Antioxidative, Anti-Inflammatory, And Anti-Aging Properties Of Mycosporine-Like Amino Acids

Keywords: mycosporine-like amino acids; mycosporine-2-glycine; UV-absorbing compound; sunscreen; anti-aging; anti-oxidation; anti-inflflammation; anti-protein-glycation activity

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1. Introduction

The skin, the largest human organ, is constantly exposed to the external environment. Exposure to a variety of environmental stress factors, particularly ultraviolet (UV) radiation in sunlight, can damage skin. Sunlight can be broken down into three types of nonionizing electromagnetic radiation—infrared (IR) (780–3000 nm), visible (400–780 nm), and UV (100–400 nm). The percentages of energy radiated to the Earth, in the total energy emitted by the Sun, are 53% IR, 39% visible, and 8% UV [1]. On the basis of its physiological and biological effffects, UV radiation can be further divided into three main bands—the 315–400 nm band (designated as UV-A), the 280–315 nm band (designated as UV-B), and the 100–280 nm band (designated as UV-C) [2]. Solar UV radiation is drastically diminished as it passes through the ozone layer and the atmosphere; as a result, the proportion of UV rays in the sunlight reaching the Earth’s surface, is made up of 95% UV-A and 5% UV-B [1]. Although it comprises only a small portion of the total UV radiation, UV-B is thought to be more harmful than UV-A, since UV-B is most active in damaging the skin and eyes [3]. UV-A and UV-B are also known to be genotoxic, meaning they can induce photochemical damage in cellular DNA and proteins [4,5]. Consequently, exposure to UV-A and UV-B, stimulates skin photoaging and can be responsible for the induction of skin cancer [6]. Skin photoaging is characterized by the development of pigmentary disorders, such as solar lentigines, fifine and coarse wrinkles, and benign, premalignant, and malignant skin tumors on sun-exposed skin [7]. Highly energetic UV-C radiation has no biological signifificance, because it does not reach the Earth’s surface, due to its complete absorption by the ozone layer and the atmosphere [1,3]. The depletion of the ozone layer, over the past few decades, has increased the amount of solar UV radiation reaching the Earth’s surface [8], in particular UV-B levels, since UV-A is not absorbed by the ozone layer [9]. Many marine organisms that are exposed to UV radiation have developed photoprotective mechanisms [10]. For example, in cyanobacteria, which dominate the marine environment, UV protection mechanisms have evolved at the molecular, cellular, and behavioral levels [11]. Cyanobacteria can synthesize various types of “sunscreen” compounds, which confer protection against UV radiation. Mycosporine-like amino acids (MAAs), scytonemin, and carotenoids are known to be key compounds in cyanobacteria that can absorb wavelengths in the UV range. These natural products are promising candidate molecules in the fifield of cosmeceutical compounds discovery [12]. In fact, MAAs have already been commercialized as Helioguard®365. This cosmetic reagent contains the liposomal MAAs, shinorine (SHI), and porphyra-334 (P334), that were originally extracted from the red alga Porphyra umbilicalis, and has been successfully commercialized as a natural and safe sunscreen compound [12]. Additionally, MAAs are thought to be multifunctional secondary metabolites, in the cells of producers [13]. Many MAAs are known to act as antioxidants [14], while several recent reports have suggested that MAAs have potential therapeutic applications for reducing skin-aging processes. From this point of view, recently, several review reports with special emphasis on the potential use of MAAs in cosmetic products, have been published [15–17]. In this paper, we review MAAs and their potential as anti-skin-aging ingredients, by describing a basic overview of their structure, before moving on to a detailed account of the most recent experimental observations, accumulated thus far. The mechanisms by which MAAs might act to protect the skin from aging is discussed at, both, the cellular and the molecular level. In particular, the prominent potential anti-aging activity of the MAA mycosporine-2-glycine (M2G), which is biosynthesized by the halotolerant cyanobacterium Aphanothece halophytica, is highlighted.

