Dietary polyphenols as photoprotective agents against UV radiation

Journal of Functional Foods 30 (2017) 108–118

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Dietary polyphenols as photoprotective agents against UV radiation Shuting Hu a, Xinchen Zhang a, Feng Chen b, Mingfu Wang a,⇑ a b

School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong Institute for Food & Bioresource Engineering, College of Engineering, Peking University, PR China

a r t i c l e

i n f o

Article history: Received 12 July 2016 Received in revised form 22 December 2016 Accepted 4 January 2017

Keywords: Dietary polyphenol UV Photoprotection DNA repair

a b s t r a c t Ultraviolet radiation in the sunlight is able to penetrate the atmosphere and cause cumulative injury to the skin. Clinically the photoaging component of skin aging accounts for the development of sunburn, tanning and wrinkling in sun-exposed areas. In addition, chronic exposure of the skin to UV radiation is a major etiologic risk factor to non-melanoma skin cancers. Recently, dietary polyphenols have been suggested as potential candidates to protect the skin from harmful effects of UV irradiation. Oral or topical treatment of some well-known dietary polyphenols such as green tea polyphenols, has great potential to prevent damages such as UV-induced sunburn response, immunosuppression and photoaging. This review introduces the major types of DNA photolesions after UV-irradiation, the following repair mechanisms and cellular defense systems. This review also summarizes the photoprotective effects of selected dietary polyphenols against UV-induced oxidative stress, DNA damage and skin inflammation. Ó 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photoprotection and DNA repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dietary polyphenols and their skin photoprotection mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Green tea polyphenols (GTPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Inhibition on UV-induced oxidative stress by GTPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Repair of DNA damage by GTPs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Anti-inflammatory effect of GTPs for skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Grape Seed Proanthocyanidins (GSPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Stilbenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Apigenin (a flavone) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Luteolin (a flavone). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Artocarpin (a flavone) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.4. Rutin (3-rhamnosyl-glucosylquercetin) (a flavonol glycoside) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.5. Cyanidin-3-glucoside (anthocyanin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Other plant extracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.1. Berries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.2. Pomegranate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.3. Silymarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.4. Pimenta pseudocaryophyllus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.5. Pistachios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.6. Spent coffee ground extract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⇑ Corresponding author. E-mail address: [email protected] (M. Wang). http://dx.doi.org/10.1016/j.jff.2017.01.009 1756-4646/Ó 2017 Elsevier Ltd. All rights reserved.

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4.

3.5.7. Honeybush extract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5.8. Combination of rosemary and citrus extracts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Polyphenols are a group of chemical substances also known as phenols or phenolics. Common polyphenol categories include catechins, stilbenes, flavonoids, proanthocyanidins, ellagitannins and anthocyanins, the natural occurrence of which in plants contribute to health benefits through diets. The main sources of dietary polyphenols include fruits, vegetables, grains, tea, essential oils, as well as their derived foods, beverages or supplements (Zhang & Tsao, 2016). Polyphenol is vital part of human diet and the approximate total intake is 1 g/day (Scalbert & Williamson, 2000). These polyphenols, particularly those from dietary sources, exhibit a wide variety of beneficial biological activities. They have been reported to have antioxidant (Rice-evans, Miller, Bolwell, Bramley, & Pridham, 1995), antimicrobial (Taguri, Tanaka, & Kouno, 2006), antiviral (Perez, 2003), antimutagenic (Lazarou, Grougnet, & Papadopoulos, 2007), anticarcinogenic (Kuroda & Hara, 1999), anti-inflammatory (Dos Santos, Almeida, Lopes, & De Souza, 2006), antiproliferative and vasodilatory actions (Matito, Mastorakou, Centelles, Torres, & Cascante, 2003; Padilla et al., 2005), after ingestion or topical application. Experimental and epidemiologic studies have suggested that polyphenols protect the skin from the adverse effects of ultraviolet (UV) radiation through multiple pathways (Afaq & Katiyar, 2011). UV radiation is classified as UVA, UVB, or UVC according to the wavelength. Most UVC can be absorbed by the ozone layer before reaching the earth surface. However, both UVA and UVB are able to penetrate the atmosphere and cause cumulative injury to the skin. The skin is the largest organ of human as an effective barrier. Lots of people love basking in the sun, but UV radiation in the sunlight potentially causes damages to the skin (e.g. sunburn, tanning) and even leads to DNA damage. These conditions adversely affect self-esteem and psychosocial well-being. In addition, chronic exposure to solar UV radiation is a major etiologic risk factor of non-melanoma skin cancers (Afaq & Katiyar, 2011).

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Unlike melanoma, a malignant tumor of melanocyte, nonmelanoma skin cancer is a kind of tumor arising from keratinocytes. These keratinocytes are located in the basal layer of the epidermis and capable of division. Compared with fully differentiated cells, the keratinocytes are more likely to transform into tumor. The DNA of keratinocytes is a main target of UV radiation to the skin. There are two major classes of mutagenic DNA lesions induced by UVA and UVB radiation: the formation of cyclobutaneprimidine dimers (CPDs) with thymine dimers (T<>T) as the major subset, and the formation of 6–4 photoproducts (6–4 PPs) (Figs. 1 and 2) (Otoshi et al., 2000). CPDs are the most abundant lesions, even more abundant than oxidative lesions, by UV radiation in cultured cells or skin (Douki, Reynaud-Angelin, Cadet, & Sage, 2003; Mouret et al., 2006; You et al., 2001). Both UVA and UVB contribute to the formation of CPDs. As a major contributor to UV mutatagenesis, CPDs were previously considered as ‘‘UVB signature mutations” in skin cancers, but nowadays, there is a general consensus that CPDs represents the main class of UVA photoproducts in human skin. This is because UVB usually causes CPDs on the surface of epidermal, while UVA-induced CPDs play a predominant role in the basal layer (Tewari, Sarkany, & Young, 2012). Only UVB is able to generate 6–4 PPs (Tewari et al., 2012). 6–4 PPs are the precursors of the valence Dewar isomers, which may also present serious mutagenic and potentially lethal effects (Mitchell & Nairn, 1989; Pfeifer, Drouin, Riggs, & Holmquist, 1991). As 6–4 PPs are excised from the mammalian genome rapidly, the chance that 6–4 PPs could induce mutation is much lower than that of CPDs (Ikehata & Ono, 2011). UVA not only induces CPDs, but also causes singlet oxygen photosensitization-induced DNA photolesions (Pfeifer, You, & Besaratinia, 2005). 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxoG) is identified as a ubiquitous biomarker of DNA oxidation in human skin (Cadet, Douki, Ravanat, & Di Mascio, 2009; Mouret et al., 2006). It has been demonstrated that in the human fibroblast model, the inducing spectra for 8-oxoG formation belong to UVA

T<>T

T<>C Fig. 1. Formation of cyclobutane-primidine dimers (CPDs).

