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The use of bioactive ingredients culled from the marine environment has increased significantly in recent years for use in skin care because of the reputed antioxidant and anti-aging activity of these substances.1-3
In the last couple of decades, secondary metabolites with bioactive properties have been identified in seaweeds. Among these substances, phlorotannins have been isolated from brown seaweeds and demonstrated to exhibit anti-allergic, anti-inflammatory, antioxidant, anticancer, and antiwrinkling activity, as well as some capacity to promote hair growth.4 Sanjeewa et al. suggest that phlorotannins, or marine polyphenols, derived from brown seaweed are well suited for use in cosmeceutical formulations and appear to exhibit skin whitening and antiwrinkling properties in particular.4 This column will discuss recent findings regarding the use of marine ingredients in cosmetic formulations, with a particular focus on substances such as fucoidan, as well as emerging evidence regarding the benefits to human skin derived from salmon eggs.
Recent studies of marine products in cosmetic formulations
In 2017, Fabrowska et al. showed in two groups of 10 volunteers each (one ranging from 20 to 30 years old and one from 40 to 50 years old) that the freshwater alga Cladophora glomerate is an effective ingredient for use as a cosmetic agent intended to moisturize and firm the skin.5
The next year, Thu et al. reported on the preparation of a cream mask composed of Vietnamese seaweeds (Caulerpa lentillifera, Sargassum crassifolium, Ulva reticulata, and Kappaphycus alvarezii), which they found to be abundant in proteins, polysaccharides, carotenoids, and other vitamins and to have potent antibacterial, cell proliferation, moisture retention, and tyrosinase inhibitory properties. The authors added that the seaweed cream mask was safe, provoked no irritation, and appeared to be effective in delivering anti-aging and moisturizing benefits.6
In 2019, Jesumani et al., in reviewing the potential cutaneous benefits of bioactive substances in seaweed, noted a significant increase in the use of ingredients found in macroalgae or seaweed in cosmetic formulations, also noting the range of reputed bioactivity (i.e., antioxidant, antitumor, anti-inflammatory, antilipidemic, antimicrobial, and anti-allergic).7 Seaweeds are a significant source of vitamins A, B, C, D, and E, and green, red, and brown algae contain pigments that protect against UV irradiation.7,8
Also that year, Hameury et al. conducted an ex vivo assessment to predict the cutaneous anti-aging benefits of an aqueous gel containing 6.1% marine ingredients (amino acid-enriched giant kelp extract, trace element-enriched seawater, and dedifferentiated sea fennel cells) topically applied on human skin explants. The investigators found that 64 proteins were significantly regulated by the gel when marine ingredients were compared with untreated skin explants, with the ingredients shown to act on the epidermis and dermis. These proteins are involved in multiple functions including gene expression, inflammatory processes, dermal extracellular matrix production, and melanogenesis and keratinocyte proliferation, suggesting, according to the authors, that marine ingredients could play a role in preventing cutaneous aging and contributing to the health of the epidermis and dermis.9
Early in 2020, Poulose et al. reported on the first use of a photoprotective cosmetic cream combining nanomelanin and seaweed that exerts antioxidant, antibacterial, and wound healing activity.10
The skin-lightening potential of fucoidan
