Morita-Baylis-Hillman adduct 2-(3-hydroxy-1-methyl-2-oxoindolin-3-il) acrylonitrile (CISACN) ameliorates the pulmonary allergic inflammation in CARAS model by increasing IFN-γ/IL-4 ratio towards the Th1 immune response.

Combined allergic rhinitis and asthma syndrome (CARAS) is an airway-type 2 immune response with a profuse inflammatory process widely affecting the world population. Due to the compromise of quality of life and the lack of specific pharmacotherapy, the search for new molecules becomes relevant. This study aimed to evaluate the effectiveness of the Morita-Bailys-Hillman adduct (CISACN) treatment in the CARAS experimental model. Female BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with CISACN. The treatment decreased the eosinophil migration to the nasal and lung cavities and tissues and the goblet cell hyperplasia/hypertrophy, attenuated airway hyperactivity by reducing the hyperplasia/hypertrophy of the smooth muscle and the extracellular matrix's thickness. Also, the treatment reduced the clinical signs of rhinitis as nasal rubbing and sneezing in a histamine-induced nasal hyperreactivity assay. The immunomodulatory effect of CISACN was by reducing OVA-specific IgE serum level, and IL-33, IL-4, IL-13, and TGF-ß production, dependent on IFN-γ increase. Furthermore, the effect of CISACN on lung granulocytes was by decreasing the p-p38MAPK/p65NF-κB signaling pathway. Indeed, CISACN reduced the p38MAPK and p65NF-κB activation. These data demonstrated the anti-inflammatory and immunomodulatory effects of the CISACN with scientific support to become a pharmacological tool to treat airway inflammatory diseases.

Carvone Enantiomers Differentially Modulate IgE-Mediated Airway Inflammation in Mice.

Carvone is a monoterpene found in nature in the form of enantiomers (S- and R-). While previous research has demonstrated the anti-inflammatory and anti-allergic effects of carvone, the influence of carvone enantiomeric composition on its anti-allergic activity remains to be investigated. This study aimed to evaluate the anti-allergic activity of carvone enantiomers in a murine model of airway allergic inflammation induced by sensitization and challenge with ovalbumin (OVA). The oral treatment with R-carvone or S-carvone 1 h before each challenge inhibited the number of leukocytes and eosinophils in the bronchoalveolar lavage (BAL). R-carvone inhibited leukocyte infiltration and mucus production in the lung, which was correlated with decreased production of OVA-specific IgE in the serum and increased concentrations of IL-10 in the BAL. On the other hand, the administration of S-carvone had little inhibitory effect on inflammatory infiltration and mucus production in the lung, which might be associated with increased production of IFN-γ in the BAL. When administered 1 h before each sensitization, both enantiomers inhibited eosinophil recruitment to the BAL but failed in decreasing the titers of IgE in the serum of allergic mice. Our data indicate that carvone enantiomers differentially modulated IgE-mediated airway inflammation in mice. In conclusion, unlike S-carvone, R-carvone has the potential to be used in anti-allergic drug development.

Curine Inhibits Macrophage Activation and Neutrophil Recruitment in a Mouse Model of Lipopolysaccharide-Induced Inflammation.

Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects of curine on macrophage activation and neutrophil recruitment. Using a murine model of lipopolysaccharide (LPS)-induced pleurisy, we demonstrated that curine significantly inhibited the recruitment of neutrophils in association with the inhibition of cytokines tumor necrosis factor (TNF-α), interleukin (IL)-1ß, IL-6, monocyte chemotactic protein (CCL2/MCP-1) as well as leukotriene B4 in the pleural lavage of mice. Curine treatment reduced cytokine levels and the expression of iNOS in in vitro cultures of macrophages stimulated with LPS. Treatment with a calcium channel blocker resulted in comparable inhibition of TNF-α and IL-1ß production, as well as iNOS expression by macrophages, suggesting that the anti-inflammatory effects of curine may be related to the inhibition of calcium-dependent mechanisms involved in macrophage activation. In conclusion, curine presented anti-inflammatory effects that are associated with inhibition of macrophage activation and neutrophil recruitment by inhibiting the production of inflammatory cytokines, LTB4 and nitric oxide (NO), and possibly by negatively modulating Ca2+ influx.