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6 -4 photoproducts Fig. 2. Formation of 6–4 photoproducts (6–4 PP).

(above 334 nm) and near visible radiations, indicating that it is UVA 1 subdomain over UVA 2 that contributes to this oxidative DNA base damage (Kvam & Tyrrell, 1997). The formation of 8-oxoG involves of a predominant reaction mediated by singlet molecular oxygen (1O2) (Cadet et al., 2009). Another oxidation reaction that may contribute to the formation of 8-oxoG has been shown to involve highly reactive hydroxyl radical (_OH) generated as a result of Fenton reaction. In addition, both singlet molecular oxygen and highly reactive hydroxyl radical can also lead to the formation of other oxidized pyrimidine bases and DNA strand breaks in UVA-irradiated cells. It has been well understood that UV-induced DNA photolesions accumulate in the epidermis and generate UV-induced mutations if the cells divide before repairing the DNA damage. Moreover, UV-induced CPDs and 8-oxodG photolesions increase with the epidermal depth, with the highest concentration in the basal layers (Halliday & Cadet, 2012). Therefore, the basal layer of epidermis is most sensitive to UV irradiation. Preventing the formation of mutations or accelerating the repair of photo damages is of great importance for skin health. 2. Photoprotection and DNA repair There are many factors that influence the progress from mutation to skin cancer, such as the depth-dependent exposure to the UV radiation, cell division rate, transformation susceptibility, cellular defense systems, and the most important DNA repair capacity. To minimize the number of heritable mutations, organisms have developed efficient DNA repair mechanisms to counteract the UV radiation induced DNA lesions (Sinha & Häder, 2002). Nucleotide excision repair (NER) is a particularly important excision mechanism used by the majority of cells to repair UV damage (Mu et al., 1995). NER can recognize a wide range of DNA distorting lesions, including CPDs and 6–4 PPs, and then correct them by cut-and-patch mechanism (Mu et al., 1997). The study of Aziz Sancar on the mechanism of NER has just won The Nobel Prize in Chemistry (2015), which is expected to attract more and more public and research attention to this topic. (TheNobelPrizeinChemistry, 2015). One important gene associated with NER is p53, a famous tumor suppressor gene that participates in the global genomic nucleotide excision repair (Ford & Hanawalt, 1997). Both UVA and UVB exposure are able to activate the overexpression of p53 protein in cell culture or in human tissues. The formation of thymine dimers after UV radiation is usually accompanied by excision repair-associated DNA strand breaks, and triggers p53 induction (Nelson & Kastan, 1994). The accumulation of p53 inhibits cell division and triggers DNA repair. As a molecular sensor of UV radiation, p53 also mediates cell cycle arrest and apoptosis

in damaged epidermal keratinocytes (Yamaizumi & Sugano, 1994; Ziegler et al., 1994). ERKs, p38, ATM, ATR, and JNK-1 MAP kinases, all participate in the phosphorylation of p53 protein serine residues in response to UV radiation (Banin et al., 1998; Milne, Campbell, Campbell, & Meek, 1995; She, Chen, & Dong, 2000; Tibbetts et al., 1999). The DNA repair capacity in the epidermis is linked to cellular defense systems, including the inhibition of reactive oxygen species (ROS) and reactive nitrogen species (RNS). It’s well known that reactive oxygen species (ROS) are formed in response to UV radiation and cause damage to DNA (Kryston, Georgiev, Pissis, & Georgakilas, 2011; Scharffetter-Kochanek et al., 1997). The chemical modification of DNA bases with change in hydrogen bonding specificity is a simple but important mutation induced by ROS (Wiseman & Halliwell, 1996). The application of antioxidants has been demonstrated to be an effective strategy to reverse the deleterious effects of ROS generated from UVA radiation. Nitric oxide, nitric dioxide, and reactive nitrogen species (RNS), are also formed by UV irradiation and are suggested to play a role in enhancing the genotoxic effects of UV radiation (Terra, Souza-Neto, Pereira, Da Silva, Costa et al., 2012; Terra, Souza-Neto, Pereira, Da Silva, Ramalho, et al., 2012). Similar to ROS, RNS also causes DNA base changes, strand breaks, damages to tumor-suppressor genes and enhances expression of proto-oncogenes. (Kryston et al., 2011; Wiseman & Halliwell, 1996). Further to DNA repair capability, mitigating UV induced chronic inflammation also contributes to the prevention of skin cancer. Early biological responses to UVA radiation, including erythema and redness of the skin, are the most prominent visible sign of inflammation and oxygen dependent. UV-induced inflammation stimulates ROS generation, induces pro-inflammatory cytokines formation (TNF-a, IL-6, IL-1b), and up-regulates the expression of COX-2 and PG metabolites, especially PGE2 (Afaq, Adhami, & Mukhtar, 2005; Buckman et al., 1998; Nichols & Katiyar, 2010). In particular, COX-2 expression is considered as a potential pharmacological target mediating human skin tumor development. Investigations in cultured keratinocytes and SKH-1 hairless mouse skin show that cellular pathways including MAPK, PI3K/AKT, STAT and NF-jB all contribute to the transcriptional activation of COX-2 gene after UV irradiation (Nichols & Katiyar, 2010). In addition to natural defense mechanisms against UV-induced harm, recent research revealed that extraneous phytochemicals, particularly dietary polyphenols, can be promising in providing extra skin photoprotection. They can affect nucleotide excision repair and be antioxidant and anti-inflammatory agents for skin cells. The photoprotective effect and mechanism of selected polyphenols are discussed in details as below.

