Chikusetsusaponin IVa Protects against H9N2 Avian Influenza Virus Infection by Inhibiting Inflammation and TLR4/NF-κB Signaling Pathways in vitro and in vivo
Qi Dai1,2,3, Xin Zheng1,2, Song-Tao Wu1,2, Peng-Tao You1,2, Xiao Huang1,2, Yan-Wen Liu1,2, Yun Wu1,2, Xiu-Qiao Zhang1,2★★ Corresponding author
- 1College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, CHINA.
- 2Hubei Key Laboratory of Resources and Chemistry of Traditional Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, CHINA.
- 3Huangjia Lake Hospital, Hubei University of Chinese Medicine, Wuhan, China.
CORRESPONDENCE
Xiu-Qiao Zhang
College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, CHINA.
Received: 30-07-2023; Accepted: 27-10-2023.
Volume 20, Issue 2 · pp. 632–645 · PUBLISHED 2024 · DOI: 10.1177/09731296231216165
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ABSTRACT
Background: The prevalence of Hemagglutinin 9 Neuraminidase 2 (H9N2) avian influenza virus (AIV) in poultry in Asia has raised serious concerns about its zoonotic transmission and the potential for a pandemic, underscoring the need for effective therapeutics. Chikusetsusaponin IVa (CHS), a bioactive triterpenoid saponin from Radix saposhnikoviae, has exhibited anti-inflammatory activity in preclinical studies. We hypothesized that CHS could mitigate immunopathology during tumor necrosis factor (TNF)-infection by suppressing excessive inflammation. Objectives: CHS is a natural saponin with anti-inflammatory activity. This research aimed to explore the in vitro and in vivo protective effects and mechanisms of CHS against H9N2 AIV infection. Materials and Methods: We employed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) analysis for the prediction of the underlying mechanisms, followed by a network analysis approach. In animal experiments, the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathways and associated proteins were assessed using immunohistochemistry and western blot analysis. Results: In A549 cells, CHS treatment reduced H9N2 AIV-induced apoptosis in a dose-dependent manner. CHS was found to have a suppressive effect on the mRNA expression of various inflammatory cytokines (including TNF-α, interleukin (IL)-6, IL-1β, and IL-8) as well as mediators such as inducible nitric oxide synthase (iNOS) and prostaglandin-endoperoxide synthase 2 (PTGS2). It can be seen that CHS does have anti-inflammatory effects. Bioinformatics analysis indicated that CHS might exhibit anti-inflammatory effects by modulating cytokine–cytokine receptor interaction and the NF-κB signaling pathways. Building upon this, it was found that CHS blocked the activation of TLR4 and NF-κB signaling pathways in A549 cells infected with H9N2 AIV. In vivo, CHS prolonged the survival time and increased the survival rate of H9N2 AIV-infected mice. CHS was found to have a protective effect on the lungs of infected mice, resulting in reduced damage and lower levels of viral load and inflammation. CHS inhibited the production of proinflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-8) and inhibited the activation of TLR4 and NF-κB signaling pathways in the pulmonary tissues of mice that were infected. Conclusion: CHS exerts protective effects against H9N2 AIV infection in vitro and in vivo. The anti-inflammatory mechanisms may involve the inhibition of cytokine production and the blockade of TLR4 and NF-κB signaling pathways.
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Dai, Q., Zheng, X., Wu, S., You, P., Huang, X., Liu, Y., Wu, Y., & Zhang, X. (2024). Chikusetsusaponin IVa Protects against H9N2 Avian Influenza Virus Infection by Inhibiting Inflammation and TLR4/NF-κB Signaling Pathways in vitro and in vivo. Pharmacognosy Magazine, 20(2), 632–645. https://doi.org/10.1177/09731296231216165