US EPA

2238281 

Journal Article 

Perthamide C inhibits eNOS and iNOS expression and has immunomodulating activity in vivo 

Bucci, M; Cantalupo, A; Vellecco, V; Panza, E; Monti, MC; Zampella, A; Ianaro, A; Cirino, G 

2013 

1 

PLoS ONE
EISSN: 1932-6203 

8 

3 

e57801 

English 

23554869 

10.1371/journal.pone.0057801 

WOS:000316252500009 

has retraction 10516278 (Retraction of Vol 8, art no E57801, 2013)

Here we have characterized perthamide C, a cyclopeptide from a Solomon Lithistid sponge Theonella swinhoei, which displays an anti-inflammatory/immunomodulatory activity. The study has been performed using the carragenan-induced mouse paw edema that displays an early (0-6 h) and a late phase (24-96 h). Perthamide C significantly inhibits neutrophils infiltration in tissue both in the early and late phases. This effect was coupled to a reduced expression of the endothelial nitric oxide synthase (eNOS) in the early phase while cyclooxygenase-1 and 2 (COX-1, COX-2), and inducible NOS (iNOS) expression were unaffected. In the late phase perthamide C reduced expression of both NOS isoforms without affecting COXs expression. This peculiar selectivity toward the two enzymes deputed to produce NO lead us to investigate on a possible action of perthamide C on lymphocytes infiltration and activation. We found that perthamide C inhibited the proliferation of peripheral lymphocytes, and that this effect was secondary to its metabolic activation in vivo. Indeed, in vitro perthamide C did not inhibit proliferation as opposite to its metabolite perthamide H. In conclusion, perthamide C selectively interferes with NO generation triggered by either eNOS or iNOS without affecting either COX-1 or COX-2. This in turn leads to modulation of the inflammatory response through a reduction of vascular permeability, neutrophil infiltration as well as lymphocyte proliferation.