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Nutritional protection against photooxidative stress in human skin and eye
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Nutritional protection against photooxidative stress in human skin and eye
20 Wilhelm Stahla, Helmut Siesa,b
a
Faculty of Medicine, Institute of Biochemistry and Molecular Biology I, Heinrich-HeineUniversity Düsseldorf, Düsseldorf, Germany b Leibniz Research Institute for Environmental Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Abstract Light-exposed tissues are affected by photooxidative stress that causes and promotes diseases, including skin cancer and cataract and age-related macular degeneration (AMD). Nutrition supplies components for powerful enzymatic and nonenzymatic defense systems. Among the micronutrients, carotenoids and flavonoids from dietary sources have been examined for their activity in studies with healthy human volunteers. Carotenoids like β-carotene, lycopene, phytoene, and phytofluene protect against UV-induced erythema largely by radical scavenging, absorption of UV light, and quenching singlet molecular oxygen. Effects are moderate, and additional protection is required at high levels of exposure to UV light in particular. Supplementation with lutein may help to prevent the onset or progression of AMD. Keywords: Photoprotection, Diet, Nutrition, Antioxidants, Sunburn, Erythema, Skin cancer, Melanoma, Cataract, Age-related macular degeneration
Introduction Upon light exposure, an array of chemical and biological reactions ensues in lightexposed target tissues, namely, the skin and the eye. An electronically excited photosensitizer can react to form radical intermediates in Type I reactions via electron or hydrogen transfer (Fig. 1). These include reactive oxygen species (ROS), oneelectron oxidation products of nucleotide bases or amino acids such as the guanine radical or tyrosine radical, respectively. In Type II reactions, singlet molecular oxygen (1O2) is generated by the transfer of energy from the excited photosensitizer to ground-state oxygen (see Blazquez-Castro et al., this book; Baptista, Cadet, et al., 2017; Di Mascio, Miyamoto, et al., 2019). Singlet oxygen is prone to react with Oxidative Stress. https://doi.org/10.1016/B978-0-12-818606-0.00020-1 © 2020 Elsevier Inc. All rights reserved.
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FIG. 1 Direct and indirect formation of reactive oxygen species following light exposure. Implication of photooxidative stress on signaling and damage. CPD, cyclobutane dimer.
dienes and adds to unsaturated fatty acids, DNA bases, and aromatic amino acids, generating peroxides (Briviba, Klotz, & Sies, 1997). The latter may decompose to radicals or react directly with other biomolecules and induce lipid peroxidation. UVB light is of sufficient energy to cleave hydrogen peroxide or lipid hydroperoxides in a homolytic reaction yielding the respective radical intermediates, which damage biomolecules (Brenneisen, Sies, & Scharffetter-Kochanek, 2002; Kammeyer & Luiten, 2015). Photooxidative damage provokes biochemical responses including inflammation or immune response. As a consequence, further ROS such as superoxide, H2O2, or peroxynitrite is generated. Photooxidative damage is employed in photodynamic therapy (PDT), where photosensitizer-dependent reactions are used to eliminate skin cancerous cells (Kessel & Oleinick, 2018). The concept of oxidative stress has been expanded, distinguishing between eustress and distress (Sies, Berndt, & Jones, 2017). While intense oxidative challenge causes damage (distress), the maintenance of physiological levels of the redox tone (eustress) is required for the regulation of biochemical processes via redox signaling. Redox regulation utilizes thiol-driven master switches like Nrf2/Keap1 or NFκB/IκB. In the context of direct and indirect ROS formation, dietary antioxidants serve as possible protectants, notably carotenoids and flavonoids (Parrado, Philips, et al., 2018; Sondenheimer & Krutmann, 2018). Enzymatic defense systems against photooxidative stress in the skin and eye play important roles. Here, we address the concepts of photoprotection of light-exposed tissues with exogenous, dietary constituents, focusing on results from human studies.
Skin
Skin Skin consists of multiple layers: epidermis and dermis, connected to subcutaneous and adipose tissue. Light penetrating the skin interacts with biological structures at the different layers. The depth of light penetration depends on structural features and on pigmentation; the longer the wavelength, the deeper the penetration. UVA and visible light reach the dermis and to some extent also the subcutis, whereas UVB practically does not pass beyond the epidermal layer. Most of the severe consequences of UV exposure are attributed to UVB. However, UVA radiation is also involved in processes of photoaging and photocarcinogenesis, playing a major role in the pathogenesis of photodermatoses (Gilchrest, 2013; Nishisgori, 2015). However, photochemical interactions are not only responsible for adverse effects (distress). The biosynthesis of vitamin D3 is due to UVB-dependent photocleavage of the precursor 7-dehydrocholesterol (eustress). Season, latitude, life style, and pigmentation have an impact on the efficacy of synthesis of vitamin D3. The use of sunscreen has been debated in this context. Further, induction of the α-melanocytestimulating hormone (α-MSH) is to be mentioned as well, stimulating pigment production by melanocytes and thereby contributing to UV protection (Hoel, Berwick, de Gruijl, & Holick, 2016; Nguyen & Fisher, 2019).
Skin cancer Sunlight is a strong genotoxic agent, and UV radiation is a primary cause in photocarcinogenesis, leading to squamous cell carcinoma, basal cell carcinoma, and melanoma. A major initial mechanism of action is related to UV-induced generation of DNA modification with cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts, typically ascribed to be the most efficient under UVB irradiation (see Epe, this book; D'Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Additionally, oxygen-dependent DNA damage after UV exposure is attributed to photosensitizing reactions, which involve endogenous or exogenous photosensitizing molecules. DNA damage can be assessed as DNA base oxidation products such as 8-oxoGua as a biomarker of oxidative DNA damage (Dąbrowska & Wiczkowski, 2017; Obrador, Liu-Smith, et al., 2019). Accumulation of DNA damage in mitochondria has been associated with cancer development in many tissues, including the human skin. The “common deletion” of mtDNA is associated with UV exposure (Berneburg, Grether-Beck, et al., 1999). Impact on carcinogenesis has been related to the mitochondrial respiratory chain (Birch-Machin, Russell, & Latimer, 2013). Exposure to sunlight predominantly induces pyrimidine dimers, with lower amounts of 8-oxoGua and strand breaks (Cadet & Douki, 2018). Models of photocarcinogenesis suggest that UVB-induced mutation initiates skin cancer, while UVA-related signal interference acts in the promotion of the malignant state (Nishisgori, 2015).