In 2017, Wang et al. investigated the antimelanogenic activity of fucoidan – a complex sulfated polysaccharide extracted from brown seaweed known to possess a broad array of biologic functions – on B16 murine melanoma cells. Their in vitro studies revealed that fucoidan suppresses B16 melanoma cell proliferation and cellular tyrosinase activity and has potential as a skin-whitening cosmeceutical agent.11
Two years later, Jesumani et al. investigated the polysaccharides extracted from the seaweed species Sargassum vachellianum, S. horneri, and S. hemiphyllum. Found to be abundant in fucose, all of the evaluated polysaccharides demonstrated dose-dependent antioxidant activity and effectiveness in hindering tyrosinase and elastase. The researchers concluded that all of the tested species display potential as key ingredients in cosmeceutical agents intended to treat wrinkles or lighten skin.12
More recently, a comparative study by the same team revealed that both fucoidan-rich polysaccharide extract and polyphenol-rich extract from the seaweed S. vachellianum delivered significant protective activity. Both protected the skin from UV harm: The fucoidan-rich extract showed superior free radical scavenging and antimicrobial activity, while the polyphenol extract performed better at absorbing UV radiation. The investigators suggested that both extracts could provide a balanced approach to skin protection when featured in skin care products.13
In addition, it is worth noting that a key monomeric component of red macroalgae (Rhodophyta), 3,6-anhydro-l-galactose, has been found in vitro to display skin-whitening activity.14
Salmon eggs
In a 2013 double-blind, randomized clinical trial with 66 patients, Lønne et al. reported that subjects treated topically with salmon egg extract experienced significant amelioration of photoaging, including wrinkles, pigmentation, erythema, and xerosis, yielding global skin appearance improvement.3,15
A pilot study by Mekas et al., which was reported 2 years later and included 75 patients, revealed that skin tone and evenness were improved by a topical exfoliative cream featuring hydrolyzed roe proteins, based on subjective and objective measures comparing 4% glycolic acid.3,16
In 2016, Yoshino et al. showed that human dermal fibroblasts incubated with salmon egg extract upregulated the expression of collagen type I genes and several oxidative genes.3,17 The topical application of hydrolyzed salmon roe proteins to human skin has also been demonstrated to eliminate cell-to-cell adhesions thus ameliorating the appearance of photodamaged skin.1,3,16
More recently, a comprehensive PubMed search on the bioactive ingredients used in Korean cosmeceuticals reported early in 2020 that there is increased interest in salmon eggs because they provide a copious supply of unsaturated fatty acids, proteins, vitamins, and minerals known to nurture cutaneous health.3,15
Conclusion
. Research into the numerous bioactive properties of these multitudinous species has ramped up in recent years and is yielding evidence regarding the efficacy and potential broader uses of such ingredients in cutaneous health care. As we build on our understanding of just how dynamic a source of treatment options may lie under the sea, we become increasingly aware, ironically, of the damage that human industrialization exerts on the planet, as well as these precious marine resources (including the possibly deleterious effects of chemical sunscreens like those that are now banned for sale in Hawai‘i). Humanity will need to become much better stewards of the Earth if we are to enhance our future opportunities and possibly harness the potent marine ingredients still available with the potential to enhance skin health and appearance.
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 has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.
