Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) may be involved in a key mechanism of the skin aging process, influencing several aspects related to the age-related degeneration of skin cells, including antioxidant unbalance. Therefore, we investigated whether the up-modulation of this nuclear receptor exerts a protective effect in a stress-induced premature senescence (SIPS) model based on a single exposure of human dermal fibroblasts to 8-methoxypsoralen plus + ultraviolet-A-irradiation (PUVA). Among possible PPARγ modulators, we selected 2,4,6-octatrienoic acid (Octa), a member of the parrodiene family, previously reported to promote melanogenesis and antioxidant defense in normal human melanocytes through a mechanism involving PPARγ activation. Exposure to PUVA induced an early and significant decrease in PPARγ expression and activity. PPARγ up-modulation counteracted the antioxidant imbalance induced by PUVA and reduced the expression of stress response genes with a synergistic increase of different components of the cell antioxidant network, such as catalase and reduced glutathione. PUVA-treated fibroblasts grown in the presence of Octa are partially but significantly rescued from the features of the cellular senescence-like phenotype, such as cytoplasmic enlargement, the expression of senescence-associated-β-galactosidase, matrix-metalloproteinase-1, and cell cycle proteins. Moreover, the alterations in the cell membrane lipids, such as the decrease in the polyunsaturated fatty acid content of phospholipids and the increase in cholesterol levels, which are typical features of cell aging, were prevented. Our data suggest that PPARγ is one of the targets of PUVA-SIPS and that its pharmacological up-modulation may represent a novel therapeutic approach for the photooxidative skin damage.
Highlights
Ultraviolet (UV) radiation elicits premature aging of the skin and cutaneous malignancies [1]
Because the chemical structure of octatrienoic acid (Octa) resembles the polyene chain of carotenoids, we evaluated the ability of this molecule to modulate the retinoidmediated signaling in human skin dermal fibroblasts (HDFs) to study the activation of retinoic acid receptor (RAR) and the subsequent transcriptional activation of RARE
Octa treatment did not exhibit any ability to induce the mRNA expression of cellular retinoic acid binding protein 2 (CRABPII) or cytochrome P450 hydroxylase (CYP26), two genes that contain RARE reporter promoters, which are directly involved in the proliferative response elicited by retinoid-like molecules, whereas atRA induced a relevant up-regulation of both genes (Fig. 1B)
Summary
Ultraviolet (UV) radiation elicits premature aging of the skin and cutaneous malignancies [1]. UVA rays generate reactive oxygen species (ROS) via photodynamic actions [2], resulting in skin degeneration and aging [3,4] and, in particular, oxidative damage to lipids, proteins, and DNA [5,6,7]. The incidence of skin photoaging and skin cancer dramatically increases with increased exposure to UVA rays [11]. To protect its structure against UV, skin has developed several defence systems which include pigmentation, antioxidant network and neuro-immune-endocrine functions, which are tightly networked to central regulatory system and are involved in the protection and in the maintenance of global homeostasis, through the production of cytokines, neurotransmitters, neuroendocrine hormones [12]. An unbalance between pro-inflammatory or anti-inflammatory responses activated by these mediators may be related to cellular degeneration in aged skin
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