Silymarin Alleviates Oxidative Stress and Inflammation Induced by UV and Air Pollution in Human Epidermis and Activates β-Endorphin Release through Cannabinoid Receptor Type 2

Background: Skin is exposed to ultraviolet radiation (UV) and air pollution, and recent works have demonstrated that these factors have additive effects in the disturbance of skin homeostasis. Nuclear-factor-erythroid-2-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AHR) appear to be appropriate targets in the management of combined environmental stressors. The protective effects of silymarin (SM), an antioxidant and anti-inflammatory complex of flavonoids, were evaluated. Methods: Reactive oxygen species (ROS) and interleukin 1-alpha (IL-1a) were quantified in UV+urban-dust-stressed reconstructed human epidermis (RHE) treated with SM. A gene expression study was conducted on targets related to AHR and Nrf2. SM agonistic activity on cannabinoid receptor type 2 (CB2R) was evaluated on mast cells. The clinical study quantified the performance of SM and cannabidiol (CBD) in skin exposed to solar radiation and air pollution. Results: SM decreased morphological alterations, ROS, and IL-1a in UV+urban-dust-stressed RHE. AHR- and Nrf2-related genes were upregulated, which control the antioxidant effector and barrier function. Interleukin 8 gene expression was decreased. The clinical study confirmed SM improved the homogeneity and perceived well-being of urban skins exposed to UV, outperforming CBD. SM activated CB2R and the release of β-endorphin from mast cells. Conclusions: SM provides protection of skin from oxidative stress and inflammation caused by two major factors of exposome and appears mediated by AHR-Nrf2. SM activation of CB2R is opening a new understanding of SM’s anti-inflammatory properties.