Beneficial regulation of matrixmetalloproteinases and their inhibitors, fibrillar collagens and transforming growth factor-β by Polypodium leucotomos, directly or in dermal fibroblasts, ultraviolet radiated fibroblasts, and melanoma cells

Abstract The extracellular matrix (ECM) that gives tissue its structural integrity is remodeled in skin aging/photoaging and cancer via the increased expression/activities of matrixmetalloproteinases (MMP), inhibition of the tissue inhibitors of matrix etalloproteinases (TIMP), or inhibition of collagen synthesis. Transforming growth factor- β (TGF- β ), a predominant regulator of the ECM, is inhibited in aging/photoaging and stimulated in carcinogenesis.

P. leucotomos (fern) extract has potential to counteract these alterations via its antioxidant, anti-inXammatory and photoprotective properties. The goal of this research was to determine the effcacy of P. leucotomos to (a) directly inhibit MMP-1, 2, 3, and 9 activities, (b) inhibit MMP-2, and stimulate TIMPs, Wbrillar collagens and TGF- β in nonirradiated or ultraviolet (UV) radiated Wbroblasts, and (c) inhibit MMPs and TGF- β, and stimulate TIMPs in melanoma cells. To this purpose, we examined the direct eVect of P. leucotomos (0–1%) on MMPs’ activities, and its effects on the expression (protein and/or transcription levels) of (1) MMPs and TIMPs in dermal fibroblasts, and melanoma cells, (2) TGF- β in non-irradiated, UVA (2.5 J/cm2) or UVB (2.5 mJ/cm2) irradiated fibroblasts, and melanoma cells, and (3) types I, III, and V collagen in non-irradiated or UV irradiated Wbroblasts. P. leucotomos directly inhibited the activities of MMPs as well as the expression of MMPs in fibroblasts, and melanoma cells while stimulating the expression of TIMPs in these cells. P. leucotomos stimulated types I, III, and V collagen in non-irradiated fibroblasts, and types I and V collagen in UV radiated fibroblasts.

P. leucotomos had predominant stimulatory effects on TGF- β expression in non-irradiated or UV radiated fibroblasts, and inhibited TGF- β expression in melanoma cells. The effects of P. leucotomos were largely similar to that of ascorbic acid. P. leucotomos demonstrated dual protective effects on the ECM via its inhibition of the ECM proteolytic enzymes and the stimulation of the structural ECM collagens. The effects of P. leucotomos on fibroblasts and melanoma cells may be partly via its cell-speciffic regulation of TGF- β expression and partly via its antioxidant property. The intake or topical application of P. leucotomos may be beneWcial to skin health, in aging and cancer prevention or treatment.