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A novel mechanism for delayed formation of CPDs has been identified in melanocytes (Premi, Wallisch, et al., 2015). It comprises a UVA-initiated reaction sequence that leads to a so-called dark reaction to the generation of “dark CPDs” and implicates intermediate generation of excited triplet state molecules. Synthesis of melanin and the expression of iNOS and NADPH oxidases (NOX) are induced. iNOS and NOX generate their metabolites nitric oxide and superoxide, respectively, which efficiently combine to peroxynitrite. The latter reacts chemically with the pigment melanin, present in the melanocytes. Degradation products of melanin transfer to the nucleus where they are prone to lead to dioxetanes and other products. 1,2-Dioxetanes are metastable, decomposing thermolytically, thereby generating carbonyl compounds in the electronically excited triplet state (Cilento & Adam, 1995). Quenching of the triplet state molecules occurs by energy transfer with ground-state oxygen to yield singlet oxygen, light emission (luminescence) or by dissipation of energy interacting with surrounding water molecules generating thermal energy (Mano, Prado, et al., 2014). However, in the presence of suitable acceptor molecules, energy could also be transferred and used to promote a reaction such as 2 + 2 cycloaddition. In such a sequence of reactions, “dark dimers” are formed. It should be noted, however, that the biosynthesis of melanin is also induced by UV light, and the presence of the polymer in the skin is unequivocally important for the protection of cells against UV radiation (Nguyen & Fisher, 2019). Thus, there appears to be a balance between protection and contribution to damage. Proteins also are targets for UV-induced ROS, impinging on protein functions, e.g., in signaling cascades or damage repair. UVA-dependent oxidation of DNA repair proteins interferes with DNA repair efficiency (Karran & Brem, 2016). Supplementation with dietary antioxidants was suggested as a strategy for preventing cancer development due to photooxidative damage. In particular, vitamins C and E and carotenoids have been studied in this context. Although their photoprotective properties were proven in vitro, meta-analysis of intervention trials indicated no support to an overall primary and secondary preventive effect of supplementation with dietary antioxidants on skin cancer (Chang, Myung, et al., 2011).
Erythema UV-induced solar erythema (sunburn) is commonly observed when the skin is excessively exposed to sunlight. Sunburn is associated with red or reddish skin, elevated skin temperature, pain, blistering, general fatigue, and second-degree burns. A typical solar erythema develops within a few hours and culminates around 24 h after irradiation. Sunburn is an immediate inflammatory response to UV exposure (Clydesdale, Dandie, & Muller, 2001). Cells that are irreversibly damaged by UV exposure undergo apoptosis, visible as so-called sunburn cells in the epidermis. Individual sensitivity toward erythematogenic UV exposure is characterized by the minimal erythemal dose (MED), which is the lowest dose of UV radiation that will produce a barely detectable erythema 24 h after exposure. UV sensitivity differs between individuals and depends on endogenous protection by melanin and on skin type.
Skin
Sunscreens are used for efficient protection against UVA and UVB radiation. However, >70% of an average annual UV dose is experienced during everyday life without protection by a sunscreen (Godar, 2001). Strengthening endogenous antioxidant defense might improve UV resistance of the organism. Dietary antioxidants came into focus, with several structurally different classes of dietary components serving in endogenous photoprotection (Sies & Stahl, 2004; Rabinovich & Kazlouskaya, 2018, Pérez-Sánchez, Barrajón-Catalán, et al., 2018).
Carotenoids Carotenoids, widespread colorants in nature, are supplied with the diet. Major carotenoids in human blood and tissue are β-carotene, lycopene, lutein, β-cryptoxanthin, α-carotene, and zeaxanthin, as well as phytoene and phytofluene, intermediate products of carotenoid biosynthesis (Stahl & Sies, 2005). β-Carotene, β-cryptoxanthin, and lutein are found in a variety of fruit and vegetables. Dietary lycopene derives mainly from tomato and corn is the major source for zeaxanthin. Carotenoids contain an extended system of 9–11 conjugated double bonds, responsible for their color (absorption maxima around 450 nm). This core structure is substituted with different cyclic and acyclic end groups, in the case of xanthophylls like lutein and zeaxanthin modified by oxygen functions. Phytoene and phytofluene, however, exhibit only three and five double bonds, and their UV spectra show maxima in the UVB and UVA range, respectively. Carotenoids are among the most efficient natural scavengers of singlet molecular oxygen (1O2) and excited triplet state molecules (Conn, Schalch, & Truscott, 1991; Di Mascio, Kaiser, & Sies, 1989). Their quenching activity is related to the number of conjugated double bonds with rate constants in the order of 109 M−1 s−1. Carotenoids also efficiently scavenge peroxyl radicals. Independent of their antioxidant activity, several other biological properties have been assigned to carotenoids, mostly related to cellular signaling. Carotenoids have been used to ameliorate symptoms of photosensitivity disorders (e.g., porphyrias) and for systemic protection of the skin against damage following sun exposure (Stahl & Sies, 2012). Dietary supplements with β-carotene as active constituent are employed as oral sun protectants. Protection was observed when treatment was for at least 10 weeks and at doses >20 mg of β-carotene per day (Biesalski, Hemmes, Hopfenmuller, et al., 1996; Lee, Jiang, Levine, & Watson, 2000; MathewsRoth, Pathak, et al., 1972; Stahl, Heinrich, et al., 2000), whereas no protection was reported when β-carotene was applied for only 3–8 weeks and at lower dose levels (Garmyn, Ribaya-Mercado, et al., 1995; McArdle, Rhodes, et al., 2004). Duration of β-carotene supplementation for protection against sunburn was confirmed as being critical in a meta-analysis comprising seven original studies (Köpcke & Krutmann, 2008). The use of ß-carotene as a photoprotectant at doses above 10–20 mg/day was questioned when adverse effects upon long-term treatment emerged in intervention studies reporting an increased risk for lung cancer (Biesalski & Obermueller-Jevic, 2001).
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Therefore, ß-carotene was partially or completely substituted by other carotenoids to decrease the daily dose. A direct comparison revealed that carotenoid mixtures are as effective as ß-carotene alone (Heinrich, Gärtner, et al., 2003). Lycopene was among the first carotenoids as alternate for ß-carotene, quenching singlet oxygen, as mentioned, and also scavenging free radicals, thus interfering with lipid oxidation (Eichler, Sies, & Stahl, 2002). Photoprotective effects of lycopene-rich dietary items were studied with tomato paste and lycopene-rich juices, carrot juice from a specific lycopene-rich variety (Aust, Stahl, et al., 2005). The sunburn reaction of the participants following irradiation with a solar light simulator was significantly decreased upon ingestion of dietary lycopene. These studies provide evidence that dietary sources can provide sufficient amounts of lycopene for endogenous photoprotection. When lycopene supplements derived from tomato extracts were tested against synthetic lycopene, it was shown that the tomato-based products were efficient in photoprotection, whereas no statistically significant effect was obtained with synthetic lycopene (Aust et al., 2005). There is evidence that additional constituents of the tomato products contribute to photoprotection. Among them, the UV-absorbing compounds phytofluene and phytoene are likely to be active (Meléndez-Martínez, Stinco, & Mapelli-Brahm, 2019). Photoprotective effects were also determined at the level of gene expression with a tomato-based supplement providing lycopene, phytoene, phytofluene, tocopherols, and phytosterols (Grether-Beck, Marini, et al., 2017; Groten, Marini, et al., 2019). Supplementation inhibited UVA1- and UVA/B-induced expression of heme oxygenase-1 (HO-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metallopeptidase 1 (MMP-1). The lycopene supplement protected against UVB-induced erythema and UVB-induced upregulation of IL6 and TNFα. Lutein, at the same dose level, showed less pronounced effects. The photoprotective properties of carotenoids have been determined in several human intervention studies (Palombo, Fabrizi, et al., 2007; Rizwan, Rodriguez-Blanco, et al., 2011), corroborated by numerous cell culture and animal studies (Camera, Mastrofrancesco, Fabbri, et al., 2009). Other members of the carotenoid group may be active in UV protection, including astaxanthin (Komatsu, Sasaki, et al., 2017), fucoxanthin (Matsui, Tanaka, et al., 2016), or aromatic carotenoids like dihydroxy isorenieratene (Martin, Kock, et al., 2009). It should be noted, however, that systemic protection due to the ingestion of carotenoids is not comparable with the localized use of a sunscreen in terms of efficiency. However, boosting the basal protection systemically contributes to life-long defense against UV-dependent skin damage, also in skin areas not usually protected by sunscreens.