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3. Dietary polyphenols and their skin photoprotection mechanism Utilization of photoprotective chemicals is one crucial approach to protect the skin from the harmful effect of UV irradiation. Currently, there is a world-wide trend to use natural materials to protect the skin from harmful effects of UV irradiation. Dietary polyphenols are one of the most important groups of natural antioxidants and chemopreventive agents found in human diets (Zhang & Tsao, 2016). Green tea polyphenols are the first well studied groups of polyphenols for the prevention of UV-induced skin photodamage and cancer. The systematical studies include the enhancement of cellular defense against UV-induced oxidation, repairing kinetics and mechanism against UV-induced CPDs, as well as the reduction of skin inflammation. Nowadays, researchers have extended their studies on other dietary polyphenols for their potential photoprotective effect, but mainly focused on free radical scavengers and antioxidant defense enzymes. This review will summarize the photoprotection mechanism and clinical trial updates of GTPs. Moreover, studies of other dietary polyphenols against UV-induced oxidative stress, DNA damage and skin inflammation in the past five years will be discussed (Table 1). 3.1. Green tea polyphenols (GTPs) 3.1.1. Inhibition on UV-induced oxidative stress by GTPs Tea is considered the most consumed beverage in the world. GTPs are the best studied groups of polyphenols for their photoprotective effect. The major polyphenols, namely catechins found in green tea include (-)-epicatechin (EC), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin (EGC), and (-)-epigallocatechin-3gallate (EGCG) (Katiyar & Elmets, 2001). Among these GTPs, EGCG accounts for around 70% of the total amount of catechins and is the key phenolic compound responsible for the antioxidant effect (Katiyar & Mukhtar, 1997). Some major progress has been made over the past decade in the study of their inhibitory effect and mechanism against UV-induced oxidative stress. In cell culture based studies, EGCG has been reported to act as a free-radical scavenger in HaCaT keratinocytes treated with either UVA or UVB (Huang et al., 2005, 2007). Same results were also obtained using human primary keratinocyte. EGCG was shown to inhibit UVB induced oxidative stress-mediated phosphorylation of epidermal growth factor receptor and mitogen-activated protein kinases (MAPK) signaling pathways (Katiyar, Afaq, Azizuddin, & Mukhtar, 2001). In cultured human fibroblast, EGCG treatment not only blocked the UV-induced increase in collagen secretion and collagenase mRNA level, but also inhibited the binding activities of nuclear transcription factors NF-jB and AP-1 (Kim et al., 2001). Based on the studies in skin model, human cell culture, or using animals, both topical application and dietary consumption of GTPs or EGCG were reported to protect the skin by acting at different active sites within the cascade of events that generate reactive oxygen species (Nichols & Katiyar, 2010). Infiltrating leukocytes, the main sources of hydrogen peroxide and nitric oxide production, are responsible for oxidative stress. Topical pre-treatment of EGCG to the mice (3 mg/3 cm2) or human skin (3 mg/2.5 cm2) with significantly reduced UVB induced hydrogen peroxide production, lipid peroxidation, as well as nitric oxide and leukocyte infiltration both in epidermis and dermis (Katiyar & Elmets, 2001; Katiyar, Matsui, Elmets, & Mukhtar, 1999). As an example, in one study, the antioxidant effect of EGCG was proven to inhibit UV-induced epidermal lipid peroxidation (Katiyar, Afaq, Perez, & Mukhtar, 2001). Similar effect was also observed in the skin of guinea pigs (Kim et al., 2001). Compared with topical application (1 mg/cm2,) the photoprotective efficacy of GTPs by oral administration (0.2%, w/v) was weaker but still significant (Vayalil, Elmets, & Katiyar,

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2003). GTPs in drinking water to mice resulted in significant prevention of UVB-induced depletion of antioxidant enzymes such as glutathione peroxidase. A more recent study using green tea seed extract as dietary supplement to mice (200 mg/kg) demonstrated the photoprotective effect of GTP as well (Lim et al., 2014). In addition, the dietary supplement of green tea seed extract significantly increased UVB suppressed antioxidant enzyme activity. Green tea seed extract attenuated UVB irradiation-induced wrinkle formation and reduce the density of dermal collagen fiber through stimulating antioxidant enzyme activity. 3.1.2. Repair of DNA damage by GTPs One important molecular trigger for photocarcinogenesis is UVinduced DNA damage with the form of CPDs, which are produced immediately after UV radiation exposure in cultured epidermal keratinocytes, as well as in the skin (Katiyar, 2013; Katiyar, Matsui, & Mukhtar, 2000). Application of a sunscreen containing green tea polyphenols to the mice skin prior to UVB exposure was found to prevent the formation of these pyrimidine dimers (Chatterjee, Agarwal, & Mukhtar, 1996). In addition, topical application of GTPs to human skin (1–4 mg/skin site/50 ll acetone) before UV radiation prevented the formation of UVB-induced CPDs (Katiyar, Perez, & Mukhtar, 2000). However, topical treatment of skin with EGCG didn’t reduce the formation of CPDs immediately after UV irradiation. The number of CPD-positive cells was only significantly reduced in the EGCG-treated mouse skin 24 or 48 h after UVB exposure, indicating that GTPs accelerated the repair of UVinduced DNA damage (Meeran, Mantena, Elmets, & Katiyar, 2006). The repairing kinetics and mechanisms of GTPs against UVinduced CPDs have been studied for a long time (Katiyar, 2011). IL-12 was suggested to be responsible for mediating the rapid repair of UV-induced CPDs by EGCG (Schwarz et al., 2005). Further study using IL-12 knockout mice illustrated that EGCG could not remove UV-induced CPDs in the skin of IL-12 knockout mice, so IL-12 should take a substantial role in facilitating rapid DNA repair by EGCG (Meeran, Mantena, Meleth, Elmets, & Katiyar, 2006). Oral administration of GTPs in the drinking water (0.2%, w/v) of mice with UVB-induced DNA damage was also carried out by the same research group (Meeran, Akhtar, & Katiyar, 2009). It was found that UVB-induced CPDs were resolved more rapidly in GTPs-treated than untreated wild-type mice, the DNA repairing effect of GTPs was less pronounced in IL-12 knockout mice. The importance of IL-12 in DNA repair after UVB irradiation was also confirmed by studies of GTPs’ effect in normal human keratinocytes or human skin equivalent systems by other researchers (Schwarz et al., 2008). Another important repair mechanism of GTPs is through enhancement of nuclear excision repair (NER) involving IL-12 after UV radiation (Meeran, Mantena, Elmets, et al., 2006; Meeran, Mantena, & Katiyar, 2006). A recent study indicated that a NER mechanism was involved in DNA repair by EGCG (Katiyar, Vaid, van Steeg, & Meeran, 2010). In this study, NER-deficient fibroblasts from an XPA patient and NER-proficient fibroblasts from a healthy person were exposed to UVB with or without prior treatment with EGCG. Results found that EGCG induced repair of UVB-induced CPDs in XPA-proficient cells but did not reduce the number of UVB-induced CPDs in XPA-deficient cells. This study also further confirmed that GTPs in drinking water enhanced the levels of NER genes in mice. Moreover, p53 protein-mediated cell cycle arrest was reported to prevent replication of damaged DNA templates. Application of green tea extract to Epiderm, a reconstituted human skin equivalent, inhibited UVA-induced DNA damage partially through p53 accumulation (Zhao et al., 1999). Similar result was also found in UVB-irradiated human skin. Oral administration of 0.6% green tea extracts was found to increase p53 and reduce apoptosis (Lu et al., 2000).

