RESUMEN
The purpose of the present study is to find the natural compound(s) having a therapeutic potential to treat lung inflammatory disorders. In our screening procedure, the methanol extract of the seeds of Cassia obtusifolia (cassiae semen) inhibited inducible nitric oxide synthase-catalyzed nitric oxide production in alveolar macrophages (MH-S). From the extract, 8 major anthraquinone derivatives were successfully isolated. They are chrysophanol, physcion, 2-hydroxy-emodin 1-methyl ether, obtusifolin, obtusin, aurantio-obtusin, chryso-obtusin, and gluco-obtusifolin, among which aurantio-obtusin (IC50 = 71.7 µM) showed significant inhibitory action on nitric oxide production from lipopolysaccharide-treated MH-S cells, mainly by downregulation of inducible nitric oxide synthase expression. This down-regulatory action of aurantio-obtusin was mediated at least in part via interrupting c-Jun N-terminal kinase/IκB kinase/nuclear transcription factor-κB pathways. Aurantio-obtusin also inhibited IL-6 production in IL-1ß-treated lung epithelial cells, A549. Importantly, this compound (10 and 100 mg/kg) by oral administration attenuated lung inflammatory responses in a mouse model of lipopolysaccharide-induced acute lung injury. Therefore, it is for the first time found that aurantio-obtusin may have a therapeutic potential for treating lung inflammatory diseases.
Asunto(s)
Antraquinonas/farmacología , Cassia/química , Inflamación/tratamiento farmacológico , Pulmón/efectos de los fármacos , Macrófagos Alveolares/efectos de los fármacos , Extractos Vegetales/farmacología , Células A549 , Animales , Emodina/análogos & derivados , Glucósidos , Humanos , Lipopolisacáridos , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Semillas/química , Transducción de Señal/efectos de los fármacosRESUMEN
Investigations into the development of new therapeutic agents for lung inflammatory disorders have led to the discovery of plant-based alternatives. The rhizomes of Anemarrhena asphodeloides have a long history of use against lung inflammatory disorders in traditional herbal medicine. However, the therapeutic potential of this plant material in animal models of lung inflammation has yet to be evaluated. In the present study, we prepared the alcoholic extract and derived the saponin-enriched fraction from the rhizomes of A. asphodeloides and isolated timosaponin A-III, a major constituent. Lung inflammation was induced by intranasal administration of lipopolysaccharide (LPS) to mice, representing an animal model of acute lung injury (ALI). The alcoholic extract (50-200 mg/kg) inhibited the development of ALI. Especially, the oral administration of the saponin-enriched fraction (10-50 mg/kg) potently inhibited the lung inflammatory index. It reduced the total number of inflammatory cells in the bronchoalveolar lavage fluid (BALF). Histological changes in alveolar wall thickness and the number of infiltrated cells of the lung tissue also indicated that the saponin-enriched fraction strongly inhibited lung inflammation. Most importantly, the oral administration of timosaponin A-III at 25-50 mg/kg significantly inhibited the inflammatory markers observed in LPS-induced ALI mice. All these findings, for the first time, provide evidence supporting the effectiveness of A. asphodeloides and its major constituent, timosaponin A-III, in alleviating lung inflammation.