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The total flavonoids from sea buckthorn (TFSB) exhibit a potent anti-inflammatory activity; however, the effect of TFSB on respiratory inflammatory disease is not fully known. The present study evaluated the potential of TFSB to prevent airway inflammation and the underlying mechanism. The results showed that TFSB remarkably inhibited lipopolysaccharide/cigarette smoke extract (LPS/CSE)-induced expression of IL-1β, IL-6, CXCL1, and MUC5AC at both mRNA and protein levels in HBE16 bronchial epithelial cells. TFSB also decreased the production of PGE 2 through inhibition the expression of COX2 in LPS/CSE-stimulated HBE16 cells. Furthermore, bronchoalveolar fluid and histological analyses revealed that LPS/cigarette smoke exposure-induced elevated cell numbers of neutrophils and macrophages in bronchoalveolar fluid, inflammatory cell infiltration, and airway remodeling were remarkably attenuated by TFSB in mice. Immunohistochemical results also confirmed that TFSB decreased the expression of IL-1β, IL-6, COX2, CXCL1, and MUC5AC in LPS/CSexposed mice. Mechanistically, TFSB blocked LPS/CSE-induced activation of ERK, Akt, and PKCα. Molecular docking further confirmed that the main components in TFSB including quercetin and isorhamnetin showed potent binding affinities to MAPK1 and PIK3CG, two upstream kinases of ERK and Akt, respectively. In summary, TFSB exerts a potent protective effect against LPS/CS-induced airway inflammation through inhibition of ERK, PI3K/Akt, and PKCα pathways, suggesting that TFSB may be a novel therapeutic agent for respiratory diseases. KEYWORDS chronic bronchitis, ERK, PI3K/Akt, and PKC pathways, lipopolysaccharide/cigarette smoke, sea buckthorn, total flavonoids

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Context: Ajuga ovalifolia Bur. et Franch. var. calantha (Diels) C. Y. Wu et C. Chen (Labiatae), a traditional Chinese medicine, has been used to treat several inflammatory diseases. Objective: To assess the anti-inflammatory activity of ajudecumin A isolated from Ajuga ovalifolia var. calantha, and its possible mechanisms. Materials and methods: Lipopolysaccharide (LPS, 0.5 lg/mL)-stimulated RAW264.7 macrophages were used to assess the anti-inflammatory activity of ajudecumin A (1-40 lM) in vitro. Nitric oxide levels were evaluated by Griess reagent. The mRNA levels of iNOS, COX-2, TNF-a, IL-1b and IL-6 were determined using qRT-PCR. Phosphorylation of ERK, JNK, p38 MAPK and IjBa were detected by western Blot. To further assess the anti-inflammatory of ajudecumin A in vivo, mice were oral treated with ajudecumin A (10 mg/kg) or dexamethasone (0.25 mg/kg, positive control) for 5 days before administration of carrageenan or xylene. Paw and ear edema were then measured, respectively. Results: Ajudecumin A (10-40 lM) decreased LPS-induced nitric oxide production with an IC 50 value of 16.19 lM. Ajudecumin A (20 and 40 lM) also attenuated cell spreading and formation of pseudopodia-like structures, and decreased the mRNA levels of iNOS (55.23-67.04%, p < 0.001), COX-2 (57.58-70.25%, p < 0.001), TNF-a (53.75-58.94%, p < 0.01-0.001), IL-1b (79.41-87.85%, p < 0.001) and IL-6 (54.26-80.52%, p < 0.01-0.001) in LPS-activated RAW264.7 cells. Furthermore, ajudecumin A suppressed LPS-induced phosphorylation of ERK, p38 MAPK, and IjBa, as well as IjBa degradation (p < 0.05-0.001). Finally, ajudecumin A (10 mg/kg) attenuated carrageenan-and xylene-induced inflammation in mice by about 28 and 24%, respectively. Discussion and conclusions: Ajudecumin A exhibited a potent anti-inflammatory activity in vitro and in vivo through inhibition on NF-jB and ERK/p38 MAPK pathways, suggesting that ajudecumin A may be potentially developed as a lead compound in anti-inflammatory drug discovery.