References
1. Kim SK. J Cosmet Dermatol. 2014;13(1):56-67.
2. Venkatesan J et al. Mar Drugs. 2017;15(5):1-18.
3. Nguyen JK et al. J Cosmet Dermatol 2020 Jul;19(7):1555-69.
4. Sanjeewa KKA et al. J Photochem Photobiol B. 2016 Sep;162:100-5.
5. Fabrowska J et al. Acta Pol Pharm. 2017 Mar;74(2):633-41.
6. Thu NTH et al. J Cosmet Sci. Nov/Dec 2018;69(6):447-62.
7. Jesumani V et al. Mar Drugs. 2019 Dec 6;17(12):688.
8. Kim MS et al. Photochem Photobiol. Jul-Aug 2013;89(4):911-8.
9. Hameury S et al. J Cosmet Dermatol. 2019 Feb;18(1):355-70.
10. Poulose N et al. J Photochem Photobiol B. 2020 Apr;205:111816.
11. Wang ZJ et al. Afr J Tradit Complement Altern Med. 2017 Jun 5;14(4);149-55.
12. Jesumani V et al. Int J Biol Macromol. 2019 Nov 1;140:216-24.
13. Jesumani V et al. PLoS One. 2020 Jan 7;15(1):e0227308.
14. Kim JH et al. Mar Drugs. 2017 Oct 20;15(10):321.
15. Lønne GK et al. Int J Cosmet Sci. 2013 Oct;35(5):515-22.
16. Mekas M et al. J Drugs Dermatol. 2015 Nov;14(11):1306-19.
17. Yoshino A et al. Clin Interv Aging. 2016;11:1159-68.
The use of bioactive ingredients culled from the marine environment has increased significantly in recent years for use in skin care because of the reputed antioxidant and anti-aging activity of these substances.1-3
In the last couple of decades, secondary metabolites with bioactive properties have been identified in seaweeds. Among these substances, phlorotannins have been isolated from brown seaweeds and demonstrated to exhibit anti-allergic, anti-inflammatory, antioxidant, anticancer, and antiwrinkling activity, as well as some capacity to promote hair growth.4 Sanjeewa et al. suggest that phlorotannins, or marine polyphenols, derived from brown seaweed are well suited for use in cosmeceutical formulations and appear to exhibit skin whitening and antiwrinkling properties in particular.4 This column will discuss recent findings regarding the use of marine ingredients in cosmetic formulations, with a particular focus on substances such as fucoidan, as well as emerging evidence regarding the benefits to human skin derived from salmon eggs.
Recent studies of marine products in cosmetic formulations
In 2017, Fabrowska et al. showed in two groups of 10 volunteers each (one ranging from 20 to 30 years old and one from 40 to 50 years old) that the freshwater alga Cladophora glomerate is an effective ingredient for use as a cosmetic agent intended to moisturize and firm the skin.5
The next year, Thu et al. reported on the preparation of a cream mask composed of Vietnamese seaweeds (Caulerpa lentillifera, Sargassum crassifolium, Ulva reticulata, and Kappaphycus alvarezii), which they found to be abundant in proteins, polysaccharides, carotenoids, and other vitamins and to have potent antibacterial, cell proliferation, moisture retention, and tyrosinase inhibitory properties. The authors added that the seaweed cream mask was safe, provoked no irritation, and appeared to be effective in delivering anti-aging and moisturizing benefits.6
In 2019, Jesumani et al., in reviewing the potential cutaneous benefits of bioactive substances in seaweed, noted a significant increase in the use of ingredients found in macroalgae or seaweed in cosmetic formulations, also noting the range of reputed bioactivity (i.e., antioxidant, antitumor, anti-inflammatory, antilipidemic, antimicrobial, and anti-allergic).7 Seaweeds are a significant source of vitamins A, B, C, D, and E, and green, red, and brown algae contain pigments that protect against UV irradiation.7,8
Also that year, Hameury et al. conducted an ex vivo assessment to predict the cutaneous anti-aging benefits of an aqueous gel containing 6.1% marine ingredients (amino acid-enriched giant kelp extract, trace element-enriched seawater, and dedifferentiated sea fennel cells) topically applied on human skin explants. The investigators found that 64 proteins were significantly regulated by the gel when marine ingredients were compared with untreated skin explants, with the ingredients shown to act on the epidermis and dermis. These proteins are involved in multiple functions including gene expression, inflammatory processes, dermal extracellular matrix production, and melanogenesis and keratinocyte proliferation, suggesting, according to the authors, that marine ingredients could play a role in preventing cutaneous aging and contributing to the health of the epidermis and dermis.9