Vitamins E and C Vitamin E comprises a group of structurally related molecules, tocopherols and tocotrienols. Due to their chromane ring system, E-vitamers show radical scavenging properties. Their antioxidant function in the human organism is related to the inhibition of lipid peroxidation, thus protecting membranes from oxidative damage.
Skin
Since UV irradiation induces lipid peroxidation in vitro, vitamin E may contribute to systemic photoprotection (Packer & Valacchi, 2002). However, there is limited evidence from human intervention studies that supplementation with vitamin E provides protection against UV-induced skin damage (Fuchs, 1998). Vitamin C (ascorbate) is a cofactor of enzymes; it is a water-soluble dietary antioxidant. No convincing effects on skin protection were determined in human studies (McArdle, Rhodes, et al., 2002).
Flavonoids Flavonoids as secondary plant constituents protect plants against bacterial or fungal infections, herbivores, and excess UV irradiation. Humans ingest them with fruits, vegetables, and herbs. Epicatechin and catechin occur in cocoa, green tea, cinnamon, and in several fruits such as apple, apricot, grape, peach, and berries. Quercetin occurs in kale, onions, and grapes; naringenin in grapefruit; and hesperidin in oranges or luteolin in bell pepper. Flavonoids absorb UV light with absorption maxima usually within the UV range. Due to their polyphenolic ring systems, flavonoids efficiently scavenge radicals and are oxidized in two-electron transfer reactions to quinones. However, their radical scavenging activity in vivo is questionable since they are efficiently conjugated in first pass metabolism, which blocks phenolic hydroxyl groups relevant for antioxidant activity. Intervention trials documented protective effects of flavonoid-rich foods against chronic disease, such as cardiovascular disease, neurodegeneration, and cancer (Del Rio, Rodriguez-Mateos, et al., 2013). Cocoa flavonoids exhibit vasodilatory properties (Heiss, Dejam, et al., 2003), affecting the blood flow in the entire organism, including the skin. Improved cutaneous blood flow was associated with flavanol effects on skin texture and hydration. In an intervention study, erythema was decreased with the high-flavanol product, but not with the low-flavanol product (Heinrich, Neukam, et al., 2006). Green tea flavonoids comprise a mixture of different flavonoids, including epicatechin, epigallocatechin, epicatechin-3-gallate, or epigallocatechin-3-gallate. A human intervention study (Rhodes, Darby, et al., 2013) demonstrated a decrease in UV-induced erythema with concurrent inhibition of UV-dependent upregulation of proinflammatory cytokines. Similar photoprotective effects were observed with beverage rich in green tea polyphenols (Heinrich, Moore, et al., 2011). Upon treatment, skin structure and water homeostasis were also positively affected, and blood flow and oxygen delivery to the skin was improved. Citrus fruits are rich in flavonoids, whereas rosemary contains diterpenes and some polyphenols. A combination of extracts from both plants was tested in human intervention studies, showing an increase in minimal erythema dose (Pérez-Sánchez, Barrajón-Catalán, et al., 2014). Supplementation with the citrus–rosemary extract was associated with a decreased response to UVB irradiation as determined by diminished erythema and decreased lipid oxidation (Nobile, Michelotti, et al., 2016).
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Numerous other natural compounds have been tested for photoprotective properties in cell culture or animal models. Among them are promising compounds like genistein and daidzein from soy, silymarin from milk thistle, quercetin, apigenin, or pomegranate flavonoids. Their effects need to be proven in human studies.
Eye The range of wavelengths from 400 to 760 nm comprises the visible spectrum of the electromagnetic spectrum that reaches the earth surface. Additionally, the light of other wavelengths including UVB, UVA (280–400 nm), and infrared radiation (>760 nm) strikes ocular tissues and poses a risk for eye disorders (Youssef, Sheibani, & Albert, 2011). Radiation first impinges on the cornea that acts as a barrier against dust, particles, and microorganisms and then passes lens and finally reaches the retina, which lines the back of the eye. The retina is equipped with photoreceptors and neurons that detect light, convert it into electrical impulses, and carry the signal to the brain via the optic nerve. The macula lutea that contains the fovea centralis and provides optimal visual acuity is an anatomic specialization of the retina unique to humans and other primates. It lacks blood vessels when in a healthy state. Depending on the wavelength, light exhibits different penetration properties through ocular tissues. Obviously, visible light completely propagates through all layers and reaches the retina as does most of the infrared light in the wavelength range of 760–1400 nm (IRA). IRB (1400–3000 nm) is increasingly absorbed by water molecules and does not reach far beyond the lens. UVA light passes the lens and may reach the retina in small amounts. UVB is absorbed more than UVA but still capable to interact with lens structures and induce damage (Ivanov, Mappes, et al., 2018). Photochemical damage plays a major role in light-induced tissue damage. Photothermal damage occurs via transfer of radiant energy (wavelengths of light at IRA). Photomechanical damage results from mechanical compressive or tensile forces due to a rapid introduction of energy, e.g., irradiation in laser eye surgery.
Cataract Cataract, a slow progressive disease due to turbidity of the eye lens, is caused by molecular changes of lens proteins. Crystallins are the predominant structural proteins in the lens, constituting about 90% of water-soluble proteins and contributing to transparency and refractive properties by a uniform concentration gradient. The highly water-soluble crystallins are altered structurally, forming poorly soluble aggregates, which tend to scatter light. Lens proteins can undergo glycation and glycosylation, phosphorylation, deamidation, and racemization (Pescosolido, Barbato, et al., 2016; Ray, 2015). Oxidation is a chemical modification frequently observed in aggregated proteins isolated from cataractous lenses. The lens contains high amounts of antioxidants and
Eye
is further protected by efficient antioxidant enzymes and repair systems. However, antioxidant defense decreases with age, and oxidative modifications accumulate over time. Oxidation of cysteine and methionine residues occurs in early stages of cataract. Oxidation products of tryptophan are detectable in cataract-affected lenses, and several particular tryptophan sites have been identified, e.g., in β-B1-crystallin. It was suggested that intake of dietary antioxidants such as vitamin C, tocopherols, or carotenoids contributes to the maintenance of eye health (Braakhuis, Donaldson, Lim, & Donaldson, 2019; Rhone & Basu, 2008). In a recent meta-analysis on dietary vitamin and carotenoid intake and the risk for age-related cataract, 12 cohort studies and eight randomized controlled intervention trials were included (Jiang, Yin, Wu, et al., 2019). In the cohort studies, an association for intake with a diminished disease risk between RR 0.8 and 0.9 was found for ascorbate, tocopherol, ß-carotene, and or zeaxanthin. However, results from intervention trials do not corroborate this finding. The data confirm reports from earlier meta-analyses on ß-carotene, vitamin C, and vitamin E and age-related cataract (Mathew, Ervin, Tao, & Davis, 2012), where no positive evidence was found. The authors come to the conclusion that health benefits of an intervention with antioxidants remain unproven and cannot yet be recommended. However, cataract develops over decades, and continuous life-long supply with dietary antioxidants may contribute to delayed onset.
