In comparison with synthetic chemicals, natural ingredients are generally considered to be cheaper and more widely available, but still exhibit comparable benefits. Among natural ingredients, bio-flavonoids, including hesperidin, apigenin, epigallocatechin gallate, and resveratrol, exhibit a wide spectrum of biological activities, including antioxidative, anti-inflammatory, anticancer, antiaging, and UV protection, while improving cutaneous functions. In this article, we review the current in frontier about the regulatory role of resveratrol in cutaneous functions.Stilbene synthase is a key enzyme in the synthesis of resveratrol in the plants. Studies demonstrated that both expression levels of stilbene synthase and resveratrol content are regulated by a transcription factor, Myb14, which binds to Box L5 motif, leading to elevated stilbene synthase gene expression. For example, leaves contain the highest level, while the shoot tips have a relatively low level of stilbene synthase protein and mRNA in 1-year-old potted grapevines of Vitis vinifera L. cv. Cabernet Sauvignon. Moreover, during grape development, expression levels of stilbene synthase mRNA increase continuously in the grape skin until they became ripe. Likewise, old leaves of Cabernet Sauvignon exhibit higher levels of stilbene synthase mRNA than young leaves. Infections of grapes can also change the expression of stilbene synthase mRNA. Dai et al. reported that incubation of cabernet sauvignon leaves with powdery mildew fungal spores for 24 hours significantly increased expression levels of stilbene synthase mRNA.
Additionally, irradiation of grape leaves with UVC not only increased the expression levels of both stilbene synthase protein and mRNA,dutch buckets system but also increased resveratrol content, starting as early as 8 hours after irradiation. In grape skin, UVB irradiation mainly increased expression levels of stilbene synthase mRNA in unripe grapes. Wilting grapes at 28°C increased trans-resveratrol content, peaking at day 60, followed by a decline. Incubation of grape leaves with 50 mM calcium chloride for 24 hours induced greater than 2-fold increase in trans-resveratrol content in comparison with vehicle control. Irradiation with UVC could further increase trans-resveratrol content in comparison with CaCl2 alone. UVC irradiation primarily increased trans-resveratrol content in young grapes. Seasonal changes in resveratrol content were also observed in grape roots, with a higher content in the months of May and August to October, and a lower content in the remaining months of the year. Fungicides and methyl jasmonate treatments can markedly reduce resveratrol content in grapes and strawberry, respectively. Taken together, environmental conditions and the stages of plant development affect resveratrol synthesis and content. Among plants, resveratrol is most abundant in the skin of red grapes. But some other foods and beverages also contain fair amounts of resveratrol. Moreover, it appears that the age of the beverage determines its resveratrol content. For instance, 15-year-old champagne wine only contains 1 mg/L trans-resveratrol while the same wine, aged for 8 years, contains 45 mg/L trans-resveratrol.Resveratrol content also varies with different parts of plants. +e highest content of resveratrol was found in the stem phloems, but the lowest in the leaves in 1-year-old potted grapevines. Likewise, resveratrol content in the grape skin is higher than that in the leaves and seeds for some grapes.
But some grape seeds contain a higher content of resveratrol than do the skins. Moreover, resveratrol content varies greatly with cultivars. For example, resveratrol content in small white Spanish peanuts is over 20-fold higher than that in White’s runner peanuts. Similarly, resveratrol content in the skin of root stock grapes is over 100 times that in table grapes. Moreover, resveratrol content in the skin of Berlandier Resseguier grapes is over 170 times of that in the skin of Dog Ridge grapes, the same as in tomatoes, in which the total resveratrol content is 18.4 μg/g fresh weight in Micro Toms, and 0.34 and 0.38 μg/g fresh weight, respectively, in Plum Toms and Ugly Ripes. +us, resveratrol content varies with the age of beverage, plant parts, and the cultivars. Other factors, such as cultivation sites and nitrogen availability, can also influence the resveratrol content in plants. For example, the trans-resveratrol content in V. vinifera grape cane grown in Yantai is lower than that grown in Yangling, China. Likewise, knotweed from Zunyi, China, contains 4.27 ± 0.09 mg/g of resveratrol. But knotweed from Yunnan only contains 2.06 ± 0.03 mg/g of resveratrol, while resveratrol was undetectable in knotweed grown in Dunstaffnage, Canada. Similarly, the total resveratrol content is as high as 3.11 mg/L in merlot red wines made from grapes cultivated in Nagano, Japan, while the same wines only contain 0.88 mg/L of total resveratrol, if the grapes are cultivated in Iwate. Variation of resveratrol content in plants is likely due to different environment/weather conditions and chemical compositions of soils. In addition, processing methods of foods and beverages can affect resveratrol content.
