Abstract
Background: Ganghuo Kanggan decoction (GHKGD) is a clinical experience prescription used for the treatment of viral pneumonia in the Lingnan area of China, and its clinical effect is remarkable. However, the mechanism of GHKGD in influenza is still unclear. Objective: To predict the active components and signaling pathway of GHKGD and to explore its therapeutic mechanism in influenza and to verified it in vivo using network pharmacology. Methods: The potential active components and therapeutic targets of GHKGD in the treatment of influenza were hypothesized through a series of network pharmacological strategies, including compound screening, target prediction and pathway enrichment analysis. Based on the target network and enrichment results, a mouse model of influenza A virus (IAV) infection was established to evaluate the therapeutic effect of GHKGD on influenza and to verify the possible molecular mechanism predicted by network pharmacology. Results: A total of 116 candidate active compounds and 17 potential targets were identified. The results of the potential target enrichment analysis suggested GHKGD may involve the RLR signaling pathway to reduce inflammation in the lungs. In vivo experiments showed that GHKGD had a protective effect on pneumonia caused by IAV-infected mice. Compared with the untreated group, the weight loss in the GHKGD group in the BALB/c mice decreased, and the inflammatory pathological changes in lung tissue were reduced (p < 0.05). The expression of NP protein and the virus titers in lung were significantly decreased (p < 0.05). The protein expression of RIG-I, NF-kB, and STAT1 and the level of MAVS and IRF3/7 mRNA were remarkably inhibited in GHKGD group (p < 0.05). After the treatment with GHKGD, the level of Th1 cytokines (IFN-γ, TNF-α, IL-2) was increased, while the expression of Th2 (IL-5, IL4) cytokines was reduced (p < 0.05). Conclusion: Through a network pharmacology strategy and in vivo experiments, the multi-target and multi-component pharmacological characteristics of GHKGD in the treatment of influenza were revealed, and regulation of the RLR signaling pathway during the anti-influenza process was confirmed. This study provides a theoretical basis for the research and development of new drugs from GHKGD.
Highlights
Influenza is an acute infectious respiratory disease caused by the influenza virus
These results indicated that GHKGD downregulated the expression of RIG-1, mitochondrial antiviral signaling protein (MAVS), interferon regulatory factor 3 (IRF3), interferon regulatory factor 7 (IRF7), NF-κB p65 and STAT1 in the RIG-I-like receptor (RLR) signaling pathway, thereby inhibiting excessive inflammatory responses
The IL-5 and IL-4 levels were markedly increased in GHKGD group, while the Ribavirin group changed without statistically significant (Figures 8D,E). These findings suggest that the differentiation of Th1 and Th2 cytokines exert critical functions during the occurrence of influenza virus pneumonia, and the GHKGD could played an immunomodulatory role by downgrading Th1 (IL-2, tumor necrosis factor-α (TNF-α), and IFN-γ) cytokines, while raising Th2 (IL-4 and IL-5) cytokines
Summary
Influenza is an acute infectious respiratory disease caused by the influenza virus. It has high morbidity, strong infectivity, widespread epidemic potential and high mortality (CordovaVillalobos et al, 2017). Death from severe influenza due to respiratory failure is closely related to increased permeability of the alveolar epithelial-vascular endothelial barrier and excessive release of inflammatory factors (Herold et al, 2015). Severe viral infections can induce the release of a large amount of cytokines in the body, causing a severe imbalance between the body’s pro-inflammatory and antiinflammatory cytokines, inducing cytokine storm and targeting the lungs, triggering acute lung injury (ALI) and even acute respiratory distress syndrome (ARDS) (Chen et al, 2018). The mechanism of GHKGD in influenza is still unclear
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