Age-related macular degeneration (AMD) The macula lutea represents a small yellow-colored area of the retina close to the optic disc, which is responsible for central vision. The fovea is localized in the center of the macula, an area that exclusively contains photoreceptor cones, which carry out color vision. The yellow color of the macula is due to the carotenoids lutein, zeaxanthin, and meso-zeaxanthin, constituting the macular pigment (Arunkumar, Calvo, Conrady, & Bernstein, 2018). There is evidence that macular carotenoids contribute to photoprotection and are required for accurate vision. AMD is a common disease that is the leading cause of vision loss among the elderly. In wet AMD, new blood vessels grow beneath the retina and compromise central vision acuity. Dry AMD is characterized by the presence of drusen (deposits on the retina) and loss of retinal pigment. Both conditions affect central vision but not peripheral vision. Dry AMD often precedes the wet form of AMD, which can be treated by VEGF inhibition. There is increasing evidence that oxidative injury to the retinal pigment epithelium contributes to the development of AMD (Marquioni-Ramella & Suburo, 2015). The macula is a tissue with high blood supply and exposed to elevated oxygen partial pressures, likely associated with an increased formation of ROS (Handa, 2012; Winkler, Boulton, Gottsch, & Sternberg, 1999). ROS are involved in physiological processes of the retinal pigment epithelium, such as regulation of the inflammatory response or phagocytosis of photoreceptor outer segments. The latter is associated with NOX-dependent generation of H2O2. Consequently, effective antioxidant systems are required in the macula. Macular
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c arotenoids play a major role in the protection of the retina against photooxidative damage. Lutein and zeaxanthin as efficient absorbers of blue light inhibit photoactivation of sensitizing molecules and quench excited triplet states of photosensitizers (Widomska & Subczynski, 2019). Macular carotenoids are not only important for vision but also may protect against AMD (Bernstein, Li, Vachali, et al., 2016). Intervention trials with healthy subjects, supplemented with macular carotenoids, showed improvements in visual performance (Stringham, O'Brien, & Stringham, 2017) even under increased stress conditions like high screen time exposure (Stringham, Stringham, & O'Brien, 2017). A number of epidemiologic studies together with clinical trials performed in small group size have shown inverse correlation between the intake of several antioxidants, carotenoids, or zinc and the risk of AMD (Gorusupudi, Nelson, & Bernstein, 2017). However, conclusive evidence on the protective effects against AMD is lacking. Even meta-analyses from the same group come to different results depending on the selection of studies with respect to inclusion criteria (Evans & Lawrenson, 2017). Positive results were reported in the Age-Related Eye Disease Study (AREDS1) with vitamins C and E, ß-carotene, and zinc, as the risk of progression to advanced AMD was decreased. An evaluation of the effects of lutein and zeaxanthin is to be expected from the ongoing AREDS2 study with carotenoids and long-chain fatty acids (docosahexaenoic acid and eicosapentaenoic acid) as active constituents (Gorusupudi et al., 2017).
Conclusion Upon exposure to light, multiple responses occur in light-exposed tissues. Reactive oxygen species like superoxide, singlet oxygen, or hydrogen peroxide are generated and may damage biomolecules or disturb the delicate redox balance. Dietary constituents with antioxidant properties can interfere with light-induced biological responses and play a role in the prevention of dermal and ophthalmological disorders. A major problem is the lack of long-term intervention studies (over years) to substantiate effects of a life-long intake of dietary antioxidants.
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Evans, J. R., & Lawrenson, J. G. (2017). Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database of Systematic Reviews, 7, CD000254. Fuchs, J. (1998). Potentials and limitations of the natural antioxidants RRR-alpha-tocopherol, L-ascorbic acid and beta-carotene in cutaneous photoprotection. Free Radical Biology & Medicine, 25, 848–873. Garmyn, M., Ribaya-Mercado, J. D., et al. (1995). Effect of beta-carotene supplementation on the human sunburn reaction. Experimental Dermatology, 4, 104–111. Gilchrest, B. A. (2013). Photoaging. Journal of Investigative Dermatology, 133, E2–E6. Godar, D. E. (2001). UV doses of American children and adolescents. Photochemistry and Photobiology, 74, 787–793. Gorusupudi, A., Nelson, K., & Bernstein, P. S. (2017). The age-related eye disease 2 study: Micronutrients in the treatment of macular degeneration. Advances in Nutrition, 8, 40–53. Grether-Beck, S., Marini, A., et al. (2017). Molecular evidence that oral supplementation with lycopene or lutein protects human skin against ultraviolet radiation: Results from a doubleblinded, placebo-controlled, crossover study. The British Journal of Dermatology, 176, 1231–1240. Groten, K., Marini, A., et al. (2019). Tomato phytonutrients balance UV response: Results from a double-blind, randomized, placebo-controlled study. Skin Pharmacology and Physiology, 32, 101–108. Handa, J. T. (2012). How does the macula protect itself from oxidative stress? Molecular Aspects of Medicine, 33, 418–435. Heinrich, U., Gärtner, C., et al. (2003). Supplementation with beta-carotene or a similar amount of mixed carotenoids protects humans from UV-induced erythema. The Journal of Nutrition, 133, 98–101. Heinrich, U., Moore, C. E., et al. (2011). Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women. The Journal of Nutrition, 141, 1202–1208. Heinrich, U., Neukam, K., et al. (2006). Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women. The Journal of Nutrition, 136, 1565–1569. Heiss, C., Dejam, A., et al. (2003). Vascular effects of cocoa rich in flavan-3-ols. JAMA, 290, 1030–1031. Hoel, D. G., Berwick, M., Gruijl de, F. R., & Holick, M. F. (2016). The risks and benefits of sun exposure. Dermato-Endocrinology, 8, e1248325. Ivanov, I. V., Mappes, T., et al. (2018). Ultraviolet radiation oxidative stress affects eye health. Journal of Biophotonics, 11, e201700377. Jiang, H., Yin, Y., Wu, C.-R., et al. (2019). Dietary vitamin and carotenoid intake and risk of age-related cataract. The American Journal of Clinical Nutrition, 109, 43–54. Kammeyer, A., & Luiten, R. M. (2015). Oxidation events and skin aging. Ageing Research Reviews, 21, 16–29. Karran, P., & Brem, R. (2016). Protein oxidation, UVA and human DNA repair. DNA Repair, 44, 178–185. Kessel, D., & Oleinick, N. L. (2018). Cell death pathways associated with photodynamic therapy: An update. Photochemistry and Photobiology, 94, 213–218. Komatsu, T., Sasaki, S., et al. (2017). Preventive effect of dietary astaxanthin on UVA-induced skin photoaging in hairless mice. PLoS ONE, 12, e0171178.