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Table 1 A summary of molecular targets or mechanism of action of some selected dietary polyphenols in skin photoprotection. Polyphenols

Major sources

Mechanisms

Testing systems

Reference

Catechins

Green tea

HaCaT, HEK, fibroblast; mice, guinea pigs, human skin

Proanthocyanidins

Grape seed

Inhibit H2O2, ROS, NO, iNOS, LPO, MPO, COX-2, PGs, IL12, NF-jB, AP-1, MAPK proteins, inflammation and skin erythema;Reduce CPDs; Enhance NER, p53, antioxidant defense enzymes Inhibit H2O2, NO, iNOS, LPO, MPO, COX-2, PGs, IL12, NF-jB, AP-1, MAPK proteins, TNF-a, inflammation; Repair DNA photolesions; Enhance NER, p53, antioxidant defense enzymes.

Huang et al. (2005, 2007), Katiyar et al. (1999, 2000, 2001, 2010), Katiyar (2011, 2013), Nichols and Katiyar (2010), Elmets et al. (2001), Kim et al. (2001), Lim et al. (2014), Heinrich et al. (2011), Rhodes et al. (2013) Mantena and Katiyar (2006), Perde-Schrepler et al. (2013), Filip et al. (2011), Sharma et al. (2007), Filip et al. (2013), Sharma et al. (2010, 2007), Filip et al. (2013)

Inhibits ROS, H2O2, NO, iNOS, LPO, COX-2, PGs, IL, NF-jB, AP-1, MAPK proteins, Keap1 protein, inflammation, sunburn and suntan; Increases Nrf2, antioxidant enzymes;Induction of autophagy. Inhibits ROS, nitrotyrosine; Reduces CPDs, 8oxodG; Increases p53

HaCaT, HEK, mice, human skin

Adhami et al. (2003), Afaq et al. (2003), Liu et al. (2011), Vitale et al. (2013), Liu et al. (2011), Park and Lee (2008), Vitale et al. (2013), Sirerol et al. (2015), Wu et al. (2013)

HEK

Aftab et al. (2010), Hu et al. (2015)

Inhibits ROS, COX-2, AMPK, NF-jB and MAPKReduces CPDs, 8-oxodGEnhances NER, p53, TSP1

HaCaT, HEK, mice, mouse

Das et al. (2013), Sharma et al. (2014), Tong et al. (2012, 2013)

Inhibits ROS, MMP-1, MAPKs, AP-1, influx of Ca2+, CaMKs, COX-2, PGs, MAPK, IL-6, IL-20, inflammation and erythema; Reduces CPDs

HaCat, fibroblasts, mice, human skin

Hwang et al. (2011), Wölfle et al. (2012)

Inhibits TNF-a, Il-1b, IL-6, COX-2, MMP1Enhances epidermal thickening

Fibroblasts, keratinocyte, Mice skin

Lee et al. (2013), Tiraravesit et al. (2015)

Citrus, mulberry, cranberries, buckwheat, asparagus.

Inhibits COX-2, iNOS, MAPK, JNK, ERK, MKK4, MKK3, NF-jB, AP1 and inflammation

Mouse,

Choi et al. (2014), Kim et al. (2013), Banjare (2012), Kamel and Mostafa (2015), de Oliveira et al. (2016)

Purple corn, blueberries, lingonberriest

Inhibits 8-OxdG, NF-jB, IjBa, IL-6, TNF-a, MAPK, Erk1/2, p38, JNK1/2 MKK4, COX-2, PGE2 and iNOS

Mice

Pratheeshkumar et al. (2014)

Plant extracts Strawberry extract Black berry extract

Strawberry Black berry

Fibroblasts HEK, mice,

Giampieri et al. (2012) Murapa, Dai, Chung, Mumper, and D’Orazio (2012), Divya et al. (2015)

Lonicera caerulea berries extract Pomegranate Extract

Lonicera caerulea berries Punica granatum L

Mice

Svobodová et al. (2013)

Mice

Khan et al. (2012)

Silymarins

Milk thistle; artichokes

Mice, HEK

Nichols & Katiyar (2010), Katiyar et al. (2011)

Skins and seeds extract of Bronte pistachios Pimenta pseudocaryophyllus extract Spent coffee ground ethanol extract Honeybush extract

