Targeting NRF2 for Improved Skin Barrier Function and Photoprotection: Focus on the Achiote-Derived Apocarotenoid Bixin

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.

Secondary Plant Metabolites for Sun Protective Cosmetics: From Pre-Selection to Product Formulation

“…Recently, Nrf2-regulated gene expression in response to solar UVA + UVB radiation in cultivated human skin cells has been reported [47]. Due to these findings, Nrf2 has been suggested as a target for modulation of skin chronological and premature photo-damage-associated skin ageing [48,49].…”

High‐energy visible light at ambient doses and intensities induces oxidative stress of skin—Protective effects of the antioxidant and Nrf2 inducer Licochalcone A in vitro and in vivo

“…Furthermore, blue light exposure can activate Nrf2 as a protective endogenous response, in human epidermal cells . Loss of Nrf2 has negative consequences for skin homeostasis, repair, and disease, suggesting that further activation is beneficial also for augmented skin photoprotection …”

“…Recent evidence suggests that plant‐derived antioxidants can protect VIS‐exposed skin from ROS‐induced oxidative stress, but their effects on Nrf2 remain to be established. A number of botanical ingredients including bixin, salidroside, tanshinones, caffeic acid, ferulic acid, quercetin, rutin, and the algae‐derived mycosporine‐like amino acids (MAAs) shinorine and porphyra‐334 were shown to mitigate UV‐induced cell damage via upregulation of Nrf2, but little is known about their protective effects against VIS. Licochalcone A (LicA) extracted from the roots of Glycyrrhiza inflata was identified as very potent antioxidant, inhibiting of UV‐induced ROS generation, and activator of Nrf2 in primary human fibroblasts .…”

Epigenetic treatment of dermatologic disorders

“…Skin is distinctively advantaged as a surface-accessible organ and thus amenable to a variety of therapeutic opportunities, including systemic (Al-Jaderi & Maghazachi, 2016;Al-Sawaf et al, 2015;Ferrándiz et al, 2018;Mrowietz et al, 2018;Vollmer, West, & Lephart, 2018) and/or localized/topical activation of Nrf2 (Abdelsalam, Samak, & Alsemeh, 2019;Hwang, Gao, Xiao, Ngo, & Yi, 2018;Ikehata & Yamamoto, 2018;Jadkauskaite et al, 2017;Kunnumakkara et al, 2017; T A B L E 1 Selected examples illustrating the participation and role of skin at the center of biological functions and health Long et al, 2015;Mathers et al, 2018;Panahi et al, 2019;Siegenthaler et al, 2018;Vega et al, 2017;Vega, Zhang, & Wondrak, 2018;Vollmer et al, 2018;Zeng & Lu, 2018). One example, ozone therapy, is increasingly considered a practical treatment in dermatology (Wang, 2018;Zeng & Lu, 2018).…”

“…Nrf2-activating compounds are becoming staple ingredients in topically applied skin-conditioning creams and other formulations that mitigate skin damage (Ahmed, 2019;Ben-Nun, 2018;Braidy et al, 2019;Burke, 2018;Davinelli, Nielsen, & Scapagnini, 2018;Gorini et al, 2019;Huang, Wang, Yang, Chou, & Fang, 2018;Kocot, Kiełczykowska, Luchowska-Kocot, Kurzepa, & Musik, 2018;Kunnumakkara et al, 2017;Lephart, 2018;Ríos, Giner, Marín, & Recio, 2018;Rodríguez-Luna et al, 2018;Simitzis, 2018;Vega et al, 2017Vega et al, , 2018Vollmer et al, 2018;Yokota, Yahagi, & Masaki, 2018), promote skin repair (Bellot et al, 2019;Davinelli, Nielsen, & Scapagnini, 2018;Ferreira & Gomes, 2018;, and enhance diabeticassociated wound healing (Bellot et al, 2019;Ben-Nun, 2018;Cuadrado et al, 2019;Ferreira & Gomes, 2018;Gorini et al, 2019;Huang et al, 2018;Kocot et al, 2018;Kunnumakkara et al, 2017;Panahi et al, 2019;Ríos et al, 2018;Sanchez, Lancel, Boulanger, & Neviere, 2018;Vega et al, 2017;Vega et al, 2018;Vollmer et al, 2018).…”