Simulation of the Elastin and Fibrillin in Non-Irradiated or UVA Radiated Fibroblasts, and Direct Inhibition of Elastase or Matrix Metalloptoteinases Activity by Nicotinamide or Its Derivatives.

Skin aging/photoaging is associated with altered the structure of collagen and elastin fibers, and increased activity of matrix metalloproteinases (MMP) and elastase. Nicotinamide and its derivatives, 2,6-dihydroxynicotinamide, 2,4,5,6-tetrahydroxynicotinamide, and 3-hydroxypicolinamide (collectively niacin derivatives) stimulate fibrillar collagen and heat shock proteins in dermal fibroblasts. The goal of this research was to extend the understanding of the anti-skin aging mechanism of these niacin derivatives through the stimulation of elastin (at the protein and promoter levels), fibrillin (1 and 2) in nonirradiated or ultraviolet (UVA) radiated dermal fibroblasts, and through the direct inhibition of MMP (1, 3, and 9) and elastase activities. UVA radiation stimulated elastin and inhibited fibrillin-1 and fibrillin-2 in dermal fibroblasts. The niacin derivatives significantly stimulated the expression of elastin (transcriptionally), fibrillin-1 and fibrillin-2 in nonirradiated and UVA radiated fibroblasts, and directly inhibited MMP or elastase activity. Overall, the niacin derivatives, more so nicotinamide and 2,6-dihydroxynicotinamide, have anti-skin aging potential through the stimulation of elastin and fibrillin, and the direct inhibition of the extracellular matrix proteolytic enzymes.

Mechanisms of Photoaging and Cutaneous Photocarcinogenesis, and Photoprotective Strategies with Phytochemicals.

Photoaging and photocarcinogenesis are primarily due to solar ultraviolet (UV) radiation, which alters DNA, cellular antioxidant balance, signal transduction pathways, immunology, and the extracellular matrix (ECM). The DNA alterations include UV radiation induced thymine-thymine dimers and loss of tumor suppressor gene p53. UV radiation reduces cellular antioxidant status by generating reactive oxygen species (ROS), and the resultant oxidative stress alters signal transduction pathways such as the mitogen-activated protein kinase (MAPK), the nuclear factor-kappa beta (NF-κB)/p65, the janus kinase (JAK), signal transduction and activation of transcription (STAT) and the nuclear factor erythroid 2-related factor 2 (Nrf2). UV radiation induces pro-inflammatory genes and causes immunosuppression by depleting the number and activity of the epidermal Langerhans cells. Further, UV radiation remodels the ECM by increasing matrixmetalloproteinases (MMP) and reducing structural collagen and elastin. The photoprotective strategies to prevent/treat photoaging and photocarcinogenesis include oral or topical agents that act as sunscreens or counteract the effects of UV radiation on DNA, cellular antioxidant balance, signal transduction pathways, immunology and the ECM. Many of these agents are phytochemical derivatives and include polyphenols and non-polyphenols. The flavonoids are polyphenols and include catechins, isoflavones, proanthocyanidins, and anthocyanins, whereas the non-flavonoids comprise mono phenolic acids and stilbenes. The natural sources of polyphenols include tea, cocoa, grape/wine, soy, pomegranate, and Polypodium leucotomos. The non-phenolic phytochemicals include carotenoids, caffeine and sulphoraphance (SFN). In addition, there are other phytochemical derivatives or whole extracts such as baicalin, flavangenol, raspberry extract, and Photomorphe umbellata with photoprotective activity against UVB radiation, and thereby carcinogenesis.