Bronte pistachios

Reduces DNA damage Inhibits ROS, LPO, iNOS, IL-6, TNF-a, MAPK, Erk1/2, p38, JNK1/2, COX-2, PGE2, MKK4, NFKb, IjBa, inflammationReduceds CPDs, 8oxodG, PCNA, cyclin D1Increases antioxidant enzymes Increases antioxidant enzymes;Reduces CPDs, H2AX phosphorylation Inhibits LPO, COX-2, iNOS, PCNA, cyclin D1, matrix metalloproteinases-2,-3,-9, NF-jB, MAPK, IjBa, IKKa/IKKb Inhibit H2O2, iNOS, COX-2, PGs, NF-jB, IKKa, AP-1, MAPK;Reduce CPDs;Mediates nucleotide excision repair Inhibit ROS;reduce erythema

Human skin

Martorana et al. (2013)

Inhibits ROS, superoxide anion, gp91phox expression, LPO, IL-1b, Skin edema, MPO and MMP-9 Inhibits ROS, MMP2 and MMP9; Reduces wrinkle and erythema Inhibits ROS, LPO, COX-2, ODC, GADD45 and OGG1/2; Reduces erythema Inhibit ROS, DNA damage; Reduce erythema

Mice

Campanini et al. (2013)

HaCaT, mice

Choi et al. (2015)

Mice

Petrova et al. (2011)

HaCaT, human

Pérez-Sánchez et al. (2014)

Stilbenoids Resveratrol

Grape skin peanuts, red wine, mulberries

Oxyresveratrol Flavone Apigenin

Luteolin

Artocarpin

Flavonol glycoside Rutin

Athocyanin Cyanidin-3-glucoside

Rosemary and citrus extracts

Chamomile, tea, onions, grapefruits, oranges, parsley Parsley, artichoke leaves, peppers, olive oil, rosemary, lemons Jack fruit, bread fruit

Pimenta pseudocaryophyllus Coffee

Rosemary, citrus

3.1.3. Anti-inflammatory effect of GTPs for skin Following the UV exposure, it was observed that orally administered 87.5% GTPs in drinking water inhibited COX-2 expression and PGE2 production, and reduced the levels of proinflammatory cytokines in mice skin (Meeran et al., 2009). In

HaCaT, HEK, mice, human skin

human volunteer participated studies, erythema is usually the first index to be evaluated as it’s the early inflammation response to UVA radiation. Topical and oral application of GTPs have been demonstrated to work against UV radiation-induced erythema in humans. A 2.5% green tea solution topical application was found

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to provide excellent protection to participate volunteers by the inhibition of the erythema response evoked by UV radiation (Elmets et al., 2001). In a 12-weeks, double-blind, placebocontrolled study, volunteer participants consumed either a beverage with green tea polyphenols providing 1402 mg total catechins/day or a control beverage. UV-induced erythema was significantly decreased in the intervention group. Skin structural characteristics that were positively affected included elasticity, roughness, scaling, density, and water homeostasis (Heinrich, Moore, De Spirt, Tronnier, & Stahl, 2011). Another study in human skin examined the protective effect of oral green tea catechins against erythema induced by UVR, with both pre- and postsupplementation (Rhodes et al., 2013). Subjects took oral supplements comprising 540 mg GTC with 50 mg vitamin C daily for 12 weeks. In this study, the reduced inflammatory response to UV radiation involved the reduction of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid, which is the most abundant pro-inflammatory eicosanoid induced in human skin by UV radiation. A more recent double-blind randomized controlled trial, however, showed a different result: daily green tea supplements dose 1080 mg GTC, 100 mg vitamin C for 12 weeks did not significantly reduce skin erythema, leukocyte infiltration, and eicosanoid response to UV radiation (Farrar et al., 2015). The author proposed the possibility of a nonlinear dose-response effect and the difference in visual erythema threshold. Therefore, future studies are of great value to further examine the dose-response effect of EGCG for its anti-inflammatory potential.

3.2. Grape Seed Proanthocyanidins (GSPs) GSPs are another group of well-studied polyphenols that present excellent photoprotective effect against UV irradiation. It has been reported that the treatment of normal human primary keratinocytes or HaCaT keratinocytes with GSPs inhibited UVB-induced hydrogen peroxide (H2O2), lipid peroxidation, protein oxidation and DNA damage (Mantena & Katiyar, 2006; Perde-Schrepler et al., 2013). In addition to cell culture system, the topical application of GSPs (2.5 mg/cm2) on SKH-1 mice skin also significantly reduced DNA photolesions after UVB exposure with significantly increased SOD activity (A. Filip et al., 2011). Moreover, dietary administration of GSPs (0.2 and 0.5%, w/w) to UVB irradiated SKH-1 mice also prevented UVB induced depletion of endogenous antioxidant defense enzymes such as GSH, GPx and catalase in the skin (Sharma, Meeran, & Katiyar, 2007). These results indicate that the photoprotective effect of GSPs was associated with the diminishing of UV-induced oxidative stress. The protective molecular mechanism of GSPs against photocarcinogenesis has been elucidated by several studies (Filip et al., 2013; Sharma & Katiyar, 2010; Sharma et al., 2007). The MAPK and NF-jB pathways were found to be involved, which are associated with high risk of photo-carcinogenesis. Phosphorylation of proteins of the MAPK family induced by UVB, including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-N-terminal-kinase (JNK), and p38, decreased significantly with the treatment of GSPs. The inhibition on UVB-induced activation of NF-jB leads to the down-regulation of NF-jB targeted proteins such as PCNA, cyclin D1, iNOS and COX-2. Moreover, the levels of proinflammatory cytokines such as TNF-a, IL-6 and IL-1b were inhibited significantly in the skin by dietary GSPs (0.2% or 0.5%, w/w). Topical application of GSPs (4 mg total polyphenols/cm2) to SKH-1 mice skin has also been demonstrated to modulate the inflammatory response after UVB irradiation by inhibiting the expression of p53, caspase-3, Bax/Bcl-2 and proliferating cell nuclear antigen, as well as inhibiting the activation of iNOS and NF-kB (Filip et al., 2013). Based on the above observations, the suppression effect of GSPs against

