Role of Phytochemicals in Skin Photoprotection via Regulation of Nrf2

Abstract

Ethnopharmacological studies have become increasingly valuable in the development of botanical products and their bioactive phytochemicals as novel and effective preventive and therapeutic strategies for various diseases including skin photoaging and photodamage-related skin problems including abnormal pigmentation and inflammation. Exploring the roles of phytochemicals in mitigating ultraviolet radiation (UVR)-induced skin damage is thus of importance to offer insights into medicinal and ethnopharmacological potential for development of novel and effective photoprotective agents. UVR plays a role in the skin premature aging (or photoaging) or impaired skin integrity and function through triggering various biological responses of skin cells including apoptosis, oxidative stress, DNA damage and inflammation. In addition, melanin produced by epidermal melanocytes play a protective role against UVR-induced skin damage and therefore hyperpigmentation mediated by UV irradiation could reflect a sign of defensive response of the skin to stress. However, alteration in melanin synthesis may be implicated in skin damage, particularly in individuals with fair skin. Oxidative stress induced by UVR contributes to the process of skin aging and inflammation through the activation of related signaling pathways such as the mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1), the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), the nuclear factor kappa B (NF-κB) and the signal transducer and activator of transcription (STAT) in epidermal keratinocytes and dermal fibroblasts. ROS formation induced by UVR also plays a role in regulation of melanogenesis in melanocytes via modulating MAPK, PI3K/Akt and the melanocortin 1 receptor (MC1R)-microphthalmia-associated transcription factor (MITF) signaling cascades. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated antioxidant defenses can affect the major signaling pathways involved in regulation of photoaging, inflammation associated with skin barrier dysfunction and melanogenesis. This review thus highlights the roles of phytochemicals potentially acting as Nrf2 inducers in improving photoaging, inflammation and hyperpigmentation via regulation of cellular homeostasis involved in skin integrity and function. Taken together, understanding the role of phytochemicals targeting Nrf2 in photoprotection could provide an insight into potential development of natural products as a promising strategy to delay skin photoaging and improve skin conditions.

Keywords: Nrf2; inflammation; photoaging; phytochemicals; skin barrier dysfunction.

FIGURE 1

Chemical structures of the different classes of phenolic compounds including phenolic acids, flavonoids, stilbenes and lignans. Phenolic compounds are classified into different groups on the basis of the number of phenolic rings they contain and of the structural elements binding the rings to one another. They are generally divided into four classes including phenolic acids, flavonoids, stilbenes and lignans. Phenolic acids are further classified as hydroxyl benzoic and hydroxyl cinnamic acid derivatives (Johnsson, 2004; Nishiumi et al., 2011).

FIGURE 2

The role of phytochemicals in skin photoprotection via regulation of Nrf2 signaling. Phytochemicals are naturally occurring compounds in botanical products which exert biological activities providing medical and nutritional benefit. Oxidative stress, an imbalance in the redox state of the cell, is the result of cellular response to various stimuli including UV and ionizing radiation, pollution, contaminants, heavy metal, pathogens, and chemical reagents. Most of the natural antioxidants are derived from plant materials such as fruits, vegetables, grains, legumes, botanical drugs, spices and plant-based beverages (including tea, coffee, wine and cocoa). The bioactive phytochemicals, e.g., isothiocyanates (in broccoli, brussels sprouts, cabbage and cauliflower), flavonoids, carotenoids, resveratrol and stilbinoid, exhibit a wide range of photoprotective effects, including anti-photoaging, anti-inflammation, and anti-melanogenesis. These protective effects involve activation of nuclear factor erythroid 2-related factor 2 related to the antioxidant response element (Nrf2-ARE) signaling pathway that regulates expression of its downstream target genes including glutamate cysteine ligase (GCL), glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1) and other antioxidant genes, to cope with various stressors including UVR. The thick arrows and bar-headed lines mean activation and inhibition of the pathway, respectively. The dash arrow means modulation of Nrf2 signaling by ROS levels.

FIGURE 3

The regulatory mechanism of Nrf2-dependent antioxidant and cytoprotective actions against photoaging, inflammation and hyperpigmentation. Phytochemicals play a photoprotective role against skin photodamage directly via scavenging reactive oxygen species (ROS) and indirectly via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, leading to upregulation of antioxidant and cytoprotective genes. In response to ultraviolet ray (UVR)-induced oxidative stress, ROS, produced in keratinocytes, melanocytes and fibroblasts, can modulate several related signaling pathways involved in photoaging, inflammation and melanogenesis. Exposure of human skin to UVR causes cells to produce ROS, which can modulate the signaling pathways involved in upregulation of matrix metalloproteinases (MMPs) which includes MMP-1/3/9, leading to collagen degradation, inflammation (nuclear factor kappa B also known as NF-κB and its downstream signaling) and the upregulation of melanogenesis-related genes including the microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), and tyrosinase related proteins (TRP-1). Dietary phytochemicals as natural sources of antioxidants play the protective roles against UVR-induced ROS by the inhibition of ROS formation and the activation of Nrf2 signaling. In response to oxidative insults, Nrf2 is activated by the phosphorylation and disassociation of Nrf2 from Kelch-ECH associated protein 1 (Keap1), a repressor protein in the cytoplasm. Then, Nrf2 translocated to the nucleus binds to the ARE in the promoter region of downstream genes encoding antioxidant and phase II detoxifying enzymes including glutamate cysteine ligase (GCL), glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1). The activation of Nrf2 improves oxidative status of the cells and promotes cytoprotection against skin oxidative damage and inflammation. The black/red arrows and bar-headed lines mean activation and inhibition of the pathway, respectively. The dash arrow means dissociation of the Keap1–Nrf2 complex.