Spilanthol Inhibits Inflammatory Transcription Factors and iNOS Expression in Macrophages and Exerts Anti-inflammatory Effects in Dermatitis and Pancreatitis.

Activated macrophages upregulate inducible nitric oxide synthase (iNOS) leading to the profuse production of nitric oxide (NO) and, eventually, tissue damage. Using macrophage NO production as a biochemical marker of inflammation, we tested different parts (flower, leaf, and stem) of the medicinal plant, Spilanthes acmella. We found that extracts prepared from all three parts, especially the flowers, suppressed NO production in RAW macrophages in response to interferon-γ and lipopolysaccharide. Follow up experiments with selected bioactive molecules from the plant (α-amyrin, ß-caryophylline, scopoletin, vanillic acid, trans-ferulic acid, and spilanthol) indicated that the N-alkamide, spilanthol, is responsible for the NO-suppressive effects and provides protection from NO-dependent cell death. Spilanthol reduced the expression of iNOS mRNA and protein and, as a possible underlying mechanism, inhibited the activation of several transcription factors (NFκB, ATF4, FOXO1, IRF1, ETS, and AP1) and sensitized cells to downregulation of Smad (TF array experiments). The iNOS inhibitory effect translated into an anti-inflammatory effect, as demonstrated in a phorbol 12-myristate 13-acetate-induced dermatitis and, to a smaller extent, in cerulein-induced pancreatitis. In summary, we demonstrate that spilanthol inhibits iNOS expression, NO production and suppresses inflammatory TFs. These events likely contribute to the observed anti-inflammatory actions of spilanthol in dermatitis and pancreatitis.

Breakdown of bioenergetics evoked by mitochondrial damage in acute pancreatitis: Mechanisms and consequences.

Acute pancreatitis is a severe inflammatory disease with unacceptably high mortality and without specific therapy. Clinical studies revealed that energy supplementation of patients via enteral feeding decreases systemic infections, multi-organ failure and mortality. These clinical observations have been supported by in vitro and in vivo experimental studies which showed that the most common pancreatitis inducing factors, such as bile acids, ethanol and non-oxidative ethanol metabolites induce intracellular ATP depletion and mitochondrial damage both in pancreatic acinar and ductal cells. Notably, the in vitro supplementation of ATP prevented the cellular damage and restored cell functions in both cell types. These observations suggest that either prevention of mitochondrial damage or restoration of intracellular ATP level might provide therapeutical benefits.