Evidence That the Anti-Inflammatory Effect of Rubiadin-1-methyl Ether Has an Immunomodulatory Context.

BACKGROUND: In spite of the latest therapeutic developments, no effective treatments for handling critical conditions such as acute lung injuries have yet been found. Such conditions, which may result from lung infections, sepsis, multiple trauma, or shock, represent a significant challenge in intensive care medicine. Seeking ways to better deal with this challenge, the scientific community has recently devoted much attention to small molecules derived from natural products with anti-inflammatory and immunomodulatory effects. AIMS: In this context, we investigated the anti-inflammatory effect of Rubiadin-1-methyl ether isolated from Pentas schimperi, using an in vitro model of RAW 264.7 macrophages induced by LPS and an in vivo model of acute lung injury (ALI) induced by LPS. METHODS: The macrophages were pretreated with the compound and induced by LPS (1 µg/mL). After 24 h, using the supernatant, we evaluated the cytotoxicity, NOx, and IL-6, IL-1ß, and TNF-α levels, as well as the effect of the compound on macrophage apoptosis. Next, the compound was administered in mice with acute lung injury (ALI) induced by LPS (5 mg/kg), and the pro- and anti-inflammatory parameters were analyzed after 12 h using the bronchoalveolar lavage fluid (BALF). RESULTS: Rubiadin-1-methyl ether was able to inhibit the pro-inflammatory parameters studied in the in vitro assays (NOx, IL-6, and IL-1ß) and, at the same time, increased the macrophage apoptosis rate. In the in vivo experiments, this compound was capable of decreasing leukocyte infiltration; fluid leakage; NOx; IL-6, IL-12p70, IFN-γ, TNF-α, and MCP-1 levels; and MPO activity. In addition, Rubiadin-1-methyl ether increased the IL-10 levels in the bronchoalveolar lavage fluid (BALF). CONCLUSIONS: These findings support the evidence that Rubiadin-1-methyl ether has important anti-inflammatory activity, with evidence of an immunomodulatory effect.

New pre-clinical evidence of anti-inflammatory effect and safety of a substituted fluorophenyl imidazole.

Acute Respiratory Distress Syndrome (ARDS) is an inflammatory condition with high mortality rates, and there is still no pharmacological approach with proven effectiveness. In the past few years, several imidazole small molecules have been developed to treat conditions in which inflammation plays a central role. In the present work, we hypothesize that a novel substituted fluorophenyl imidazole synthetized by our research group would present in vivo anti-inflammatory effect in an ARDS murine model induced by LPS. Results shows that the fluorophenyl imidazole has the ability to inhibit leukocyte migration to the bronchoalveolar lavage fluid and lung tissue of animals challenged intranasally with LPS. Furthermore, this inhibition is followed with reduction in myeloperoxidase activity, nitric oxide metabolites generation and cytokines (TNF-α, IL-6, IL-17, IFN-γ and IL-10) secretion. This effect is at least partly related to the capacity of the fluorophenyl imidazole in inhibit p38 MAPK and NF-κB phosphorylation. Finally, fluorophenyl imidazole showed no signs of acute oral toxicity in the toxicological protocol suggested by OECD 423. Taken together, the results shows that fluorophenyl imidazole is a promising prototype for the development of a novel anti-inflammatory drug in which p38 MAPK and NF-κB plays a pivotal role.

7-prenyloxi-6-methoxycoumarin from Polygala sabulosa A.W. Bennett Regulates p38 MAPK and NF-kB Pathways Inhibiting the Inflammation Induced by Carrageenan in the Mouse Model of Pleurisy.

CONTEXT: Polygala sabulosa, popularly known as "timutu-pinheirinho," has been used in Brazilian folk medicine for the treatment of bowel and kidney disorders and as an expectorant. OBJECTIVE: Evaluate the anti-inflammatory effects of the crude extract (CE), acetonic fraction (Ac), and the main compound, 7-prenyloxi-6-methoxycoumarin (PC) on a mouse model of carrageenan-induced pleurisy. MATERIALS AND METHODS: A mouse model of carrageenan-induced pleurisy was used to investigate the effects of P. sabulosa CE, Ac and PC on leukocyte migration, exudate formation, activities of myeloperoxidase (MPO), and adenosine-deaminase (ADA), levels of tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß) and nitric oxide (NO). In addition, the effect of the plant material on lung histology was also evaluated. The effects of PC on the TNF-α, IL-1ß and NO synthase 2 (NOS2) mRNA expression, were also investigated. Finally, the effect of PC on the nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK) was also evaluated. RESULTS: CE, Ac and PC reduced inflammation in the pleural cavity and lungs. This effect was evidenced by reduction on all inflammatory parameters evaluated; the exception being the inability of the CE to inhibit exudate formation. In isolation, PC showed reduction on mRNA levels of TNF-α, IL-1ß and NOS2, and on activation of the NF-κB and p38 MAPK pathways. CONCLUSION: The presented results show that P. sabulosa has significant anti-inflammatory activity, as does its main compound, PC. Moreover, the results suggest that PC exerts its effects mainly by inhibited the NF-κB and p38 MAPK pathways.