1. Academic Validation
  2. 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

  • Cell Mol Biol Lett. 2022 Sep 30;27(1):82. doi: 10.1186/s11658-022-00381-1.
Sushan Yang  # 1 Linxin Wang  # 2 Xiping Pan  # 2 Yueyun Liang 1 Yuehan Zhang 1 Jing Li 3 4 Beixian Zhou 5
Affiliations

Affiliations

  • 1 The People's Hospital of Gaozhou, Gaozhou, 525200, China.
  • 2 Guangzhou Laboratory, Guangzhou, China.
  • 3 State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China. lijinghenan@163.com.
  • 4 Institute of Chinese Integrative Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China. lijinghenan@163.com.
  • 5 The People's Hospital of Gaozhou, Gaozhou, 525200, China. zbeixian@126.com.
  • # Contributed equally.
Abstract

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.

Keywords

5-Methoxyflavone; AMPKα; Anti-inflammatory; Antiviral; Influenza A virus.

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