Braylin belongs to the group of natural coumarins, a group of compounds with a wide range of pharmacological properties. Here we characterized the pharmacological properties of braylin in vitro, in silico and in vivo in models of inflammatory/immune responses. In in vitro assays, braylin exhibited concentration-dependent suppressive activity on activated macrophages. Braylin (10–40 μM) reduced the production of nitrite, IL-1β, TNF-α and IL-6 by J774 cells or peritoneal exudate macrophages stimulated with LPS and IFN-γ. Molecular docking calculations suggested that braylin present an interaction pose to act as a glucocorticoid receptor ligand. Corroborating this idea, the inhibitory effect of braylin on macrophages was prevented by RU486, a glucocorticoid receptor antagonist. Furthermore, treatment with braylin strongly reduced the NF-κB-dependent transcriptional activity on RAW 264.7 cells. Using the complete Freund’s adjuvant (CFA)-induced paw inflammation model in mice, the pharmacological properties of braylin were demonstrated in vivo. Braylin (12.5–100 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on CFA model. Braylin did not produce antinociception on the tail flick and hot plate tests in mice, suggesting that braylin-induced antinociception is not a centrally-mediated action. Braylin exhibited immunomodulatory properties on the CFA model, inhibiting the production of pro-inflammatory cytokines IL-1β, TNF-α and IL-6, while increased the anti-inflammatory cytokine TGF-β. Our results show, for the first time, anti-inflammatory, antinociceptive and immunomodulatory effects of braylin, which possibly act through the glucocorticoid receptor activation and by inhibition of the transcriptional activity of NF-κB. Because braylin is a phosphodiesterase-4 inhibitor, this coumarin could represent an ideal prototype of glucocorticoid receptor ligand, able to induce synergic immunomodulatory effects.

This study represents the first phytochemical analysis of Stillingia loranthacea (S. loranthacea) and describes new terpenoids obtained from the root bark of this species. The fractionation of the hexane extract from the root bark led to the isolation of two new 28-nor-taraxarenes derivatives, loranthones A and B (1 and 2), four new tigliane diterpenes (5−8), three known tigliane diterpenes (9−11), and three known flexibilene diterpenes, tonantzitlolones A−C (12−14). The investigation of these compounds and the use of a molecular networking-based prioritization approach afforded two other new 28-nor-taraxarenes, loranthones C and D (3 and 4). The cytotoxicity of compounds 1, 2, and 5−14 was evaluated against Vero cells, and their 20% cytotoxic concentration (CC 20 ) values varied from 8.7 to 328 μM; antiviral activity was tested against an epidemic Zika virus (ZIKV) strain circulating in Brazil. Six out of 12 compounds (2, 5, 9−11, and 14) exhibited significant antiviral effects against ZIKV. Specifically, compounds 2 and 5 offered the most promise as lead compounds as they had a 1.7 and 1.8 log 10 TCID 50 /mL reduction in ZIKV replication, respectively. Together, the present findings have identified S. loranthacea terpenoids as potent anti-ZIKV inhibitors and pave the way to the development of possible new treatments against this devastating pathogen.

These results demonstrate that DHC acts as a chemosensitizing agent selective for glioma cells not affecting non-tumor cells. Considering tumor heterogeneity, DHC demonstrated an anti-cancer potential to activate different cell death pathways. DHC demonstrated could be used for chemotherapy and immunotherapy applications in glioblastomas in the future.

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Recebido em 20/4/12; aceito em 18/9/12; publicado na web em 26/10/12 ALKALOIDS OF ROOT BARKS OF Zanthoxylum spp. In 1959, Gottlieb and Antonaccio published a study reporting the occurrence of lignan sesamin and triterpene lupeol in Zanthoxylum tingoassuiba. In this work we describe the phytochemical study of the root bark of the Z. tingoassuiba which allowed the identification of the lupeol, sesamin, and alkaloids dihydrochelerythrine, chelerythrine, anorttianamide, cis-N-methyl-canadine, predicentine, 2, 3-methylenedioxy-10,11-dimethoxy-tetrahydro protoberberine. The investigation of hexane and methanol extracts of the root bark of Z. rhoifolium and Z. stelligerum also investigated showed the presence of alkaloids dihydrochelerythrine, anorttianamide, cis-N-methyl-canadine, 7,9-dimethoxy-2,3-methylenedioxybenzophen anthridine and angoline. The occurrence of 2,3-methylenedioxy-10,11-dimethoxy-tetrahydro protoberberine is first described in Z. tingoassuiba and Z. stelligerum. This is also the first report of the presence of hesperidin and neohesperidin in roots of Z. stelligerum.