How polyphenols may help to protect your skin from damage by UV radiation.

Laboratory, clinical and epidemiological studies have shown that solar ultraviolet (UV) radiation can induce various skin diseases, such as premature ageing and cancers. Excessive UV radiation exposure induces skin diseases and skin disorders caused by the induction of inflammation, oxidative stress and DNA damage. The use of chemopreventive agents, such as plant polyphenols, is gaining attention.

Chemopreventive are agents that can inhibit, reverse or retard the harmful effects caused by exposure to UV radiation. A wide variety of polyphenols and phytochemicals, most from dietary supplements, have a photoprotection effect on the skin. In this article I will talk about some polyphenols photoprotective effect, such as green tea polyphenols, grape seed

proanthocyanidins, resveratrol, silymarin and genistein, as well as the action of these components on cutaneous inflammation, oxidative stress and DNA damage. The polyphenols use in sunscreen is seen as promising as the use of these substances in the treatment to some skin diseases.

Polyphenols are a large family of naturally occurring plant products and are widely distributed in plant foods, such as, fruits, vegetables, nuts, flowers and barks. Important and common polyphenols sources are onions (flavonoids); cocoa, grape seed (proanthocyanidins); tea, apples, and red wine (flavonoids and catechins); citrus fruits (flavanones); berries and cherries (anthocyanidins) and soy (isoflavones). These polyphenols contribute to vegetables and fruits beneficial effects.

Topics covered:

● Ultraviolet radiation and skin;

● Polyphenols and skin photoprotection;

● Carcinogenesis inhibition;

● Sun protection effect;

● Anti-inflammatory effects;

● Antioxidant effects;

● Green tea polyphenols: DNA damage repair;

● Polyphenols performance in the UVB reduction induced inflammation.

Ultraviolet radiation and skin

The skin is the largest organ of the human body, possessing an area of ​​approximately 1.5 – 2.0 m². The skin function is to protect the body organs by acting as a barrier against the chemical and physical agents that can damage the body. Exposure to solar radiation is a crucial factor to the development of many skin disorders such as wrinkles, skin dryness, blemishes, hyperpigmentation, hypopigmentation, and skin cancers.

Solar radiation can be divided into three segments: UVA, UVB and UVC. The most harmful are UVA and UVB. UVB radiation can penetrate the skin, traversing the epidermis and penetrating the dermis. It can induce adverse biological effects such as oxidative stress, DNA damage, premature skin ageing and multiple effects on the immune system. It is also a tumor initiator and promoter. Although the skin has an enzymatic and non-enzymatic defense system against these biological responses, excessive exposure to UV rays

overwhelms and depletes these defense systems, leading to the development of various skin disorders, such as cancer.

UVA is the largest UV radiation spectrum. UVA penetrates deep into the epidermis and dermis of the skin. It has been shown that excessive exposure to UVA rays can lead to benign tumors formation as well as malignant cancers. UVA exposure can induce singlet oxygen (a kind of electronically excited oxygen) and hydroxyl radical generation that can cause damage to macromolecules cells such as lipids, proteins and DNA. UVA is an expressive source of oxidative stress on the skin, which causes photoaging.

Polyphenols and skin photoprotection

Lately the interest in the use of natural plant products has grown, including polyphenols. They are mainly used to prevent skin damage induced by UV rays, such as the risk to develop skin cancer. Polyphenols have anti-inflammatory, antioxidant and immunomodulatory properties and it can be used as a chemopreventive agent in many skin disorders.

Chemoprevention is a cancer control based on the use of natural or synthetic chemicals that are capable of suppressing, delaying or reversing carcinogenesis process. In this respect,

chemopreventive can act to control the risk of cancer. And in addition, the use of chemopreventive is a practical solution to a control problem difficulty, as it is possible for an individual to change their diet and lifestyle in combination with a skincare routine, preventing damage from sun exposure. Studies have shown the efficacy of some natural polyphenols, such as green tea polyphenols, silymarin, and proanthocyanidin from grape seed. These components acted against UV radiation induced inflammation, oxidative stress, DNA damage and suppression of immune responses.

