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Outline
This study aims to investigate the effect and mechanism of the chromone compound 19A derived from Saposhnikovia divaricata in ameliorating acute lung injury (ALI) in mice. Molecular docking, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and dual-luciferase reporter gene assays were employed to elucidate the binding mode of 19A with farnesoid X receptor (FXR) and its regulatory effect on FXR transcriptional activity. In vitro, an inflammatory model was established by stimulating bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS), and the effects of 19A on cell viability, nitric oxide (NO) release, mRNA expression of inflammatory cytokines, and NF-κB p65 phosphorylation were evaluated. The FXR-dependence of these effects was verified in BMDMs derived from Fxr-/- mice. In vivo, two ALI mouse models were established via intratracheal instillation of LPS and Escherichia coli (E. coli) to evaluate lung function, total protein concentration in bronchoalveolar lavage fluid (BALF), pulmonary inflammatory histopathology, inflammatory cytokine levels, and reverse validation was performed in Fxr-/- mice. The use of animals in this study was approved by the Ethics Committee of Shanghai University of Traditional Chinese Medicine, with the approval number: PZSHUTCM2412200007. 19A forms stable interactions with FXR, enhancing its transcriptional activity. In vitro, 19A inhibited LPS-induced NO release and the mRNA expression of inflammatory cytokines, reduced IκBα degradation and phosphorylation, and decreased NF-κB p65 phosphorylation; these anti-inflammatory and NF-κB-inhibitory effects were markedly attenuated or abolished in Fxr-/- BMDMs. In wild-type mice, 19A markedly improved LPS-induced lung dysfunction, reduced lung index and BALF total protein, alleviated structural damage and inflammatory cell infiltration in lung tissue, and downregulated pulmonary inflammatory cytokine mRNA levels and NF-κB p65 phosphorylation. In contrast, these protective effects of 19A were largely lost in Fxr-/- mice. In summary, the Saposhnikoviae Radix chromone 19A attenuates LPS-induced macrophage inflammatory responses and ALI in mice by activating FXR and inhibiting the NF-κB signaling pathway. Compound 19A may serve as a lead candidate for ALI prevention and treatment based on the chromone scaffold of Saposhnikoviae Radix, providing experimental support for the modernization of the traditional Chinese medicine Fangfeng and the development of new therapeutics for ALI.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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