Sipeimine ameliorates PM2.5-induced lung injury by inhibiting ferroptosis via the PI3K/Akt/Nrf2 pathway: A network pharmacology approach

  • Ecotoxicol Environ Saf. 2022 Jul 1:239:113615. doi: 10.1016/j.ecoenv.2022.113615.
Yilan Wang  1 ,  Zherui Shen  1 ,  Sijing Zhao  1 ,  Demei Huang  1 ,  Xiaomin Wang  1 ,  Yongcan Wu  1 ,  Caixia Pei  1 ,  Shihua Shi  1 ,  Nan Jia  1 ,  Yacong He  2 ,  Zhenxing Wang  3
Affiliations
  • 1. Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan 610075, China.
  • 2. School of Pharmacy, Chengdu University of Traditional Chinese Medicine, No.1166 Liutai Avenue, Chengdu, Sichuan 611137, China. Electronic address: [email protected].
  • 3. Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan 610075, China. Electronic address: [email protected].
PMID: 35567927 DOI: 10.1016/j.ecoenv.2022.113615
Abstract

Fine particulate matter (PM2.5) exposure can cause lung injury and a large number of respiratory diseases. Sipeimine is a steroidal alkaloid isolated from Fritillaria roylei which has been associated with anti-inflammatory, antitussive and antiasthmatic properties. In this study, we explored the potential effects of sipeimine against PM2.5-induced lung injury in Sprague Dawley rats. Sipeimine alleviated lung injury caused by PM2.5 and decreased pulmonary edema, inflammation and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid. In addition, sipeimine upregulated the glutathione (GSH) expression and downregulated the expression of 4-hydroxynonenal (4-HNE), tissue iron and malondialdehyde (MDA). The downregulation of proteins involved in Ferroptosis, including nuclear factor E2-related factor 2 (Nrf2), Glutathione Peroxidase 4 (GPX4), heme oxygenase-1 (HO-1) and solute carrier family 7 member 11 (SLC7A11) was reversed by sipeimine. The administration of RSL3, a potent ferroptosis-triggering agent, blocked the effects of sipeimine. Using network pharmacology, we found that the effects of sipeimine were presumably mediated through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. A PI3K Inhibitor (LY294002) blocked the PI3K/Akt signaling pathway and reversed the effects of sipeimine. Overall, this study suggested that the protective effect of sipeimine against PM2.5-induced lung injury was mainly mediated through the PI3K/Akt pathway, ultimately leading to a reduction in Ferroptosis.

Keywords
Ferroptosis; Lung injury; Network pharmacology; PI3K/Akt/Nrf2; PM2.5; Sipeimine (PubChem CID: 442977).
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