Carcinogenesis inhibition

Non-melanoma skin cancer, such as basal cell carcinoma and epidermoid carcinoma, is the most common malignant neoplasm in humans. Studies have reported that solar radiation is the main etiological agent in the skin cancer development. Several animal models have been used to study the anti-photocarcinogenic effects of phytochemicals, such as polyphenols. It has been found that polyphenols oral administration from green tea resulted in skin protection against tumorigenesis (a tumor process formation).

An extract taken from green tea leaves, which consists in polyphenols,mixture was able to inhibit UVB-induced tumorigenesis in rats. Topical treatment in hairless mice with green tea polyphenols or epigallocatechin-3-gallate (EGCG, flavonoids) in a hydrophilic ointment was able to inhibit the development of UVB-induced tumorigenesis.

Proanthocyanidins from grape seed orally used in hairless mice were able to inhibit photocarcinogenesis, as well as tumors incidence. Proanthocyanidins intake from grape seed also prevented papilloma to carcinoma malignant progression. Resveratrol is found in the grapes bark, peanuts, as well as in red wine and blackberries. The topical resveratrol application inhibits the tumor formation induced by UVB, as well as the progression. Silymarin, a flavonoid found in milk thistle (Silybum marianum) also showed anti-photocarcinogenic action. Silymarin topical treatment in hairless mice inhibited the tumor incidence. Silibinin, a major component of silymarin, has been shown to inhibit photocarcinogenesis when used topically or orally.

Action Mechanism and Polyphenols Molecular Targets

Sun protection effect

Most natural polyphenols are pigments, usually yellow, red or purple, and are capable of absorbing UV radiation. Therefore, through topical treatment polyphenols can prevent radiation penetration into the skin. The radiation that polyphenols can absorb includes the entire UVB spectrum, and part of the UVA and UVC spectrum. The natural polyphenols ability to act as sunscreen can reduce inflammation, oxidative stress and DNA damage.

Anti-inflammatory effects

Erythema-induced UV, edema and hyperplastic epithelial responses are inflammation signs and play a crucial role in the cutaneous tumors development. The cyclooxygenase-2 (COX-2) expression induced by UVB and the subsequent increase of prostaglandin (PG, a lipid substance that acts as a mediator in pathogenic processes, as well as in inflammatory responses) metabolites (intermediate products of metabolic reactions) production is a keratinocytes characteristic response to acute or chronic exposure to UV radiation. COX-2 is an enzyme induced and rapidly expresses when there is inflammation, and generates new prostaglandin metabolites from arachidonic acid.

The COX-2 expression has been linked to the pathophysiology inflammation and cancer. Many studies have demonstrated COX-2 over expressed in chronically UVB-irradiated skin, as well as in UVB-induced premalignant lesions, as well as basal cell carcinoma and skin squamous. Photocarcinogenesis studies have shown that oral polyphenols administration from green tea inhibited UV-induced skin edema as well as erythema. Topical treatment with green tea polyphenols prior to exposure to UV radiation reduced the UV-induced hyperplastic response (cell turnover) as well as an enzyme myeloperoxidase (a key enzyme in the production of reactive oxygen species) activity. It also reduced the inflammatory leukocytes number in the skin.

Topical treatment with epigallocatechin-3-gallate (EGCG) also demonstrated similar effects to green tea polyphenols, since EGCG are applied prior to exposure to UVB radiation, also reduced the number of inflammatory leukocytes as well as the myeloperoxidase activity. EGCG topical application has also resulted in the prostaglandin metabolites production inhibition, including PGE2, PGF2α and PGD2, which play a key role in the inflammatory development and proliferative cutaneous diseases.

Skin exposure to UV radiation increases the number of proinflammatory cytokines, which increases inflammatory responses. The increase in proinflammatory cytokines, such as tumor necrosis factor (TNF) -α and interleukin (IL) -1β and IL-6, contribute to the stimulus tumor process. This effect would result in the tumors appearance and their rapid progression.