Early in 2020, Poulose et al. reported on the first use of a photoprotective cosmetic cream combining nanomelanin and seaweed that exerts antioxidant, antibacterial, and wound healing activity.10
The skin-lightening potential of fucoidan
In 2017, Wang et al. investigated the antimelanogenic activity of fucoidan – a complex sulfated polysaccharide extracted from brown seaweed known to possess a broad array of biologic functions – on B16 murine melanoma cells. Their in vitro studies revealed that fucoidan suppresses B16 melanoma cell proliferation and cellular tyrosinase activity and has potential as a skin-whitening cosmeceutical agent.11
Two years later, Jesumani et al. investigated the polysaccharides extracted from the seaweed species Sargassum vachellianum, S. horneri, and S. hemiphyllum. Found to be abundant in fucose, all of the evaluated polysaccharides demonstrated dose-dependent antioxidant activity and effectiveness in hindering tyrosinase and elastase. The researchers concluded that all of the tested species display potential as key ingredients in cosmeceutical agents intended to treat wrinkles or lighten skin.12
More recently, a comparative study by the same team revealed that both fucoidan-rich polysaccharide extract and polyphenol-rich extract from the seaweed S. vachellianum delivered significant protective activity. Both protected the skin from UV harm: The fucoidan-rich extract showed superior free radical scavenging and antimicrobial activity, while the polyphenol extract performed better at absorbing UV radiation. The investigators suggested that both extracts could provide a balanced approach to skin protection when featured in skin care products.13
In addition, it is worth noting that a key monomeric component of red macroalgae (Rhodophyta), 3,6-anhydro-l-galactose, has been found in vitro to display skin-whitening activity.14
Salmon eggs
In a 2013 double-blind, randomized clinical trial with 66 patients, Lønne et al. reported that subjects treated topically with salmon egg extract experienced significant amelioration of photoaging, including wrinkles, pigmentation, erythema, and xerosis, yielding global skin appearance improvement.3,15
A pilot study by Mekas et al., which was reported 2 years later and included 75 patients, revealed that skin tone and evenness were improved by a topical exfoliative cream featuring hydrolyzed roe proteins, based on subjective and objective measures comparing 4% glycolic acid.3,16
In 2016, Yoshino et al. showed that human dermal fibroblasts incubated with salmon egg extract upregulated the expression of collagen type I genes and several oxidative genes.3,17 The topical application of hydrolyzed salmon roe proteins to human skin has also been demonstrated to eliminate cell-to-cell adhesions thus ameliorating the appearance of photodamaged skin.1,3,16
More recently, a comprehensive PubMed search on the bioactive ingredients used in Korean cosmeceuticals reported early in 2020 that there is increased interest in salmon eggs because they provide a copious supply of unsaturated fatty acids, proteins, vitamins, and minerals known to nurture cutaneous health.3,15
Conclusion
. Research into the numerous bioactive properties of these multitudinous species has ramped up in recent years and is yielding evidence regarding the efficacy and potential broader uses of such ingredients in cutaneous health care. As we build on our understanding of just how dynamic a source of treatment options may lie under the sea, we become increasingly aware, ironically, of the damage that human industrialization exerts on the planet, as well as these precious marine resources (including the possibly deleterious effects of chemical sunscreens like those that are now banned for sale in Hawai‘i). Humanity will need to become much better stewards of the Earth if we are to enhance our future opportunities and possibly harness the potent marine ingredients still available with the potential to enhance skin health and appearance.
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 has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.