2. Mechanisms of the UV-Induced Skin Aging

UV radiation is important for our health as UV-B exposure can induce the production of a crucial nutrient, vitamin D, in our skin [18]. However, long-term and repeated exposure to UV can promote the skin photoaging process, including skin cancer formation [19]. The mechanisms by which UV-mediated cellular damage is induced are brieflfly described in this section. 2.1. Cellular DNA Damage Direct and indirect toxic effffects of UV radiation on the DNA molecule, mediate photoaging. Direct absorption of UV-B photons by DNA, can result in the generation of pyrimidine dimers, leading to defects in the DNA strand [20]. UV-B radiation leads mostly to the formation of cis-syn cyclobutadipyrimidines (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). 6-4PPs can be converted into related Dewar valence isomers (DewPPs), upon UV-excitation at 314 nm. Such DNA damage interferes with DNA replication and transcription, and brings various harmful effffects to the cell, such as mutation, instability of the chromosome, and cell death. UV-A does not directly alter the structure of DNA as DNA does not strongly absorb radiation in the UV-A range [21]. However, UV-A can damage DNA indirectly, via a photosensitized reaction mediated by generating the radical singlet oxygen (1O2), resulting in purine base modififications [20]. The singlet oxygen anion oxidizes the guanine moiety, followed by the generation of 8-oxo-7,8-dihydroguanine (8-oxo-G) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dG). As 8-oxo-G and 8-oxo-dG can associate with adenine instead of cytosine, transition mutations might occur. 2.2. Reactive Oxygen Species Generation Reactive oxygen species (ROS), initiators of oxidative stress, are oxygen-containing reactive chemical species that include hydrogen peroxide (H2O2), hydroxyl radicals (·OH), superoxide anion radicals (·O2 −), and 1O2. In our skin, exposure to UV radiation is known to be associated with the generation of ROS. These ROS can activate skin-aging cascades, such as matrix metalloproteinase (MMP)-1-mediated aging and NF-κB-TNF-α-mediated, inflflammation-induced aging [22]. The variety of ROS generation mechanism by UV, depend on the UV radiation wavelength range. In addition to 1O2 generation, as mentioned above, it has been reported that UV-A radiation can induce the generation of ·O2 − by the activation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NOX [23], and association with advanced glycation end-products (AGEs) [24]. Sakurai et al. elucidated that both 1O2 and ·O2 - were generated in the skin of mice exposed to UV-A [25]. H2O2, ·O2 −, and ·OH species might be generated in AGEs, during exposure to UV-A [24]. UV-B is also known to lead to the production of H2O2, ·O2 −, and ·OH [26]. Although the source of these UV-B-induced ROS remains unclear, recently it was reported that NADPH oxidase, NOX1, is associated with UV-B-induced p38/MAPK activation and cytotoxicity, via ROS generation in keratinocytes [26]. To prevent skin damage induced by excess UV-induced ROS and regulate epidermal homeostasis, skin cells possess an antioxidative function that acts as an endogenous defense system [20]. This system mainly consists of six enzymes—superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), thioredoxin oxidase (TRXR), and peroxiredoxin (PRDX) (Figure 1). SOD and CAT eliminate ·O2 − and H2O2, respectively, and ultimately convert ·O2 − to H2O, whereas GPX, GR, TRXR, and PRDX eliminate H2O2, by regulation of the redox conditions of glutathione and thioredoxin. In addition to this enzymatic system, non-enzymatic molecules, such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), glutathione, and ureic acid, play a major role as antioxidants in the skin [27]. These small molecules scavenge and neutralize free radicals, by providing an extra electron to make an electron pair.

Figure 1. Removal of reactive oxygen species (ROS) by an antioxidant defense system consisting of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), thioredoxin oxidase (TRXR), and peroxiredoxin (PRDX). GSHred and GSSGox indicate reduced glutathione and oxidized glutathione, respectively. TRXred and TRXox indicate reduced thioredoxin and oxidized thioredoxin, respectively.

2.3. Inflammatory Responses

Exposure to UV radiation induces inflammation by triggering chemical reactions in the skin. Distinct patterns of inflammation are caused by exposure to specific wavelengths of light. The three groups, UV-A, UV-B, and UV-C, have been classifified, based on these difffferent patterns of inflflammation [28]. Erythema induced in the skin, following exposure to UV-B radiation is characterized as sunburn. Inflflammatory responses induced by UV-B are mostly achieved through a variety of mediators, including nitric oxide (NO), inducible NO synthase (iNOS), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and other cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6) (Figure 2). These molecules are predominantly regulated by nuclear factor-kappa B (NF-κB), and mostly produced in keratinocytes, which are the predominant cell type in the epidermis [29]. It has been reported that the expression of the COX-2 protein, which is responsible for PGE2 production, is upregulated, following exposure to UV-B, in both human skin and in cultured human keratinocytes [30]. ROS are also known to be associated with the inflflammatory response, as it has been observed that COX-2 expression was induced by ROS in difffferent cell types [31]

Figure 2. UV-B-induced inflflammatory response. Nitric oxide (NO), inducible NO synthase (iNOS),prostaglandin E2 (PGE 2), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and other cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), are shown as mediators. 

2.4. Induction of Matrix Metalloproteinases

UV radiation upregulates the expression of matrix metalloproteinases (MMPs) in the skin. MMPs, which are known to be responsible for the destruction of extracellular matrix (ECM) proteins, such as collagen, play an important role in maintaining skin homeostasis and skin aging [32]. MMPs are secreted by keratinocytes and dermal fifibroblasts, in response to multiple stimuli, including oxidative stress and cytokines, in addition to UV radiation. The repeated induction of these collagen-degrading enzymes, over the long-term, is thought to cause collagen damage, which is one of the reasons for photoaging. Although several MMPs are expressed in the mammalian skin, it has been suggested that MMP-1 is the major collagen-degrading enzyme responsible for collagen destruction, in severely photo-damaged skin [33]. The upregulation of MMP expression is stimulated by the activator protein-1 (AP-1), which is known to be a UV-inducible transcription factor [34]. In fact, AP-1 regulatory element exists in the 5’ flflanking region of MMP genes. Transforming growth factor-beta (TGF-β) and NF-κB are also known to be involved in the induction of MMPs in the skin [34].

2.5. Induction of Protein Glycation

Protein glycation (non-enzymatic glycosylation), also known as the first step of the Maillard reaction, involves the formation of covalent bonds between proteins and reducing sugars. A condensation reaction between the free amino groups of proteins and the carbonyl groups of sugars, results in the formation of a Schiff base, followed by an Amadori product. Excessive products are oxidized and dehydrated to form stable, molecular, cross-linking products, called advanced glycation end-products (AGEs) [35]. Protein glycation inflfluences the physical and functional properties of a protein, as it causes conformational changes in the protein structure [36]. In skin, it has been reported that glycation of collagen type I is associated with the development of skin dullness and decreased skin elasticity [37]. AGEs are also involved in the generation of ROS. Masaki et al. reported that exposure of AGEs to UV-A irradiation in vitro, resulted in the generation of ROS, such as ·O2 −, H2O2, and ·OH, as mentioned above [24]. In humans, skin autoflfluorescence, a biomarker for AGEs, can function as an endogenous photosensitizer that induces ROS generation, following exposure to UV-A radiation [35]. Thus, a glycation reaction followed by AGE formation is thought to be one of the fundamental mechanisms associated with skin aging, under environmental conditions, especially UV radiation [24].

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