Abstract
The skin barrier and its endogenous protective mechanisms cope daily with exogenous stressors, of which ultraviolet radiation (UVR) poses an imminent danger. Although the skin is able to reduce the potential damage, there is a need for comprehensive strategies for protection. This is particularly important when developing pharmacological approaches to protect against photocarcinogenesis. Activation of NRF2 has the potential to provide comprehensive and long-lasting protection due to the upregulation of numerous cytoprotective downstream effector proteins that can counteract the damaging effects of UVR. This is also applicable to photodermatosis conditions that exacerbate the damage caused by UVR. This review describes the alterations caused by UVR in normal skin and photosensitive disorders, and provides evidence to support the development of NRF2 activators as pharmacological treatments. Key natural and synthetic activators with photoprotective properties are summarized. Lastly, the gap in knowledge in research associated with photodermatosis conditions is highlighted.
| Original language | English |
|---|---|
| Pages (from-to) | 262-276 |
| Number of pages | 15 |
| Journal | Free Radical Biology and Medicine |
| Volume | 188 |
| DOIs | |
| State | Published - 1 Aug 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors
Funding
The skin and more specifically, the SC within the epidermal layer is the most exposed layer of the human body. SC is the outermost layer of the epidermis and it is mainly surrounded by enriched lipid matrix which provides support to maintain proper SC barrier integrity and function [17]. One of the important functions of the epidermis is to maintain homeostasis. For instance, regulation of water evaporation from the body to the atmosphere (trans-epidermal water loss (TEWL)) is imperative. In addition, the skin acts as the principal gatekeeper, reducing or blocking chemicals, pollutants, microbes and other environmental stressors systemic absorption [18]. This layer is also contributing to the protection from UVR. Although the effect of UVR on the epidermal barrier function is still incompletely understood, recent studies show that exposure to UVR, and mainly UVB radiation, affects epidermal morphology. This includes compensatory increase in the mean SC thickness, and disruption of the permeability barrier which causes morphological changes in SC lipids, and increased epidermal water loss [19–21]. The barrier properties are also tightly linked to keratinocyte differentiation, keratin synthesis and the generation of desmosomes, which are all regulated by cytokines and UV-induced inflammation in the skin (reviewed in Ref. [22]). In addition, it was shown that this exposure poses a threat to the skin by increasing biomechanical driving force for damage while decreasing the skin's natural ability to resist, compromising the critical barrier function of the skin [21]. Lipsky and German have recently determined the mechanical properties of isolated SC under UVR exposure and found that both UVA and UVB radiation cause mechanical and structural degradation [23]. Regardless of these harmful effects, UVB radiation was shown to have positive compensatory effects on the epidermal barrier when administered in low doses and over a relatively short period [24,25]. This therapeutic strategy is being used for the treatment of skin diseases with a disrupted epidermal barrier, such as atopic dermatitis, avoiding the possible side effects by applying only reduced intensity and exposure.This review is based upon collaboration initiated by COST Action CA20121 “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases”, supported by COST (European Cooperation in Science and Technology). G.C. and S.K. are thankful for the support of their work by the Israel Ministry of Science and Technology, Regional R&D Centers, Scholarship number 3–16752. A.T.D.-K. is grateful to Cancer Research UK (C20953/A18644), the BBSRC (BB/T017546/1 and BB/T508111/1), the Ninewells Cancer Campaign, and Reata Pharmaceuticals for supporting research in her laboratory. This review is based upon collaboration initiated by COST Action CA20121 “Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases”, supported by COST ( European Cooperation in Science and Technology ). G.C. and S.K. are thankful for the support of their work by the Israel Ministry of Science and Technology , Regional R&D Centers, Scholarship number 3–16752. A.T.D.-K. is grateful to Cancer Research UK (C20953/A18644), the BBSRC (BB/T017546/1 and BB/T508111/1), the Ninewells Cancer Campaign, and Reata Pharmaceuticals for supporting research in her laboratory.
| Funders | Funder number |
|---|---|
| Israel Ministry of Science and Technology , Regional R&D Centers | 3–16752 |
| Israel Ministry of Science and Technology, Regional R&D Centers | |
| Ninewells Cancer Campaign | |
| Reata Pharmaceuticals | |
| UVR | |
| Biotechnology and Biological Sciences Research Council | BB/T017546/1, BB/T508111/1 |
| Cancer Research UK | C20953/A18644 |
| European Cooperation in Science and Technology | CA20121 |
Keywords
- NRF2
- Pharmacological intervention
- Photocarcinogens
- Photodamage
- Photodermatosis
- Sulforaphane
- UVA
- UVB
- Ultraviolet