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Modulation of metalloproteinases by alkylphenols from Phagnalon rupestre
Matrix metalloproteinases (MMPs)*, a family of zinc-dependent endopeptidases involved in the remodelling of the extracellular matrix (EM), play an important role in many biological processes. They are produced not only by structural cells, but also by inflammatory cells including neutrophils, macrophages, and lymphocytes. Their activation leads to destruction of connective tissue, thus contributing to the pathology of a large number of skin diseases involving inflammatory infiltrates and the remodelling of the EM . The present communication examines three phenolics isolated from Phagnalon rupestre (Asteraceae) : 2-isoprenylhydroquinone-1-glucoside, 3,5-dicaffeoylquinic acid, and the methyl ester of the latter, and uses Western blot analysis to evaluate their effects on the induction of MMP-9 expression by lipopolysaccharide (LPS) in RAW 264.7 cells. All three compounds have been previously described as inhibitors of peroxynitrite reactivity  as well as of various contact hypersensitivity reactions . They all exhibited a moderate ability to inhibit the activation of MMP-9 in a dose-dependent manner in LPS-stimulated macrophages. Both dicaffeoylquinic derivatives reduced MMP-9 activation by around 50% at 100µM. The reference drug epigallocatechin gallate (EGCG) completely abolished MMP-9 expression at 100µM. Previous research  had shown that these test compounds moderately reduce the levels of IL-1β and TNF-α, both cytokines having been described as powerful elicitors of the transcription of MMP-9 . In light of these previous findings, the present results suggest that these principles are able to modulate MMP-9 activation in part via a reduction in the release of inflammatory cytokines.
*MMPs are secreted as inactive proenzymes and need to be activated by proteolytic cleavage. Stimulation or repression of proMMPs synthesis is regulated mostly at the transcriptional level by growth factors and cytokines.
Acknowledgements: This work was supported by the Spanish Ministry of Science and Technology (SAF 2006–06726) and by the Generalitat Valenciana (Project GV 353/06).
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