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Pérez-Sánchez, A., Barrajón-Catalán, E., et al. (2014). Protective effects of citrus and rosemary extracts on UV-induced damage in skin cell model and human volunteers. Journal of Photochemistry and Photobiology B: Biology, 136, 12–18. Pérez-Sánchez, A., Barrajón-Catalán, E., et al. (2018). Nutraceuticals for skin care: A comprehensive review of human clinical studies. Nutrients, https://doi.org/10.3390/nu10040403. Pescosolido, N., Barbato, A., et al. (2016). Age-related changes in the kinetics of human lenses: Prevention of the cataract. International Journal of Ophthalmology, 9, 1506–1517. Premi, S., Wallisch, S., et al. (2015). Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure. Science, 347, 842–847. Rabinovich, L., & Kazlouskaya, V. (2018). Herbal sun protection agents: Human studies. Clinics in Dermatology, 36, 369–375. Ray, N. J. (2015). Biophysical chemistry of the ageing eye lens. Biophysical Reviews, 7, 353–368. Rhodes, L. E., Darby, G., et al. (2013). Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid. The British Journal of Nutrition, 110, 891–900. Rhone, M., & Basu, A. (2008). Phytochemicals and age-related eye diseases. Nutrition Reviews, 66, 465–472. Rizwan, M., Rodriguez-Blanco, I., et al. (2011). Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: A randomized controlled trial. The British Journal of Dermatology, 164, 154–162. Sies, H., Berndt, C., & Jones, D. P. (2017). Oxidative stress. Annual Review of Biochemistry, 86, 715–748. Sies, H., & Stahl, W. (2004). Nutritional protection against skin damage from sunlight. Annual Review of Nutrition, 24, 173–200. Sondenheimer, K., & Krutmann, J. (2018). Novel means for photoprotection. Frontiers in Medicine, 5, 162. Stahl, W., Heinrich, U., et al. (2000). Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans. The American Journal of Clinical Nutrition, 71, 795–798. Stahl, W., & Sies, H. (2005). Bioactivity and protective effects of natural carotenoids. Biochimica et Biophysica Acta, 1740, 101–107. Stahl, W., & Sies, H. (2012). Photoprotection by dietary carotenoids: Concept, mechanisms, evidence and future development. Molecular Nutrition & Food Research, 56, 287–295. Stringham, J. M., O'Brien, K. J., & Stringham, N. T. (2017). Contrast sensitivity and lateral inhibition are enhanced with macular carotenoid supplementation. Investigative Ophthalmology & Visual Science, 58, 2291–2295. Stringham, J. M., Stringham, N. T., & O'Brien, K. J. (2017). Macular carotenoid supplementation improves visual performance, sleep quality, and adverse physical symptoms in those with high screen time exposure. Food, https://doi.org/10.3390/foods6070047. Widomska, J., & Subczynski, W. K. (2019). Mechanisms enhancing the protective functions of macular xanthophylls in the retina during oxidative stress. Experimental Eye Research, 178, 238–246. Winkler, B. S., Boulton, M. E., Gottsch, J. D., & Sternberg, P. (1999). Oxidative damage and age-related macular degeneration. Molecular Vision, 5, 32. Youssef, P. N., Sheibani, N., & Albert, D. M. (2011). Retinal light toxicity. Eye, 25, 1–14.
Nutritional protection against photooxidative stress in human skin and eye
20 Wilhelm Stahla, Helmut Siesa,b
a
Faculty of Medicine, Institute of Biochemistry and Molecular Biology I, Heinrich-HeineUniversity Düsseldorf, Düsseldorf, Germany b Leibniz Research Institute for Environmental Medicine, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
Abstract Light-exposed tissues are affected by photooxidative stress that causes and promotes diseases, including skin cancer and cataract and age-related macular degeneration (AMD). Nutrition supplies components for powerful enzymatic and nonenzymatic defense systems. Among the micronutrients, carotenoids and flavonoids from dietary sources have been examined for their activity in studies with healthy human volunteers. Carotenoids like β-carotene, lycopene, phytoene, and phytofluene protect against UV-induced erythema largely by radical scavenging, absorption of UV light, and quenching singlet molecular oxygen. Effects are moderate, and additional protection is required at high levels of exposure to UV light in particular. Supplementation with lutein may help to prevent the onset or progression of AMD. Keywords: Photoprotection, Diet, Nutrition, Antioxidants, Sunburn, Erythema, Skin cancer, Melanoma, Cataract, Age-related macular degeneration
Introduction Upon light exposure, an array of chemical and biological reactions ensues in lightexposed target tissues, namely, the skin and the eye. An electronically excited photosensitizer can react to form radical intermediates in Type I reactions via electron or hydrogen transfer (Fig. 1). These include reactive oxygen species (ROS), oneelectron oxidation products of nucleotide bases or amino acids such as the guanine radical or tyrosine radical, respectively. In Type II reactions, singlet molecular oxygen (1O2) is generated by the transfer of energy from the excited photosensitizer to ground-state oxygen (see Blazquez-Castro et al., this book; Baptista, Cadet, et al., 2017; Di Mascio, Miyamoto, et al., 2019). Singlet oxygen is prone to react with Oxidative Stress. https://doi.org/10.1016/B978-0-12-818606-0.00020-1 © 2020 Elsevier Inc. All rights reserved.
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FIG. 1 Direct and indirect formation of reactive oxygen species following light exposure. Implication of photooxidative stress on signaling and damage. CPD, cyclobutane dimer.
dienes and adds to unsaturated fatty acids, DNA bases, and aromatic amino acids, generating peroxides (Briviba, Klotz, & Sies, 1997). The latter may decompose to radicals or react directly with other biomolecules and induce lipid peroxidation. UVB light is of sufficient energy to cleave hydrogen peroxide or lipid hydroperoxides in a homolytic reaction yielding the respective radical intermediates, which damage biomolecules (Brenneisen, Sies, & Scharffetter-Kochanek, 2002; Kammeyer & Luiten, 2015). Photooxidative damage provokes biochemical responses including inflammation or immune response. As a consequence, further ROS such as superoxide, H2O2, or peroxynitrite is generated. Photooxidative damage is employed in photodynamic therapy (PDT), where photosensitizer-dependent reactions are used to eliminate skin cancerous cells (Kessel & Oleinick, 2018). The concept of oxidative stress has been expanded, distinguishing between eustress and distress (Sies, Berndt, & Jones, 2017). While intense oxidative challenge causes damage (distress), the maintenance of physiological levels of the redox tone (eustress) is required for the regulation of biochemical processes via redox signaling. Redox regulation utilizes thiol-driven master switches like Nrf2/Keap1 or NFκB/IκB. In the context of direct and indirect ROS formation, dietary antioxidants serve as possible protectants, notably carotenoids and flavonoids (Parrado, Philips, et al., 2018; Sondenheimer & Krutmann, 2018). Enzymatic defense systems against photooxidative stress in the skin and eye play important roles. Here, we address the concepts of photoprotection of light-exposed tissues with exogenous, dietary constituents, focusing on results from human studies.