Green tea polyphenols oral administration reduced the level of proinflammatory cytokines in UVB-irradiated skins. Polyphenols from green tea also reduced the levels of cell proliferation biomarkers in UV-irradiated skins, such as proliferation nuclear antigen (PCNA) and cyclin D1 (a protein that acts on the cell cycle, and when enhanced contributes to tumor genesis).

The inhibitory effects from green tea polyphenols on these biomarkers inflammation on UV-irradiated skin show their anticarcinogenic role.

A study was conducted to analyze the effect of EGCG on UV-induced inflammation in hairless mice. EGCG oral use has been shown to increase skin tolerance, so that the minimum dose required for the erythema induction has been increased. Also, there was disturbance in the epidermal barrier and skin damage inhibition.

In another study, a green tea extract topical administration before and during treatment with psoralen and UVA (a treatment combining plant derived substances psoralens with exposure to UVA radiation administration) has been demonstrated that was able to reduce hyperplasia, hyperkeratosis (enlargement of the superficial layer of the skin), erythema and edema. These in vivo studies, conducted in animal and human models, demonstrate the anti-inflammatory protective effects present in green tea polyphenols.

The in vivo effects of other polyphenols, such as resveratrol, grape seed proanthocyanidins and silymarin have also been examined in studies using animal models. Topical or dietary treatment with proanthocyanidins from grape seed and/or silymarin inhibited edema induced by UVB radiation, erythema, inflammatory leukocytes infiltration and myeloperoxidase activity in an animal model.

Silymarin has been shown to inhibit UVB-induced COX-2 expression, as well as the prostaglandin metabolites generation, factors that are considered tumor promoters in the skin. Silymarin has also been shown to inhibit the ornithine decarboxylase expression, an enzyme required for the synthesis of polyamine (molecules related to cell proliferation and differentiation), which plays an important role in the cutaneous tumor formation induced by UVB.

Resveratrol topical application prior to UVB irradiation resulted in the inhibition of hyperplastic responses, leukocyte infiltration, as well as COX-2 and ornithine decarboxylase activity. Therefore, part of the anti-photocarcinogenic effect present in these polyphenols can be explained by the inhibitory effect they have, minimizing UVB-induced inflammatory responses.

Antioxidant effects

The skin has its own antioxidant system to deal with UV-induced oxidative stress. However, excessive exposure to UV rays can overload the skin’s antioxidant system, resulting in various skin diseases, immunosuppression, premature skin ageing and cancers.

Green tea polyphenols have been shown to inhibit lipid peroxidation (a radical-generating chain reaction). Topical treatment in animal and human models with ECGC prior to UV exposure reduced nitric oxide (free radical) production and hydrogen peroxide (oxidant), as well as leukocyte infiltration. It has been shown that infiltrating leukocytes are nitric oxide major source and hydrogen peroxide, which results in the state of oxidative stress. Although reactive oxygen species aid in the destruction of microorganisms, excessive and uncontrolled production can damage skin tissues, resulting in many diseases.

However, the application of EGCG may have a beneficial effect, improving the damage induced by UVB radiation, through the ability to reduce reactive oxygen species generation. Treatment with EGCG in UVB-irradiated skin has also been shown to reduce hydrogen peroxide and nitric oxide in the epidermis and dermis production. This treatment also inhibited UV-induced lipid peroxidation in the epidermis, in addition to protect the antioxidant defense enzymes. One study has shown that an aqueous extract of green tea has a potent ozone-depleting effect, and blocks UV-induced damage in the DNA, which, at least in part, explains the inhibitory photocarcinogenesis effect on green tea. Overall, this information suggests that green tea may play an important role in the reduction of UV induced oxidative stress, as well as aid in the prevention of various skin disorders, such as premature ageing.

The oxidation of some amino acid residues, such as lysine, arginine and proline, lead to the carbonyl derivatives formation that affects the nature and proteins functions. The carbonyl groups presence in proteins is one reason for the occurrence of oxidative stress and protein damage. Skin exposure to UV radiation resulted in an increase carbonyl level in proteins. In separate animal model studies, topical treatment with EGCG, grape seed proanthocyanidins and green tea polyphenols has been reported to inhibit protein oxidation induced by UV irradiation. The protein oxidation inhibition induced by UVB can result in the photodamage reduction, and more specifically, it can prevent premature skin aging.