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UVB-induced inflammation is suggested to be attributable to their antioxidant activity and stimulation of DNA repair capacity. 3.3. Stilbenoids Resveratrol, a simple polyphenol in grape, red wine and mulberries, attracts much attention due to its potent antioxidative effect against UV radiation. Either in human epidermal keratinocytes or on SKH-1 hairless mice, pretreatment with resveratrol could significantly suppress the UV radiation-induced increase of cellular ROS and lipid peroxidation (Adhami, Afaq, & Ahmad, 2003; Afaq, Adhami, & Ahmad, 2003; Liu et al., 2011; Vitale et al., 2013). As an example, the pre-treatment of HaCaT cells with resveratrol before UVA or UVB irradiation resulted in an increase of cell viability, which might be due to the reduction of reactive oxygen species production (Liu et al., 2011; Park & Lee, 2008). The protective mechanisms after UVA or UVB irradiation were slightly different. In UVB irradiated HaCaT cells, the attenuation of caspase-3 and caspase-8 activation contributed to the increased cell survival rate with resveratrol pre-treatment, while in UVA irradiated HaCaT cells, it is the degradation of Keap1 protein and Nrf2 accumulation in the nucleus up-regulated the activity of antioxidant enzymes, leading to increased cell survival rate after treatment with resveratrol. In addition, resveratrol also exerted its photo-preventive effects partly through the induction of autophagy, preventing damaged cells escaping from programmed cell death and initiating malignant transformation (Vitale et al., 2013). Topical application of resveratrol (25 lmol/0.2 ml, or 0.05%) to SKH-1 hairless mouse skin reduced inflammation-related parameters, as well as UVBmediated infiltration of leukocytes and PG metabolites PGE2 and PGD2 (Afaq et al., 2003; Martorana et al., 2013; Sirerol et al., 2015). Similar results were also observed in the human skin. With the support of Estee Lauder Companies, Inc, 1% resveratrol was found to exert its protective effects against repetitive solar simulator ultraviolet radiation-induced sunburn and suntan (Wu et al., 2013). Oxyresveratrol is a derivative of resveratrol extracted from the roots of Morus australis. It has a similar structure to resveratrol and presents stronger antioxidative activity than resveratrol (Aftab, Likhitwitayawuid, & Vieira, 2010). Oxyresveratrol could enhance the cell survival rate of human primary keratinocyte by inhibiting ROS and nitrotyrosine levels after UVA irradiation (Hu, Chen, & Wang, 2015). The photoprotective mechanism was found to involve the diminishing of UV photolesions, CPDs and 8-oxodG partly by augment of the expression of p53. However, in vivo studies through oral or topical application of oxyresveratrol, are still needed to further evaluate its photoprotective potential. 3.4. Flavonoids 3.4.1. Apigenin (a flavone) Apigenin is a flavonoid polyphenol found in fruits, vegetables, spices and herbs. In HaCaT and mice system, apigenin suppressed ROS generation, accelerated the reversal of UV-B-induced CPDs by up-regulating NER genes as well as down-regulating NF-jB and MAPK (Das, Das, Paul, Samadder, & Khuda-Bukhsh, 2013). As a potent antioxidant, apigenin also presented significant suppression on the formation of 8-oxodG and protected exposed epithelial cells from apoptosis (H. Sharma, Kanwal, Bhaskaran, & Gupta, 2014). Moreover, the application of apigenin to keratinocytes resulted in a wide variety of antitumorigenic and chemopreventive actions, including suppression of COX-2 expression, enhancement of p53 expression, and induction of cell cycle arrest and apoptosis (Tong, Smith, & Pelling, 2012). The mechanism studies conducted by the same research group demonstrated that pretreatment with apigenin prior to UV radiation activated AMP-activated protein

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kinase (AMPK) dramatically in mouse and human keratinocyte cell lines, primary normal human epidermal keratinocytes as well as mouse epidermis in vivo (Tong, Bridgeman, Smith, Avram, & Pelling, 2012). In this study, apigenin completely inhibited UVmediated mTOR phosphorylation in SKH-1 mice epidermis. These findings demonstrate that the chemoprevention of UV-induced skin cancer by apigenin involves AMPK/mTOR axis and the activation of AMPK which further induces autophagy to suppress UVinduced tumorigenesis. Additionally, apigenin was demonstrated to promote Trombospondin-1 (TSP1) expression in UVBirradiated epidermis via HuR, leading to inhibition of angiogenesis (Tong et al., 2013). TSP1 was the first identified endogenous inhibitor of angiogenesis. Its expression was remarkably down-regulated in epidermis following UVB irradiation and throughout distinct steps of skin carcinogenesis. The author suggested that the identification of TSP1 as a key target of apigenin is significant for the potential use of apigenin for non-melanoma skin cancer prevention. 3.4.2. Luteolin (a flavone) Luteolin is one of the most potent antioxidative plant flavone found in parsley, artichoke leaves, celery, peppers, olive oil, rosemary, lemons, peppermint, sage, thyme and other foods. In HaCat cells, luteolin increased cell viability and inhibited ROS production after UVA irradiation (Hwang, Oh, Yun, & Jeong, 2011). Luteolin also inhibited UVA-induced production of the collagenases such as MMP-1 and the expression of c-Jun and c-Fos through MAPKs and AP-1-dependent signaling. Furthermore, luteolin decreased the UVA-induced influx of Ca2+ into HaCaT cells and the phosphorylation of Ca2+calmodulin-dependent kinases (CaMKs). Similar results were also found in UVB-induced HeCat keratinocytes as well as SKH-1 mice (10 or 40 nmol in 200 ll acetone) (S. H. Lim et al., 2013). In human skin, 2.5% luteolin effectively reduced the formation of UVB-induced cyclobutane pyrimidine dimers (Wölfle et al., 2011). In addition to DNA repair effect, luteolin also inhibited UVB-induced skin erythema as well as up-regulated COX2 and prostaglandin E2 production in human skin via interference with the MAPK pathway. The same research group further studied the direct and indirect effects of luteolin on dermal fibroblasts as the major target of photoaging (Wölfle et al., 2012). In dermal fibroblasts, luteolin inhibited UVA-induced increase of IL-6 and matrix metalloproteinase (MMP-1) expression via interference with the p38 mitogen-activated protein kinase (MAPK) pathway. In keratinocytes, luteolin inhibited solar-simulated radiation (SSR)-induced production of IL-20, also via interference with the p38 MAPK pathway. Moreover, the research group found that the supernatant of keratinocyte induced the expressions of IL-6 and MMP-1 in fibroblasts, but IL-6 and MMP-1 expression was reduced with pretreatment of luteolin. These results suggest that lutenolin modulates SSR-mediated production of soluble factors in keratinocytes and attenuates photoaging in dermal fibroblasts. Taken together, lutenolin shows a great potential as an agent for the prevention of UV-induced skin aging and damage. 3.4.3. Artocarpin (a flavone) Artocarpin, a prenylated flavone isolated from an agricultural plant Artocarpus communis and other species, has been documented to possess anti-inflammatory activity in hairless mice at a topical dose of 0.05% and 0.1% via the down-regulation of TNF-a, Il-1b and COX-2 (Lee et al., 2013). A more recent study investigated the ability of artocarpin-enriched Artocarpus altilis heartwood extract (50 lg/mL) to prevent UVB-induced photodamage. The study revealed that artocarpin-enriched extract suppressed structural alterations in skin damaged by UVB irradiation. This suppression was partly mediated by decrease in MMP-1 production in fibroblasts and TNF-a and IL-6 production in