Skin
Skin Skin consists of multiple layers: epidermis and dermis, connected to subcutaneous and adipose tissue. Light penetrating the skin interacts with biological structures at the different layers. The depth of light penetration depends on structural features and on pigmentation; the longer the wavelength, the deeper the penetration. UVA and visible light reach the dermis and to some extent also the subcutis, whereas UVB practically does not pass beyond the epidermal layer. Most of the severe consequences of UV exposure are attributed to UVB. However, UVA radiation is also involved in processes of photoaging and photocarcinogenesis, playing a major role in the pathogenesis of photodermatoses (Gilchrest, 2013; Nishisgori, 2015). However, photochemical interactions are not only responsible for adverse effects (distress). The biosynthesis of vitamin D3 is due to UVB-dependent photocleavage of the precursor 7-dehydrocholesterol (eustress). Season, latitude, life style, and pigmentation have an impact on the efficacy of synthesis of vitamin D3. The use of sunscreen has been debated in this context. Further, induction of the α-melanocytestimulating hormone (α-MSH) is to be mentioned as well, stimulating pigment production by melanocytes and thereby contributing to UV protection (Hoel, Berwick, de Gruijl, & Holick, 2016; Nguyen & Fisher, 2019).
Skin cancer Sunlight is a strong genotoxic agent, and UV radiation is a primary cause in photocarcinogenesis, leading to squamous cell carcinoma, basal cell carcinoma, and melanoma. A major initial mechanism of action is related to UV-induced generation of DNA modification with cyclobutane pyrimidine dimers (CPD) and pyrimidine (6–4) pyrimidone photoproducts, typically ascribed to be the most efficient under UVB irradiation (see Epe, this book; D'Orazio, Jarrett, Amaro-Ortiz, & Scott, 2013). Additionally, oxygen-dependent DNA damage after UV exposure is attributed to photosensitizing reactions, which involve endogenous or exogenous photosensitizing molecules. DNA damage can be assessed as DNA base oxidation products such as 8-oxoGua as a biomarker of oxidative DNA damage (Dąbrowska & Wiczkowski, 2017; Obrador, Liu-Smith, et al., 2019). Accumulation of DNA damage in mitochondria has been associated with cancer development in many tissues, including the human skin. The “common deletion” of mtDNA is associated with UV exposure (Berneburg, Grether-Beck, et al., 1999). Impact on carcinogenesis has been related to the mitochondrial respiratory chain (Birch-Machin, Russell, & Latimer, 2013). Exposure to sunlight predominantly induces pyrimidine dimers, with lower amounts of 8-oxoGua and strand breaks (Cadet & Douki, 2018). Models of photocarcinogenesis suggest that UVB-induced mutation initiates skin cancer, while UVA-related signal interference acts in the promotion of the malignant state (Nishisgori, 2015).
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A novel mechanism for delayed formation of CPDs has been identified in melanocytes (Premi, Wallisch, et al., 2015). It comprises a UVA-initiated reaction sequence that leads to a so-called dark reaction to the generation of “dark CPDs” and implicates intermediate generation of excited triplet state molecules. Synthesis of melanin and the expression of iNOS and NADPH oxidases (NOX) are induced. iNOS and NOX generate their metabolites nitric oxide and superoxide, respectively, which efficiently combine to peroxynitrite. The latter reacts chemically with the pigment melanin, present in the melanocytes. Degradation products of melanin transfer to the nucleus where they are prone to lead to dioxetanes and other products. 1,2-Dioxetanes are metastable, decomposing thermolytically, thereby generating carbonyl compounds in the electronically excited triplet state (Cilento & Adam, 1995). Quenching of the triplet state molecules occurs by energy transfer with ground-state oxygen to yield singlet oxygen, light emission (luminescence) or by dissipation of energy interacting with surrounding water molecules generating thermal energy (Mano, Prado, et al., 2014). However, in the presence of suitable acceptor molecules, energy could also be transferred and used to promote a reaction such as 2 + 2 cycloaddition. In such a sequence of reactions, “dark dimers” are formed. It should be noted, however, that the biosynthesis of melanin is also induced by UV light, and the presence of the polymer in the skin is unequivocally important for the protection of cells against UV radiation (Nguyen & Fisher, 2019). Thus, there appears to be a balance between protection and contribution to damage. Proteins also are targets for UV-induced ROS, impinging on protein functions, e.g., in signaling cascades or damage repair. UVA-dependent oxidation of DNA repair proteins interferes with DNA repair efficiency (Karran & Brem, 2016). Supplementation with dietary antioxidants was suggested as a strategy for preventing cancer development due to photooxidative damage. In particular, vitamins C and E and carotenoids have been studied in this context. Although their photoprotective properties were proven in vitro, meta-analysis of intervention trials indicated no support to an overall primary and secondary preventive effect of supplementation with dietary antioxidants on skin cancer (Chang, Myung, et al., 2011).
Erythema UV-induced solar erythema (sunburn) is commonly observed when the skin is excessively exposed to sunlight. Sunburn is associated with red or reddish skin, elevated skin temperature, pain, blistering, general fatigue, and second-degree burns. A typical solar erythema develops within a few hours and culminates around 24 h after irradiation. Sunburn is an immediate inflammatory response to UV exposure (Clydesdale, Dandie, & Muller, 2001). Cells that are irreversibly damaged by UV exposure undergo apoptosis, visible as so-called sunburn cells in the epidermis. Individual sensitivity toward erythematogenic UV exposure is characterized by the minimal erythemal dose (MED), which is the lowest dose of UV radiation that will produce a barely detectable erythema 24 h after exposure. UV sensitivity differs between individuals and depends on endogenous protection by melanin and on skin type.
Skin
Sunscreens are used for efficient protection against UVA and UVB radiation. However, >70% of an average annual UV dose is experienced during everyday life without protection by a sunscreen (Godar, 2001). Strengthening endogenous antioxidant defense might improve UV resistance of the organism. Dietary antioxidants came into focus, with several structurally different classes of dietary components serving in endogenous photoprotection (Sies & Stahl, 2004; Rabinovich & Kazlouskaya, 2018, Pérez-Sánchez, Barrajón-Catalán, et al., 2018).
