJ;Hardie DG
通讯作者：
Hardie DG
影响因子：
3.1
作者：
Huang, Bee-Piao;Lin, Chun-Hsiang;Kao, Shao-Hsuan
通讯作者：
Kao, Shao-Hsuan
影响因子：
24.3
作者：
Herold, Susanne;Becker, Christin;Budinger, G. R. Scott
通讯作者：
Budinger, G. R. Scott