keratinocytes. Moreover, the topical administration of the extract suppressed epidermal thickening and collagen loss in chronically UVB-exposed skin in mice (Tiraravesit et al., 2015). These studies indicate that artocarpin or artocarpin-enriched plant extract has great potential for the prevention of skin photo damage. 3.4.4. Rutin (3-rhamnosyl-glucosylquercetin) (a flavonol glycoside) Rutin (3-rhamnosyl-glucosylquercetin) is a polyphenol present in many edible plants such as citrus, mulberry, cranberries, buckwheat, and asparagus. 1 or 5 lmol rutin was observed to exert anti-inflammatory effects in UVB-irradiated mouse skin by suppressing the expression of COX-2 and iNOS, which is attributable to its suppression of p38 MAP kinase and JNK signaling responsible for AP-1 activation (K.-S. Choi, Kundu, Chun, Na, & Surh, 2014). In another study, rutin was found to attenuate UVB-induced phosphorylation of ERK, MKK4, MKK3, but not MEK in mouse epidermal skin (Kim, Kim, Lee, & Kang, 2013). Moreover, the activation of nuclear factor (NF)-jB and activator protein-1 induced by UVB has been demonstrated to be inhibited by rutin treatment in a dose-dependent manner. The application of rutin is limited due to its low water solubility. Polyphenol, especially flavonoid nanoparticles, show good performance with enhanced flavonoid content and improved bioactivity with new physical and functional characteristics. In the recent years, more and more researchers have been focusing on the development of rutin encapsulated nanoparticles. Rutin nanoparticles have been demonstrated to be safe and of high efficacy with increased SPF value (Banjare, 2012; de Oliveira et al., 2015; Kamel & Mostafa, 2015). In HaCat systems, the antioxidant capability and the SPF value were enhanced significantly by rutin nanoparticles (de Oliveira et al., 2016). These studies provide new strategy for the development of photoprotective agents from natural sources. 3.4.5. Cyanidin-3-glucoside (anthocyanin) Cyanidin-3-glucoside, also known as chrysanthemin, is anthocyanin that rich in many vegetables and fruits, especially in edible berries. Treatment of mice skin with cyanidin-3-glucoside inhibited UVB-induced 8-oxodG production. Cyanidin-3-glucoside (250 and 500 lM in acetone) provided protection by mediating nuclear translocation of NF-jB and degradation of IjBa in mice skin (Pratheeshkumar et al., 2014). Cyanidin-3-glucoside not only modulated the repair of UVB induced DNA damage, but also led to significant decrease of IL-6 and TNF-a, which were associated with cutaneous inflammation. UVB-induced inflammatory responses were diminished by cyanidin-3-glucoside with a significant reduction of phosphorylated MAP kinases, Erk1/2, p38, JNK1/2 and MKK4. Besides, cyanidin-3-glucoside also reduced UVB-induced COX-2, PGE2 and iNOS levels (Pratheeshkumar et al., 2014). 3.5. Other plant extracts 3.5.1. Berries As shown above, in addition to purified dietary phenolic compounds, some edible plant extracts which are rich in polyphenols also presented photoprotective effect. Berries are flavorful and sweet fruits that have a long list of health benefits. Strawberry extracted fraction containing cyanidin-3-glucoside was found to increase cell viability and alleviate DNA damage after UVA irradiation on human fibroblasts (Giampieri et al., 2012). In addition to strawberry, black berry extract (BBE) also protected human primary keratinocytes by its strong antioxidant properties. BBE was found to reduce UV-induced ROS by up-regulating the expression of catalase, MnSOD, Gpx1/2 and Gsta1 antioxidant enzymes (Murapa, Dai, Chung, Mumper, & D’Orazio, 2012). A recent study

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examined the photoprotective effect of cyanidin-3-glucoside enriched BBE in vivo systematically (Divya et al., 2015). In the SKH-1 hairless mice skin, 10% or 20% BBE treatment lowered glutathione depletion, lipid peroxidation, and myeloperoxidase in mouse skin after chronic UVB exposure. The levels of IL-6 and TNF-a in UVB-exposed skin were also significantly reduced and there was remarkable reduction of phosphorylated MAP Kinases, Erk1/2, p38, JNK1/2 and MKK4, indicating that UVB-induced inflammatory responses were alleviated by BBE. COX-2, PGE2 and iNOS levels were all reduced by BBE in UVB-exposed skin. In the study of the repair of DNA damage by BBE, immunohistochemistry analysis revealed that topical application of BBE inhibited the expression of CPDs, 8-oxodG, PCNA and cyclin D1 in UVB-exposed skin. The repair capacity was associated with the inhibition of UVB-induced NF-jB and degradation of IjBa in mouse skin. Similar results were also found in Lonicera caerulea berries oral administration studies of UVB exposed SKH-1 mice (Svobodová et al., 2013). Feeding with L. caerulea berries-enriched diet (10%, w/w) stimulated antioxidant enzyme activity/expression, includes NADPH quinone oxidoreductase-1, heme oxygenase-1, and gamma-glutamylcysteine synthetase catalytic. Administration of the L. caerulea berry-enriched diet also led to a reduction CPDs formation and H2AX phosphorylation, a marker of double strand breaks. Taken together, berries have great potential as photoprotective agents due to their antioxidant, anti-inflammation and DNA repair capabilities. Further clinical studies with human volunteers will be a plus.