Carotenoids Carotenoids, widespread colorants in nature, are supplied with the diet. Major carotenoids in human blood and tissue are β-carotene, lycopene, lutein, β-cryptoxanthin, α-carotene, and zeaxanthin, as well as phytoene and phytofluene, intermediate products of carotenoid biosynthesis (Stahl & Sies, 2005). β-Carotene, β-cryptoxanthin, and lutein are found in a variety of fruit and vegetables. Dietary lycopene derives mainly from tomato and corn is the major source for zeaxanthin. Carotenoids contain an extended system of 9–11 conjugated double bonds, responsible for their color (absorption maxima around 450 nm). This core structure is substituted with different cyclic and acyclic end groups, in the case of xanthophylls like lutein and zeaxanthin modified by oxygen functions. Phytoene and phytofluene, however, exhibit only three and five double bonds, and their UV spectra show maxima in the UVB and UVA range, respectively. Carotenoids are among the most efficient natural scavengers of singlet molecular oxygen (1O2) and excited triplet state molecules (Conn, Schalch, & Truscott, 1991; Di Mascio, Kaiser, & Sies, 1989). Their quenching activity is related to the number of conjugated double bonds with rate constants in the order of 109 M−1 s−1. Carotenoids also efficiently scavenge peroxyl radicals. Independent of their antioxidant activity, several other biological properties have been assigned to carotenoids, mostly related to cellular signaling. Carotenoids have been used to ameliorate symptoms of photosensitivity disorders (e.g., porphyrias) and for systemic protection of the skin against damage following sun exposure (Stahl & Sies, 2012). Dietary supplements with β-carotene as active constituent are employed as oral sun protectants. Protection was observed when treatment was for at least 10 weeks and at doses >20 mg of β-carotene per day (Biesalski, Hemmes, Hopfenmuller, et al., 1996; Lee, Jiang, Levine, & Watson, 2000; MathewsRoth, Pathak, et al., 1972; Stahl, Heinrich, et al., 2000), whereas no protection was reported when β-carotene was applied for only 3–8 weeks and at lower dose levels (Garmyn, Ribaya-Mercado, et al., 1995; McArdle, Rhodes, et al., 2004). Duration of β-carotene supplementation for protection against sunburn was confirmed as being critical in a meta-analysis comprising seven original studies (Köpcke & Krutmann, 2008). The use of ß-carotene as a photoprotectant at doses above 10–20 mg/day was questioned when adverse effects upon long-term treatment emerged in intervention studies reporting an increased risk for lung cancer (Biesalski & Obermueller-Jevic, 2001).
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Therefore, ß-carotene was partially or completely substituted by other carotenoids to decrease the daily dose. A direct comparison revealed that carotenoid mixtures are as effective as ß-carotene alone (Heinrich, Gärtner, et al., 2003). Lycopene was among the first carotenoids as alternate for ß-carotene, quenching singlet oxygen, as mentioned, and also scavenging free radicals, thus interfering with lipid oxidation (Eichler, Sies, & Stahl, 2002). Photoprotective effects of lycopene-rich dietary items were studied with tomato paste and lycopene-rich juices, carrot juice from a specific lycopene-rich variety (Aust, Stahl, et al., 2005). The sunburn reaction of the participants following irradiation with a solar light simulator was significantly decreased upon ingestion of dietary lycopene. These studies provide evidence that dietary sources can provide sufficient amounts of lycopene for endogenous photoprotection. When lycopene supplements derived from tomato extracts were tested against synthetic lycopene, it was shown that the tomato-based products were efficient in photoprotection, whereas no statistically significant effect was obtained with synthetic lycopene (Aust et al., 2005). There is evidence that additional constituents of the tomato products contribute to photoprotection. Among them, the UV-absorbing compounds phytofluene and phytoene are likely to be active (Meléndez-Martínez, Stinco, & Mapelli-Brahm, 2019). Photoprotective effects were also determined at the level of gene expression with a tomato-based supplement providing lycopene, phytoene, phytofluene, tocopherols, and phytosterols (Grether-Beck, Marini, et al., 2017; Groten, Marini, et al., 2019). Supplementation inhibited UVA1- and UVA/B-induced expression of heme oxygenase-1 (HO-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metallopeptidase 1 (MMP-1). The lycopene supplement protected against UVB-induced erythema and UVB-induced upregulation of IL6 and TNFα. Lutein, at the same dose level, showed less pronounced effects. The photoprotective properties of carotenoids have been determined in several human intervention studies (Palombo, Fabrizi, et al., 2007; Rizwan, Rodriguez-Blanco, et al., 2011), corroborated by numerous cell culture and animal studies (Camera, Mastrofrancesco, Fabbri, et al., 2009). Other members of the carotenoid group may be active in UV protection, including astaxanthin (Komatsu, Sasaki, et al., 2017), fucoxanthin (Matsui, Tanaka, et al., 2016), or aromatic carotenoids like dihydroxy isorenieratene (Martin, Kock, et al., 2009). It should be noted, however, that systemic protection due to the ingestion of carotenoids is not comparable with the localized use of a sunscreen in terms of efficiency. However, boosting the basal protection systemically contributes to life-long defense against UV-dependent skin damage, also in skin areas not usually protected by sunscreens.
Vitamins E and C Vitamin E comprises a group of structurally related molecules, tocopherols and tocotrienols. Due to their chromane ring system, E-vitamers show radical scavenging properties. Their antioxidant function in the human organism is related to the inhibition of lipid peroxidation, thus protecting membranes from oxidative damage.
Skin
Since UV irradiation induces lipid peroxidation in vitro, vitamin E may contribute to systemic photoprotection (Packer & Valacchi, 2002). However, there is limited evidence from human intervention studies that supplementation with vitamin E provides protection against UV-induced skin damage (Fuchs, 1998). Vitamin C (ascorbate) is a cofactor of enzymes; it is a water-soluble dietary antioxidant. No convincing effects on skin protection were determined in human studies (McArdle, Rhodes, et al., 2002).
Flavonoids Flavonoids as secondary plant constituents protect plants against bacterial or fungal infections, herbivores, and excess UV irradiation. Humans ingest them with fruits, vegetables, and herbs. Epicatechin and catechin occur in cocoa, green tea, cinnamon, and in several fruits such as apple, apricot, grape, peach, and berries. Quercetin occurs in kale, onions, and grapes; naringenin in grapefruit; and hesperidin in oranges or luteolin in bell pepper. Flavonoids absorb UV light with absorption maxima usually within the UV range. Due to their polyphenolic ring systems, flavonoids efficiently scavenge radicals and are oxidized in two-electron transfer reactions to quinones. However, their radical scavenging activity in vivo is questionable since they are efficiently conjugated in first pass metabolism, which blocks phenolic hydroxyl groups relevant for antioxidant activity. Intervention trials documented protective effects of flavonoid-rich foods against chronic disease, such as cardiovascular disease, neurodegeneration, and cancer (Del Rio, Rodriguez-Mateos, et al., 2013). Cocoa flavonoids exhibit vasodilatory properties (Heiss, Dejam, et al., 2003), affecting the blood flow in the entire organism, including the skin. Improved cutaneous blood flow was associated with flavanol effects on skin texture and hydration. In an intervention study, erythema was decreased with the high-flavanol product, but not with the low-flavanol product (Heinrich, Neukam, et al., 2006). Green tea flavonoids comprise a mixture of different flavonoids, including epicatechin, epigallocatechin, epicatechin-3-gallate, or epigallocatechin-3-gallate. A human intervention study (Rhodes, Darby, et al., 2013) demonstrated a decrease in UV-induced erythema with concurrent inhibition of UV-dependent upregulation of proinflammatory cytokines. Similar photoprotective effects were observed with beverage rich in green tea polyphenols (Heinrich, Moore, et al., 2011). Upon treatment, skin structure and water homeostasis were also positively affected, and blood flow and oxygen delivery to the skin was improved. Citrus fruits are rich in flavonoids, whereas rosemary contains diterpenes and some polyphenols. A combination of extracts from both plants was tested in human intervention studies, showing an increase in minimal erythema dose (Pérez-Sánchez, Barrajón-Catalán, et al., 2014). Supplementation with the citrus–rosemary extract was associated with a decreased response to UVB irradiation as determined by diminished erythema and decreased lipid oxidation (Nobile, Michelotti, et al., 2016).