An in vitro study demonstrated that treatment of keratinocytes with EGCG inhibited the intracellular release of hydrogen peroxide, as well as the inhibition of UVB induced oxidative stress. Similar effects were also noted with the use of epicatechin-3-gallate (EGC), which worked by eliminating free radicals in photodamaged keratinocytes by UVA and UVB radiation. EGCG formulations containing creams or green tea polyphenols were developed, and their photoprotective effects evaluated.

An exceptionally high photoprotective effect on green tea polyphenols and EGCG was observed as it protected the skin from oxidative stress induced by UV radiation. Topical treatment with EGCG, or oral with green tea polyphenols, inhibited the destruction of antioxidant defense enzymes such as catalase, glutathione peroxidase, superoxide dismutase, and glutathione.

A sunscreen containing green tea extracts was evaluated in a survey. The researchers reported that sunscreen provided significant protection against biological events associated with photoaging and photoimmunology. Similar to green tea, proanthocyanidins from grape seed, dietary supplementation, exhibited chemo-preventive effect. Grape seed proanthocyanidins intake in acute or chronic UVB pelts was able to inhibit the destruction of glutathione peroxidase, catalase and glutathione. It also inhibited lipid peroxidation, as well as hydrogen peroxide and nitric oxide in an animal model skin.

In one study, the grape seed proanthocyanidins dietary administration was able to inhibit the expression of natural proliferation nuclear antigen (PCNA, a protein associated with proliferative activity), cyclin D1 (an important regulator of the cell progression cycle, which is linked to cancer development and progression), inducible nitric oxide synthase (iNOS, isoenzyme capable of producing nitric oxide for a long time, which can generate inflammatory processes) and COX-2 in the skin.

In another study, the effects of oligomeric proanthocyanidins on melanocytes and the melanogenesis process were observed. According to the results, it was suggested that oligomeric proanthocyanidins have a photoprotective effect on melanocytes, in addition to the sequestration of intracellular reactive oxygen species. Resveratrol is also a potent polyphenolic antioxidant.

Pretreatment of human keratinocytes with resveratrol inhibited UVB-mediated activation of the NF-kB transcription factor (expression regulator in many genes involved in the cancer development and progression, such as proliferation and migration). In an animal model, resveratrol topical treatment inhibited the inflammatory responses induced by UVB, as well as the hydrogen peroxide production, which is a stable source of oxidative stress in the skin. Inhibition of these critical events by resveratrol may contribute to the UV-induced skin cancer prevention. In one study, it was demonstrated that HaCat cells (cells with unlimited replicability) treatment with resveratrol prior to UVB irradiation resulted in an increase of survival irradiated cells, besides reducing oxygen reactive species production.

Resveratrol also decreased the caspase-3 and caspase-8 (a family of endoproteases, important in controlling inflammation and cell death) activation, which has shown that they may be involved in cell survival after UVB irradiation. Soy is a rich source of isoflavones, such as genistein and daidzein. Studies have shown that genistein topical application in an animal model was able to reduce the activation of c-fos and c-jun, which are proto-oncogenes related to cell proliferation, differentiation and survival processes, as well as carcinogenesis and cancer. Genistein has also been shown to reduce oxidative and photodynamic damage in DNA. Treatment in human keratinocytes with genistein also limited lipid peroxidation and increased generation of reactive oxygen species.

Green tea polyphenols: DNA damage repair

DNA damage induced by UV is an important cell signaling pathway initiator. DNA photoproducts (photochemicals) generated from UV-induced DNA damage, are altered DNA structures that activate a series of responses, DNA repair being one of them. Exposure to UV rays can impair DNA repair, resulting in oncogenic mutations. DNA damage induced by UV may occur in the form of pyrimidine cyclobutane (CPD – a form of UV induced damage).