Studies have shown that neither raw nor dry-roasted peanuts contain detectable trans-resveratrol, but trans-resveratrol content was ≈1.6 mg/100g in boiled peanuts and 10 to 50 μg/100 g in peanut butter. Moreover, preparation and/or processing methods can influence resveratrol content in beverages. For example, ultrasonic cleaning of grapes could increase resveratrol by as much as over 50% in comparison with that without ultrasonic cleaning. Similarly, heating high bush Michigan blueberries at 190°C for 18 min reduced trans-resveratrol by over 40% as compared to raw blueberries. Moreover, methanol extraction of grapes yields resveratrol as much as two times of acetone extraction. In summary, plants and fruits contain a fair amount of resveratrol. But environmental conditions, developmental stage, and the parts of plants or fruits largely determine resveratrol content, while processing methods and storage conditions can affect the resveratrol content of foods and beverages. +e content of resveratrol in certain foods, plants, and beverages is summarized in Supplemental Table 1.Both keratinocyte proliferation and differentiation are required for the epidermis to reach its ultimate goal of the formation of the stratum corneum, an essential structure for epidermal permeability barrier. Several studies have demonstrated that resveratrol inhibits keratinocyte proliferation while stimulating differentiation. Resveratrol at a concentration as low as 2 μM markedly inhibits DNA synthesis in keratinocyte cultures. Inhibitory effect of resveratrol on DNA synthesis occurred as early as 24 hr after addition to cultures, with an IC50 range of 2–8 μM. Incubation of keratinocytes with resveratrol, at concentrations as low as 0.25 μM for 72 hr, could induce a dose-dependent reduction in the number of living cells. Wu et al. reported that 20 μM resveratrol inhibited keratinocyte proliferation by over 80%, using the 5-bromo-2-deoxyuridine assay. With long term treatments , even 0.197 μM resveratrol was sufficed to inhibit keratinocyte proliferation by 80% [82]. +e activities of keratinocyte proliferation and differentiation are coordinated in an inverse manner, while terminal differentiation is crucial for the formation of permeability barrier. In contrast to proliferation, resveratrol stimulates keratinocyte differentiation. For example, treatment of keratinocytes with 3 μM resveratrol until 3 days after post confluence increased involucrin expression by 1.5-fold. Moreover, formation of cornified envelopes, criticalstructures for epidermal permeability barrier, requires transglutaminase. Treatment of keratinocytes with resveratrol induced a dose-dependent increase in transglutaminase activity, while simultaneously inhibiting DNA synthesis, with a half-maximal concentration of 35 μM. Finally, resveratrol and 1, 252D3 synergistically increased transglutaminase activity. +us, resveratrol inhibits keratinocyte proliferation, while stimulating differentiation.While suberythemogenic doses of UVB irradiation instead enhance epidermal function,dutch buckets including improvements in epidermal permeability barrier function, stimulation of epidermal lipid synthesis and keratinocyte differentiation, and antimicrobial defense, excessive exposure to UV irradiation can damage the skin, causing sunburns, skin cancers, and photoaging. Both in vivo and in vitro studies have demonstrated that resveratrol protected the skin from UV irradiation. For example, addition of 0.1 μM resveratrol to the culture medium immediately postirradiation provided 100% protection against UVA induced reductions in keratinocyte proliferation and an increase in malondialdehyde content. In parallel, both superoxide dismutase and glutathione peroxidase contents in UVA-irradiated keratinocytes were normalized by treatment with resveratrol. Either prior to or post-UVA irradiation, treatment of keratinocytes with resveratrol decreased lipid peroxidation. But only pretreatment, not posttreatment with resveratrol, increased SOD and glutathione S-transferase protein levels. In addition to UVA irradiation, resveratrol can also protect keratinocytes from UVB-induced damages. For example, treatment of keratinocytes with resveratrol 1 hr prior to UVB irradiation decreased apoptosis rates by over 50%.