3.5.2. Pomegranate Pomegranate (Punica granatum L.) fruit possessed as strong antioxidant and anti-inflammatory properties in previous studies. Oral feeding of pomegranate fruit extract (PFE, 0.2%, wt/vol) to mice was found to afforded substantial protection from the adverse effects of single UVB radiation (Khan, Syed, Pal, Mukhtar, & Afaq, 2012; Svobodová et al., 2013). UVB-induced epidermal hyperplasia, infiltration of leukocytes, protein oxidation and lipid peroxidation were inhibited by PFE. PFE consumption also presented significant suppression on UVB-induced protein expression of COX-2, iNOS, PCNA, cyclin D1 and matrix metalloproteinases-2, -3 and -9. Moreover, the protection mechanism of PFE involves the inhibition of UVB-induced nuclear translocation and phosphorylation of NF-jB /p65, phosphorylation and degradation of IjBa, activation of IKKa/IKKb as well as phosphorylation of MAPK and c-Jun. In another study, pomegranate seed oil nanoemulsion entrapping polyphenol-rich ethyl acetate fractions were able to protect the cells’ DNA against UVB-induced damage in HaCaT cell line (Baccarin, Mitjans, Ramos, Lemos-Senna, & Vinardell, 2015).

3.5.3. Silymarins Silymarins is a mixture of silibinin, isosilibinin, silicristin, silidianin and other polyphenols found in milk thistle (Silybum marianum). The most common food source of silymarin is artichokes (Cynara Scolymus), which is also a member of the thistle family. Silymarin has been shown to inhibit UVB-induced intracellular production of H2O2, iNOS, COX-2 expression and subsequently the production of PG metabolites as well as NF-jB, IKKa, AP-1, MAPK proteins (Nichols & Katiyar, 2010). In the studies of DNA repair capacity, research has demonstrated that topical application of silymarins (1.0 mg/cm2 skin area) to the mice skin prior to UVB exposure prevented the formation of pyrimidine dimers (Vaid et al., 2013). Silymarisn also reduced UVB-induced CPDs in normal human primary keratinocyte and the DNA repair mechanism was mediated through nucleotide excision repair (Katiyar, Mantena, & Meeran, 2011).

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3.5.4. Pimenta pseudocaryophyllus Pimenta pseudocaryophyllus is a species largely distributed in pantropical and subtropical regions, including Central America and South America. The leaves are used to prepare a refreshing drink. Topical application of 5% Pimenta pseudocaryophyllus ethanolic extract (PPE) on hairless mice skin reduced UV-B-induced oxidative and inflammatory skin damages via the inhibition of superoxide anion, gp91phox expression, lipid peroxidation and IL-1b production. Skin edema, MPO and MMP-9 activity were also inhibited by PPE (Campanini et al., 2013). As a native species in Brazil, using PPE might be a promising strategy for preventing UV-induced oxidative and inflammatory damage of the skin for people in South America. 3.5.5. Pistachios Pistachio (Pistacia vera L.) seeds are widely consumed as food. The nuts are rich source of phenolic compounds which known for their high antioxidant activity. Topical application of 2% polyphenol-rich extract from skins and decorticated seeds of Bronte pistachios both presented radical scavenger/antioxidant properties and reduced UV-B-induced skin erythema in human volunteers (Martorana et al., 2013). Polyphenol-rich extract from skins showed better photoprotective effects than that from decorticated seeds, as the phenols in the skin extract is about ten times richer. 3.5.6. Spent coffee ground extract The photoprotective effect of ethanol spent coffee ground extract (ESCG) was evaluated (H.-S. Choi, Park, Park, & Suh, 2015). In HaCaT cells, ESCG significantly decreased the UVBinduced ROS. Moreover, ESCG administration effectively reduced UVB-induced wrinkle and erythema formation in mice dorsal skin with the down-regulation of collagen-degrading matrix metalloproteinase 2 (MMP2) and 9 (MMP9) expressions. 3.5.7. Honeybush extract The leaves of honeybush are commonly used to make herbal teas. Polyphenolic extracts of honeybush (1%, w/v), was reported to render protection against UVB-induced skin damage such as erythema in mice (Petrova, Davids, Rautenbach, & Marnewick, 2011). The protection mechanism involves the modulation of induced-oxidative damage, as well as the reduction of COX-2, ornithine decarboxylase (ODC), GADD45 and OGG1/2 expression. 3.5.8. Combination of rosemary and citrus extracts In addition to single plant extract, the combination of rosemary and citrus bioflavonoids extracts, was found to inhibit UVBinduced ROS and DNA damage in HaCaT cells (Pérez-Sánchez et al., 2014). Moreover, oral daily consumption of the combination of citrus and rosemary extract (phenolic content of 36.32 ± 3.91 GAE/100 g dw) by human volunteers revealed a significant minimal erythema dose increase after eight weeks. These result indicate that the combination of different kinds of phenolic compounds or plant extracts might lead to synergistic photoprotection, but more studies are needed to validate this hypothesis. 4. Conclusion In a summary, previous studies suggested that the photoprotective effects and anti-photocarcinogenic activity of polyphenols are associated with the inhibition of UV-induced ROS, DNA damage, as well as inflammatory mediators in a synergistic way. Plant polyphenols, whether they were administered in the drinking water, as dietary supplements, or applied topically, all have great potential for the prevention of UV-induced skin photo-damage and skin cancer.

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