This form of damage can result in immunosuppression and photocarcinogenesis initiation. Several studies have documented that skin exposure to UV radiation results in the immediate formation of pyrimidine cyclobutane in skin cells. Most of the CPDs were found in the epidermis, but some were also detected in the dermis. The damage location depends on the ability of the UV radiation to penetrate the skin. It has been discovered that exposure to UV rays (at a dose lower than that required for erythema) has been enough to cause damage to certain human skin cells.

The UVB- induced pyrimidine cyclobutane (CPD) formation occurs after the protons interaction with DNA molecule. In an in vitro study, the EGCG use in a human cell culture (lung fibroblasts, skin fibroblasts and epidermal keratinocytes) was able to reduce DNA damage. Topical application of green tea polyphenols also showed a similar result as it inhibited UVB- induced damage in DNA. The green tea polyphenols topical application also inhibited the formation of CPD. Green tea extracts or white tea, also applied topically, protect the skin against the harmful effects of UV light, which can damage skin immunity.

Several studies had been conducted on the polyphenols effects, their kinetics and mechanism. These studies have shown that topical application of EGCG does not immediately prevent the formation of CPD. However, after 24h or 48h of sun exposure, the number of cells with CPD decreased after treatment with EGCG. It was then suggested that the repair mechanism presented by EGCG is mediated through the stimulation of the cytokine (protein molecule that can act on inhibition in cells of the immune system) IL-12. The IL-12 cytokine has been shown to induce repair of DNA damage. To confirm this hypothesis, an animal model with IL-12 deficiency was used.

The EGCG application in this animal model was not able to remove or reduce the presence of CPD in skin cells. In this way, the role of the IL-12 cytokine, associated with polyphenol, in the DNA damage repair was confirmed. Green tea polyphenols oral administration also showed EGCG-like effects. DNA damage in CPD form was resolved rapidly in the treatment with polyphenols from green tea. This repair effect was decreased in an animal model with IL-12 absence, which was also seen in the treatment with EGCG. The mechanisms by green tea polyphenols repaired CPD were identical to EGCG mechanisms.

The use of an aqueous green tea extract inhibited oxidative DNA damage in an in vitro system, acting against hydrogen peroxide. All of these studies on green tea polyphenols show their chemoprotective effect, as well as their performance in DNA repair.

Polyphenols performance in the reduction of UVB-induced inflammation

Pyrimidine cyclobutane (CPD) is formed immediately upon exposure of the skin to UV radiation. Then the development of inflammation occurs. After exposure to UV radiation, it was noted that damaged DNA repair in the form of CPD occurred faster with topical EGCG treatment or oral treatment with green tea polyphenols. Therefore, the inflammation levels influenced by UVB were lower in skins treated with these two substances. To assess inflammation levels, the biomarkers of inflammation, such as COX-2 expression, PGE2 production, and proinflammatory cytokine levels were analyzed.

As already mentioned, the effects of green tea polyphenols and EGCG were not observed in animal models with IL-12 deficiency, since, in these models, there was no DNA repair. This information supports the idea that DNA damage caused by UV, in addition to inflammatory responses, increases the risk of photocarcinogenesis. These in vivo studies evidence that the inflammatory inhibitory effect of these polyphenols possess is capable to prevent skin cancer. However, consumption of green tea or topical treatment with green tea polyphenols is efficient ways to prevent inflammation as well as diseases related to inflammation.

Conclusion

The polyphenols presented in this article have anti-inflammatory and antioxidant effect plus DNA damage repair. These protective effects may also contribute to the anti-photocarcinogenic effect, as well as void the chemical processes mediated by UV solar radiation. Based on studies using animal and human models, in addition to in vivo and in vitro systems, it is suggested that topical use or use of polyphenols may protect human skin from the harmful effects of UV rays. The polyphenols use in sun protection formulations and skin care lotions, for example, is very efficient. These polyphenols can act by soothing the negative effects of sun exposure on the skin, as well as protecting the skin from diseases caused by overexposure to UV rays.

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