References
1. Kim SK. J Cosmet Dermatol. 2014;13(1):56-67.
2. Venkatesan J et al. Mar Drugs. 2017;15(5):1-18.
3. Nguyen JK et al. J Cosmet Dermatol 2020 Jul;19(7):1555-69.
4. Sanjeewa KKA et al. J Photochem Photobiol B. 2016 Sep;162:100-5.
5. Fabrowska J et al. Acta Pol Pharm. 2017 Mar;74(2):633-41.
6. Thu NTH et al. J Cosmet Sci. Nov/Dec 2018;69(6):447-62.
7. Jesumani V et al. Mar Drugs. 2019 Dec 6;17(12):688.
8. Kim MS et al. Photochem Photobiol. Jul-Aug 2013;89(4):911-8.
9. Hameury S et al. J Cosmet Dermatol. 2019 Feb;18(1):355-70.
10. Poulose N et al. J Photochem Photobiol B. 2020 Apr;205:111816.
11. Wang ZJ et al. Afr J Tradit Complement Altern Med. 2017 Jun 5;14(4);149-55.
12. Jesumani V et al. Int J Biol Macromol. 2019 Nov 1;140:216-24.
13. Jesumani V et al. PLoS One. 2020 Jan 7;15(1):e0227308.
14. Kim JH et al. Mar Drugs. 2017 Oct 20;15(10):321.
15. Lønne GK et al. Int J Cosmet Sci. 2013 Oct;35(5):515-22.
16. Mekas M et al. J Drugs Dermatol. 2015 Nov;14(11):1306-19.
17. Yoshino A et al. Clin Interv Aging. 2016;11:1159-68.
The use of bioactive ingredients culled from the marine environment has increased significantly in recent years for use in skin care because of the reputed antioxidant and anti-aging activity of these substances.1-3
In the last couple of decades, secondary metabolites with bioactive properties have been identified in seaweeds. Among these substances, phlorotannins have been isolated from brown seaweeds and demonstrated to exhibit anti-allergic, anti-inflammatory, antioxidant, anticancer, and antiwrinkling activity, as well as some capacity to promote hair growth.4 Sanjeewa et al. suggest that phlorotannins, or marine polyphenols, derived from brown seaweed are well suited for use in cosmeceutical formulations and appear to exhibit skin whitening and antiwrinkling properties in particular.4 This column will discuss recent findings regarding the use of marine ingredients in cosmetic formulations, with a particular focus on substances such as fucoidan, as well as emerging evidence regarding the benefits to human skin derived from salmon eggs.
Recent studies of marine products in cosmetic formulations
In 2017, Fabrowska et al. showed in two groups of 10 volunteers each (one ranging from 20 to 30 years old and one from 40 to 50 years old) that the freshwater alga Cladophora glomerate is an effective ingredient for use as a cosmetic agent intended to moisturize and firm the skin.5
The next year, Thu et al. reported on the preparation of a cream mask composed of Vietnamese seaweeds (Caulerpa lentillifera, Sargassum crassifolium, Ulva reticulata, and Kappaphycus alvarezii), which they found to be abundant in proteins, polysaccharides, carotenoids, and other vitamins and to have potent antibacterial, cell proliferation, moisture retention, and tyrosinase inhibitory properties. The authors added that the seaweed cream mask was safe, provoked no irritation, and appeared to be effective in delivering anti-aging and moisturizing benefits.6
In 2019, Jesumani et al., in reviewing the potential cutaneous benefits of bioactive substances in seaweed, noted a significant increase in the use of ingredients found in macroalgae or seaweed in cosmetic formulations, also noting the range of reputed bioactivity (i.e., antioxidant, antitumor, anti-inflammatory, antilipidemic, antimicrobial, and anti-allergic).7 Seaweeds are a significant source of vitamins A, B, C, D, and E, and green, red, and brown algae contain pigments that protect against UV irradiation.7,8
Also that year, Hameury et al. conducted an ex vivo assessment to predict the cutaneous anti-aging benefits of an aqueous gel containing 6.1% marine ingredients (amino acid-enriched giant kelp extract, trace element-enriched seawater, and dedifferentiated sea fennel cells) topically applied on human skin explants. The investigators found that 64 proteins were significantly regulated by the gel when marine ingredients were compared with untreated skin explants, with the ingredients shown to act on the epidermis and dermis. These proteins are involved in multiple functions including gene expression, inflammatory processes, dermal extracellular matrix production, and melanogenesis and keratinocyte proliferation, suggesting, according to the authors, that marine ingredients could play a role in preventing cutaneous aging and contributing to the health of the epidermis and dermis.9
Early in 2020, Poulose et al. reported on the first use of a photoprotective cosmetic cream combining nanomelanin and seaweed that exerts antioxidant, antibacterial, and wound healing activity.10
The skin-lightening potential of fucoidan
In 2017, Wang et al. investigated the antimelanogenic activity of fucoidan – a complex sulfated polysaccharide extracted from brown seaweed known to possess a broad array of biologic functions – on B16 murine melanoma cells. Their in vitro studies revealed that fucoidan suppresses B16 melanoma cell proliferation and cellular tyrosinase activity and has potential as a skin-whitening cosmeceutical agent.11
