Review of plant phenolics, part 3: Nonflavonoid compounds

Polyphenols are widely distributed in the plant kingdom, and are found in copious supply in multiple vegetables, fruits, herbs, grains, tea, coffee beans, honey, and red wine, for example. They are an especially important source of antioxidants and are increasingly the focus of research due to their potent and diverse biologic activities. In the conclusion to my three-part review of polyphenols, this column identifies representative compounds from the classes of nonflavonoid polyphenols and provides a brief update on research.

Phenolic acids: ferulic acid

Derived from curcumin, ferulic acid is noted for exhibiting multiple biologic activities, including antiapoptotic, anticarcinogenic, antidiabetic, hepatoprotective, and cardioprotective, among others. Its beneficial effects are thought to be mediated through its antioxidant and anti-inflammatory characteristics.¹ In a small 2008 study, a stable formulation of 15% l-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid was applied topically to normal-appearing human skin for 4 days and was found to impart significant photoprotection against solar-simulated UV radiation and was especially effective at diminishing thymine dimer mutations, which are linked to skin cancer. The authors also noted that the mechanism of action of this antioxidant formulation differs from that of sunscreens and, therefore, may serve as a supplement to such products.² (It is worth noting that ferulic acid has been approved as a sunscreen agent in Japan.³)

In 2015, Ambothi et al. used Swiss albino mice to assess the photochemopreventive effects of ferulic acid against chronic (30-week) UVB, finding the intraperitoneal and topical administration of the phenolic acid effective in significantly lowering the incidence of UVB-induced tumor volume and weight in the mice skin.⁴ The next year, Hahn et al. reported that pretreatment with ferulic acid protects human dermal fibroblasts from UVA-induced photodamage.⁵ Also in 2016, Chaiprasongsuk et al. found that several dietary phenolics, including ferulic acid, deliver protection against UVA-induced melanogenesis through indirect regulation of the Nrf2-ARE pathway.⁶

Lignans: flaxseed

Flaxseed lignans, which exhibit a wide range of biologic activities, are best known for their antioxidant properties.⁷ In a 2017 study using atopic dermatitis–induced NC/Nga mice, Yang et al. found that fermented flaxseed oil administered orally was successful in relieving symptoms such as erythema, edema, pruritus, and epithelial damage.⁸ Two years earlier, Draganescu et al. developed a topical flaxseed extract formulation that displayed wound healing capabilities on Wistar rats.⁷ Emulsions produced from the oils and seeds of transgenic flax have also been found to protect against oxidative stress in hamster fibroblasts, with investigators suggesting that the emulsions have potential to protect the skin against such damage.⁸

Stilbenes: resveratrol

The antioxidant potency of resveratrol has been cited for conferring a wide range of salutary effects, including antitumorigenic as well as antiaging activity. In 2008, a resveratrol-based skin care formulation intended to combat photoaging was reported to exhibit 17-fold greater antioxidant activity than idebenone.⁹ In a different study that year, resveratrol, the primary active polyphenolic constituent in red wine, was assessed in terms of topical/transdermal delivery viability, given previously established benefits shown via systemic administration. Several hydrogel systems used as resveratrol vehicles were shown to be safe and effective methods for cutaneously delivering the therapeutic effects of this antioxidant.¹⁰ Since then, resveratrol has been demonstrated to penetrate the skin via topical administration, reinforcing the antioxidant system of the stratum corneum and delivering increases of antioxidants to human epidermal tissue.¹¹

In 2014, Farris et al. showed that a proprietary topical antioxidant blend of resveratrol, baicalin, and vitamin E applied topically at night yielded statistically significant amelioration of fine lines and wrinkles, as well as skin firmness, elasticity, laxity, hyperpigmentation, radiance, and roughness over a 12-week period.¹²Resveratrol has also been shown in mice to suppress the inflammatory response and improve survival from severe burns with bacterial infections.¹³

Hydrolyzable tannins: ellagic acid

Ellagic acid, a dimer of gallic acid, has been reported to impart anti-inflammatory, antitumor, immunomodulatory, and antifungal activities.^14-16 Ortiz-Ruiz et al. have noted that while ellagic acid is used as a whitening agent, it can act as a substrate to rather than an inhibitor of tyrosinase, as it is oxidized by the enzyme to an unstable o-quinone. However, as a potent antioxidant, ellagic acid can block melanogenesis by reducing o-quinones and semiquinones.¹⁷

In a double-blind, placebo-controlled, 4-week trial to assess the effects of orally administered ellagic acid–rich pomegranate extract on the pigmentation of 13 women after UV exposure, with healthy volunteers randomly assigned to high-dose, low-dose, and control groups, luminance values decreased by 1.73% in the high-dose group and 1.35% in the low-dose group, as compared with the control group, and stains and freckles were reported to be diminished.¹⁸ A 2016 study in human dermal fibroblasts by Baek et al. suggested that ellagic acid displays antiphotoaging activity, as the polyphenol protected against UVB-induced oxidative stress potentially through an Nrf2-dependent pathway.¹⁵

Condensed tannins (Proanthocyanidins): pycnogenol

Pycnogenol has been used in an antioxidant mixture also including vitamins C and E, as well as evening primrose that when orally administered for 10 weeks to female SKH-1 hairless mice exposed three times weekly to UVB irradiation demonstrated the capacity to significantly inhibit wrinkle formation by markedly suppressing UVB-induced MMP activity while promoting collagen production.¹⁹ In a 2012 study of 112 women with mild to moderate photoaging, orally administered pycnogenol was shown to yield significant reductions in clinical grading of skin photoaging scores.²⁰ Four years later, a review by Grether-Beck et al. suggested that oral administration of pycnogenol imparts photoprotection, diminishes hyperpigmentation, and improves skin barrier function and the stability of the extracellular matrix.²¹

Lignins: various woody plants

Recognized as efficient natural scavengers of reactive oxygen species, lignins are complex phenolic polymers that are abundant in nature, particularly in various tree species and agricultural products. In 2004, Dizhbite et al. isolated lignin samples from deciduous and coniferous trees to assess their capacity as natural antioxidants. Samples were assessed against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical in homogeneous conditions, with the commercially available kraft lignin noted for displaying antibacterial activity associated with its radical-scavenging properties.²² Four years later, Ugartondo et al. studied several lignins and reported a strong antioxidant capacity at various concentrations that were innocuous to normal human cells and stable when exposed to UVA. The investigators concluded that lignins may be viable for inclusion in cosmetic and topical medical formulations.²³

Conclusion

A brief survey of the polyphenolic landscape obviously cannot do the subject justice. From the dermatologic perspective, this diverse family of compounds factor into the skin care formulations becoming more prevalent in the established armamentarium, as well as the direct-to-consumer market. Given the increasing attention paid here and elsewhere to the impact of diet on the skin, the status of this dynamic class of polyphenolic compounds, which includes several antioxidants and is found in numerous plants, appears to be well deserved and warrants much more research.

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

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