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Numerous other natural compounds have been tested for photoprotective properties in cell culture or animal models. Among them are promising compounds like genistein and daidzein from soy, silymarin from milk thistle, quercetin, apigenin, or pomegranate flavonoids. Their effects need to be proven in human studies.
Eye The range of wavelengths from 400 to 760 nm comprises the visible spectrum of the electromagnetic spectrum that reaches the earth surface. Additionally, the light of other wavelengths including UVB, UVA (280–400 nm), and infrared radiation (>760 nm) strikes ocular tissues and poses a risk for eye disorders (Youssef, Sheibani, & Albert, 2011). Radiation first impinges on the cornea that acts as a barrier against dust, particles, and microorganisms and then passes lens and finally reaches the retina, which lines the back of the eye. The retina is equipped with photoreceptors and neurons that detect light, convert it into electrical impulses, and carry the signal to the brain via the optic nerve. The macula lutea that contains the fovea centralis and provides optimal visual acuity is an anatomic specialization of the retina unique to humans and other primates. It lacks blood vessels when in a healthy state. Depending on the wavelength, light exhibits different penetration properties through ocular tissues. Obviously, visible light completely propagates through all layers and reaches the retina as does most of the infrared light in the wavelength range of 760–1400 nm (IRA). IRB (1400–3000 nm) is increasingly absorbed by water molecules and does not reach far beyond the lens. UVA light passes the lens and may reach the retina in small amounts. UVB is absorbed more than UVA but still capable to interact with lens structures and induce damage (Ivanov, Mappes, et al., 2018). Photochemical damage plays a major role in light-induced tissue damage. Photothermal damage occurs via transfer of radiant energy (wavelengths of light at IRA). Photomechanical damage results from mechanical compressive or tensile forces due to a rapid introduction of energy, e.g., irradiation in laser eye surgery.
Cataract Cataract, a slow progressive disease due to turbidity of the eye lens, is caused by molecular changes of lens proteins. Crystallins are the predominant structural proteins in the lens, constituting about 90% of water-soluble proteins and contributing to transparency and refractive properties by a uniform concentration gradient. The highly water-soluble crystallins are altered structurally, forming poorly soluble aggregates, which tend to scatter light. Lens proteins can undergo glycation and glycosylation, phosphorylation, deamidation, and racemization (Pescosolido, Barbato, et al., 2016; Ray, 2015). Oxidation is a chemical modification frequently observed in aggregated proteins isolated from cataractous lenses. The lens contains high amounts of antioxidants and
Eye
is further protected by efficient antioxidant enzymes and repair systems. However, antioxidant defense decreases with age, and oxidative modifications accumulate over time. Oxidation of cysteine and methionine residues occurs in early stages of cataract. Oxidation products of tryptophan are detectable in cataract-affected lenses, and several particular tryptophan sites have been identified, e.g., in β-B1-crystallin. It was suggested that intake of dietary antioxidants such as vitamin C, tocopherols, or carotenoids contributes to the maintenance of eye health (Braakhuis, Donaldson, Lim, & Donaldson, 2019; Rhone & Basu, 2008). In a recent meta-analysis on dietary vitamin and carotenoid intake and the risk for age-related cataract, 12 cohort studies and eight randomized controlled intervention trials were included (Jiang, Yin, Wu, et al., 2019). In the cohort studies, an association for intake with a diminished disease risk between RR 0.8 and 0.9 was found for ascorbate, tocopherol, ß-carotene, and or zeaxanthin. However, results from intervention trials do not corroborate this finding. The data confirm reports from earlier meta-analyses on ß-carotene, vitamin C, and vitamin E and age-related cataract (Mathew, Ervin, Tao, & Davis, 2012), where no positive evidence was found. The authors come to the conclusion that health benefits of an intervention with antioxidants remain unproven and cannot yet be recommended. However, cataract develops over decades, and continuous life-long supply with dietary antioxidants may contribute to delayed onset.
Age-related macular degeneration (AMD) The macula lutea represents a small yellow-colored area of the retina close to the optic disc, which is responsible for central vision. The fovea is localized in the center of the macula, an area that exclusively contains photoreceptor cones, which carry out color vision. The yellow color of the macula is due to the carotenoids lutein, zeaxanthin, and meso-zeaxanthin, constituting the macular pigment (Arunkumar, Calvo, Conrady, & Bernstein, 2018). There is evidence that macular carotenoids contribute to photoprotection and are required for accurate vision. AMD is a common disease that is the leading cause of vision loss among the elderly. In wet AMD, new blood vessels grow beneath the retina and compromise central vision acuity. Dry AMD is characterized by the presence of drusen (deposits on the retina) and loss of retinal pigment. Both conditions affect central vision but not peripheral vision. Dry AMD often precedes the wet form of AMD, which can be treated by VEGF inhibition. There is increasing evidence that oxidative injury to the retinal pigment epithelium contributes to the development of AMD (Marquioni-Ramella & Suburo, 2015). The macula is a tissue with high blood supply and exposed to elevated oxygen partial pressures, likely associated with an increased formation of ROS (Handa, 2012; Winkler, Boulton, Gottsch, & Sternberg, 1999). ROS are involved in physiological processes of the retinal pigment epithelium, such as regulation of the inflammatory response or phagocytosis of photoreceptor outer segments. The latter is associated with NOX-dependent generation of H2O2. Consequently, effective antioxidant systems are required in the macula. Macular
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c arotenoids play a major role in the protection of the retina against photooxidative damage. Lutein and zeaxanthin as efficient absorbers of blue light inhibit photoactivation of sensitizing molecules and quench excited triplet states of photosensitizers (Widomska & Subczynski, 2019). Macular carotenoids are not only important for vision but also may protect against AMD (Bernstein, Li, Vachali, et al., 2016). Intervention trials with healthy subjects, supplemented with macular carotenoids, showed improvements in visual performance (Stringham, O'Brien, & Stringham, 2017) even under increased stress conditions like high screen time exposure (Stringham, Stringham, & O'Brien, 2017). A number of epidemiologic studies together with clinical trials performed in small group size have shown inverse correlation between the intake of several antioxidants, carotenoids, or zinc and the risk of AMD (Gorusupudi, Nelson, & Bernstein, 2017). However, conclusive evidence on the protective effects against AMD is lacking. Even meta-analyses from the same group come to different results depending on the selection of studies with respect to inclusion criteria (Evans & Lawrenson, 2017). Positive results were reported in the Age-Related Eye Disease Study (AREDS1) with vitamins C and E, ß-carotene, and zinc, as the risk of progression to advanced AMD was decreased. An evaluation of the effects of lutein and zeaxanthin is to be expected from the ongoing AREDS2 study with carotenoids and long-chain fatty acids (docosahexaenoic acid and eicosapentaenoic acid) as active constituents (Gorusupudi et al., 2017).
Conclusion Upon exposure to light, multiple responses occur in light-exposed tissues. Reactive oxygen species like superoxide, singlet oxygen, or hydrogen peroxide are generated and may damage biomolecules or disturb the delicate redox balance. Dietary constituents with antioxidant properties can interfere with light-induced biological responses and play a role in the prevention of dermal and ophthalmological disorders. A major problem is the lack of long-term intervention studies (over years) to substantiate effects of a life-long intake of dietary antioxidants.
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