Geniposide attenuates influenza virus-induced pneumonia by regulating inflammatory cytokines production. Evidences to elucidate the followed pathway

Yu Zhang; Pengqian Wang; Zihan Geng; Lei Bao; Shuangrong Gao; Jing Sun; Xian Liu; Xiaowei Yang; Ronghua Zhao; Shuran Li; Yanyan Bao; Xiaolan Cui; Shanshan Guo

doi:10.1016/j.phymed.2024.156018

Geniposide attenuates influenza virus-induced pneumonia by regulating inflammatory cytokines production. Evidences to elucidate the followed pathway

Phytomedicine. 2024 Sep 8:135:156018. doi: 10.1016/j.phymed.2024.156018. Online ahead of print.

Authors

Yu Zhang¹, Pengqian Wang¹, Zihan Geng¹, Lei Bao¹, Shuangrong Gao¹, Jing Sun¹, Xian Liu¹, Xiaowei Yang¹, Ronghua Zhao¹, Shuran Li¹, Yanyan Bao¹, Xiaolan Cui², Shanshan Guo³

Affiliations

¹ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
² Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: cuixiaolan2812@126.com.
³ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: ssguo@icmm.ac.cn.

PMID: 39303507
DOI: 10.1016/j.phymed.2024.156018

Abstract

Background: Influenza virus-induced pneumonia (IVP) is an infectious pulmonary disease characterized by exacerbated pulmonary inflammation caused by invasion of the influenza virus. IVP continues to threaten public health due to its high morbidity and mortality rates. Geniposide is one of the major bioactive constituents of G. jasminoides, which exerts antiviral and anti-inflammatory effects on influenza A virus (IAV) infection.

Purpose: To investigate therapeutic effects and comprehensive mechanisms of geniposide on IAV infection and subsequent pneumonia.

Methods: ICR mice were infected intranasally with H1N1 (A/FM/1/47) to detect the anti-IAV activity of geniposide. Proteomics combined with function-integrated analysis were conducted to gain insight into the comprehensive mechanisms of geniposide. Subsequently, western blot was used to detect the phosphorylation of signal transducer and activator of transcription 1 (STAT1), signal transducer and activator of transcription 2 (STAT2), Interferon regulatory factor 9 (IRF9) and Janus kinase 1 (JAK1) in Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in lung tissue. Finally, RT-qPCR was used to detect the levels of interleukin 6 (IL-6), interleukin 17 (IL-17), interferon-γ (IFN-γ) and the STAT1 inhibitor (fludarabine) was used to verify the targeting between STAT1 and geniposide in RAW cells.

Results: Geniposide could significantly reduce the lung index, diminish lung pathology, decrease the virus loads and the inflammatory cytokines expression induced by IAV infection. A total of 411 differentially expressed proteins were identified among control, model, and geniposide-treated group in proteomic analysis. According to function-integrated analysis, 15 KEGG pathways were enriched and divided into 9 groups (modules), including influenza A, NOD-like receptor signaling, RIG-I-like receptor signaling, and so on. Among these modules, the most intensely interacting module pair was the NOD-like receptor signaling and influenza A, in which STAT1 and STAT2 acted as hubs with critical bridgeness role in the target network of geniposide. This indicated that geniposide may mitigate inflammation and alleviate IVP by JAK/STAT signaling pathways. Moreover, validation experiments confirmed that geniposide can significantly inhibit STAT1 and STAT2 phosphorylation as well as down-regulated expression of IL-6, IFN-γ and IL-17 in lung. Furthermore, when RAW cells were treated with the STAT1 inhibitor (fludarabine), the inhibitory effect of geniposide on IFN-γ and IL-6 was attenuated significantly.

Conclusions: Geniposide can attenuate IAV-induced pneumonia by regulating inflammatory cytokines production through the JAK/STAT pathway.

Keywords: Geniposide; Influenza A virus; JAK/STAT pathway; Multi-target and multi-pathway; STAT1.