Abstract
The transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response. Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV (ultraviolet) radiation. The apocarotenoid bixin, a Food and Drug Administration (FDA)-approved natural food colorant (referred to as ‘annatto’) originates from the seeds of the achiote tree native to tropical America, consumed by humans since ancient times. Use of achiote preparations for skin protection against environmental insult and for enhanced wound healing has long been documented. We have recently reported that (i) bixin is a potent canonical activator of the NRF2-dependent cytoprotective response in human skin keratinocytes; that (ii) systemic administration of bixin activates NRF2 with protective effects against solar UV-induced skin damage; and that (iii) bixin-induced suppression of photodamage is observable in Nrf2+/+ but not in Nrf2−/− SKH-1 mice confirming the NRF2-dependence of bixin-induced antioxidant and anti-inflammatory effects. In addition, bixin displays molecular activities as sacrificial antioxidant, excited state quencher, PPAR (peroxisome proliferator-activated receptor) α/γ agonist, and TLR (Toll-like receptor) 4/NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) antagonist, all of which might be relevant to the enhancement of skin barrier function and environmental stress protection. Potential skin photoprotection and photochemoprevention benefits provided by topical application or dietary consumption of this ethno-pharmacologically validated phytochemical originating from the Americas deserves further preclinical and clinical examination.
Highlights
Solar Radiation, Photodamage, Photoaging, and Skin PhotocarcinogenesisExposure to solar ultraviolet (UV) radiation is a causative factor in acute skin photodamage, chronic photoaging, and photocarcinogenesis [1,2,3,4]
Upon exposure to reactive oxygen species (ROS) or to electrophilic compounds, key sensor cysteine residues in Kelch-ECH associated protein 1 (KEAP1) are chemically modified, causing a conformational change in KEAP1 that prevents degradation of nuclear factor-E2-related factor-E2-related factor 2 (NRF2), which remains complexed to KEAP1 [23,24]
Recent studies strongly suggest a protective role of NRF2-mediated gene expression in the suppression of cutaneous photodamage induced by solar UV radiation, and NRF2 activation has been shown to protect cutaneous keratinocytes and fibroblasts against the cytotoxic effects of UVA and UVB [16,18,19,31,33,81,82,83,84,85,86,87,88]
Summary
Exposure to solar ultraviolet (UV) radiation is a causative factor in acute skin photodamage, chronic photoaging, and photocarcinogenesis [1,2,3,4]. A causative role of solar photons in the visible and infrared spectral range contributing to skin photodamage has been substantiated [5,6,7,8]. 2. NRF2: A Master Regulator of Skin Barrier Function, Cellular Defense Mechanisms against. The redox-sensitive transcription factor NRF2 (nuclear factor-E2-related factor 2) orchestrates major cellular defense mechanisms including phase-II detoxification, inflammatory signaling, DNA repair, and antioxidant response, and recent experimental evidence supports an important role of NRF2 in skin barrier function. NRF2 has emerged as a promising molecular target for the pharmacological prevention of human pathologies resulting from exposure to environmental toxicants including solar UV-induced damage and carcinogenesis [15,16,17,18]. The potential of NRF2 for modulation of skin chronological and photodamage-associated aging has attracted considerable attention [9,19,20]
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