Two years later, Jesumani et al. investigated the polysaccharides extracted from the seaweed species Sargassum vachellianum, S. horneri, and S. hemiphyllum. Found to be abundant in fucose, all of the evaluated polysaccharides demonstrated dose-dependent antioxidant activity and effectiveness in hindering tyrosinase and elastase. The researchers concluded that all of the tested species display potential as key ingredients in cosmeceutical agents intended to treat wrinkles or lighten skin.12
More recently, a comparative study by the same team revealed that both fucoidan-rich polysaccharide extract and polyphenol-rich extract from the seaweed S. vachellianum delivered significant protective activity. Both protected the skin from UV harm: The fucoidan-rich extract showed superior free radical scavenging and antimicrobial activity, while the polyphenol extract performed better at absorbing UV radiation. The investigators suggested that both extracts could provide a balanced approach to skin protection when featured in skin care products.13
In addition, it is worth noting that a key monomeric component of red macroalgae (Rhodophyta), 3,6-anhydro-l-galactose, has been found in vitro to display skin-whitening activity.14
Salmon eggs
In a 2013 double-blind, randomized clinical trial with 66 patients, Lønne et al. reported that subjects treated topically with salmon egg extract experienced significant amelioration of photoaging, including wrinkles, pigmentation, erythema, and xerosis, yielding global skin appearance improvement.3,15
A pilot study by Mekas et al., which was reported 2 years later and included 75 patients, revealed that skin tone and evenness were improved by a topical exfoliative cream featuring hydrolyzed roe proteins, based on subjective and objective measures comparing 4% glycolic acid.3,16
In 2016, Yoshino et al. showed that human dermal fibroblasts incubated with salmon egg extract upregulated the expression of collagen type I genes and several oxidative genes.3,17 The topical application of hydrolyzed salmon roe proteins to human skin has also been demonstrated to eliminate cell-to-cell adhesions thus ameliorating the appearance of photodamaged skin.1,3,16
More recently, a comprehensive PubMed search on the bioactive ingredients used in Korean cosmeceuticals reported early in 2020 that there is increased interest in salmon eggs because they provide a copious supply of unsaturated fatty acids, proteins, vitamins, and minerals known to nurture cutaneous health.3,15
Conclusion
. Research into the numerous bioactive properties of these multitudinous species has ramped up in recent years and is yielding evidence regarding the efficacy and potential broader uses of such ingredients in cutaneous health care. As we build on our understanding of just how dynamic a source of treatment options may lie under the sea, we become increasingly aware, ironically, of the damage that human industrialization exerts on the planet, as well as these precious marine resources (including the possibly deleterious effects of chemical sunscreens like those that are now banned for sale in Hawai‘i). Humanity will need to become much better stewards of the Earth if we are to enhance our future opportunities and possibly harness the potent marine ingredients still available with the potential to enhance skin health and appearance.
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 has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Revance, Evolus, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a company that independently tests skin care products and makes recommendations to physicians on which skin care technologies are best. Write to her at dermnews@mdedge.com.
References
1. Kim SK. J Cosmet Dermatol. 2014;13(1):56-67.
2. Venkatesan J et al. Mar Drugs. 2017;15(5):1-18.
3. Nguyen JK et al. J Cosmet Dermatol 2020 Jul;19(7):1555-69.
4. Sanjeewa KKA et al. J Photochem Photobiol B. 2016 Sep;162:100-5.
5. Fabrowska J et al. Acta Pol Pharm. 2017 Mar;74(2):633-41.
6. Thu NTH et al. J Cosmet Sci. Nov/Dec 2018;69(6):447-62.
7. Jesumani V et al. Mar Drugs. 2019 Dec 6;17(12):688.
8. Kim MS et al. Photochem Photobiol. Jul-Aug 2013;89(4):911-8.
9. Hameury S et al. J Cosmet Dermatol. 2019 Feb;18(1):355-70.
10. Poulose N et al. J Photochem Photobiol B. 2020 Apr;205:111816.
11. Wang ZJ et al. Afr J Tradit Complement Altern Med. 2017 Jun 5;14(4);149-55.
12. Jesumani V et al. Int J Biol Macromol. 2019 Nov 1;140:216-24.
13. Jesumani V et al. PLoS One. 2020 Jan 7;15(1):e0227308.
14. Kim JH et al. Mar Drugs. 2017 Oct 20;15(10):321.
15. Lønne GK et al. Int J Cosmet Sci. 2013 Oct;35(5):515-22.
16. Mekas M et al. J Drugs Dermatol. 2015 Nov;14(11):1306-19.
17. Yoshino A et al. Clin Interv Aging. 2016;11:1159-68.