Moreover, treatment of keratinocytes with resveratrol prior to UV irradiation decreased the expression levels of proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, by ≈50% from untreated keratinocytes. Likewise, addition of 10 μM resveratrol immediately after UVA and UVB irradiation also lowered the expression levels of IL-1-beta and IL-6. In addition, treatment of dermal fibroblasts with resveratrol after UVB irradiation decreased the contents of reactive oxygen species, TNF-α and IL-6, inducible nitric oxide synthase , and expression levels of matrix metallopeptidase I, while increasing procollagen 1 and elastin. It appeared that pretreatment of keratinocytes with low concentration of resveratrol did not inhibit UV irradiation induced inflammation. +e protective effects of resveratrol against UV irradiation have also been demonstrated in vivo. Afag et al. reported that topical application of 25 μM resveratrol 30 min prior to UVB irradiation decreased skin thickness and punch weight of ear by over 50 and 81%, respectively, in comparison with vehicle-treated controls. Moreover, cutaneous inflammatory infiltration and ornithine decarboxylase protein levels decreased significantly in mouse skin treated with topical resveratrol prior to UVB irradiation. Yet, topical applications of resveratrol post-UVB irradiation decreased whole skin thickness, but not epidermal thickness. Some studies showed that resveratrol and UV irradiation synergistically enhanced expression levels of IL-8 mRNA and protein, and DNA damage in keratinocytes as compared to UV irradiation alone. +ese discrepant results could be attributable to variations, including the doses of resveratrol and UV irradiation, treatment timing, and/or the status of growth and differentiation in these cells. +us, further studies are needed to clarify the effects of resveratrol on cutaneous function.A number of factors, including psychological stress, cigarette smoke, air pollution, and UV irradiation, can cause oxidative stress, contributing to the development of aging and a line of disorders such as dermatoses, inflammation, cardiovascular diseases, cancer, and neurodegenerative diseases. Accordingly,antioxidants have been utilized to prevent and treat certain disorders. Among the antioxidants, benefits of resveratrol have also been studied extensively both in vitro and in vivo. Phase II enzymes, including GSH-Px, quinone dehydrogenase , GST, SOD, and GSH, are responsible for antioxidation in living organisms. Soeur et al. reported that 10 μM resveratrol induced an over 2-fold increase in expression levels of mRNA for GSH-Px and NQO1, along with over 1-fold increase in glutathione synthesis, in keratinocytes, in addition to an over 7-fold increase in expression levels of mRNA for GSH-Px and NQO1 in reconstructed human skin. Resveratrol can also protect keratinocytes from damages caused by oxidative stressors, including nitric oxide , H2O2, cigarette smoke, and arsenic. Surprisingly, topical resveratrol did not mitigate UVB irradiation-induced reductions in both activity and expression levels of antioxidant enzymes, including catalase, SOD, and GSH-Px, in a mouse model of chronic UVB irradiation. NO is a free radical required for maintenance of normal function, but excessive NO can induce oxidative stress, leading to apoptosis. Topical applications of human skin with NO donor caused cutaneous inflammation and keratinocyte apoptosis. Likewise, 3 mM sodium nitroprusside induced ≈70% inhibition of keratinocyte proliferation. Treatment of keratinocytes with the combination of 30 μM resveratrol and 3 mM sodium nitroprusside reduced caspase 3 and 9 activity as well as apoptotic rate by 80% from cultures treated with sodium nitroprusside alone. H2O2 is commonly used as stressor to induce oxidative stress. Following the treatment of keratinocytes with 400 μM H2O2, reactive oxygen species content increased 1.5-fold over the controls. Resveratrol at concentrations of 25 μM and 100 μM lowered ROS contents by 25% and 40%, respectively, in comparison with cells treated with H2O2 alone. Finally, the protective effects of resveratrol against oxidative stress have also been demonstrated in keratinocytes treated with either arsenic or cigarette smoke. +e skin, an interface between the body and external environment, is vulnerable to environmental insults, including oxidative stress, leading to acceleration of skin aging and the development of a variety of skin disorders. +erefore, enhancement of antioxidant defense of the skin could help manage various cutaneous dermatoses. Krajka-Ku´zniak et al. showed that a single topical treatment of mouse skin with 16 μM resveratrol for 4 hr increased GST activity by 63% and GST content by 22% over controls. Similarly, a greater than 1-fold increase in GST activity was observed in mouse epidermis 24 hr after topical application of 16 μM resveratrol.