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Herbal medicines that benefit epidermal permeability barrier function
DERMATOLOGICA SINICA 33 (2015) 90e95
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Dermatologica Sinica journal homepage: http://www.derm-sinica.com
INVITED ARTICLE
Herbal medicines that benefit epidermal permeability barrier function Lizhi Hu 1, a, **, Huibin Man 2, a, Peter M. Elias 3, 4, Mao-Qiang Man 3, 4, * 1
School of Basic Medical Sciences, Tianjing Medical University, Tianjing, PR China Wendeng Central Hospital, Shandong, PR China 3 Dermatology Service, Veterans Affairs Medical Center, San Francisco, CA, USA 4 Department of Dermatology, University of California San Francisco, San Francisco, CA, USA 2
a r t i c l e i n f o
a b s t r a c t
Article history: Received: Apr 21, 2014 Revised: Mar 19, 2015 Accepted: Apr 19, 2015
Epidermal permeability barrier function plays a critical role in regulating cutaneous functions. Hence, researchers have been searching for effective and affordable regimens to enhance epidermal permeability barrier function. In addition to topical stratum corneum lipids, peroxisome proliferator-activated receptor, and liver X receptor ligands, herbal medicines have been proven to benefit epidermal permeability barrier function in both normal and diseased skin, including atopic dermatitis, glucocorticoid-induced skin damage, and UVB-damaged skin. The potential mechanisms by which herbal medicines improve the permeability barrier include stimulation of epidermal differentiation, lipid production, antimicrobial peptide expression, and antioxidation. Therefore, utilization of herbal medicines could be a valuable alternative approach to enhance epidermal permeability barrier function in order to prevent and/or treat skin disorders associated with permeability barrier abnormalities. Copyright © 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: dermatitis herbal medicines permeability barrier skin
Introduction Epidermal permeability barrier function influences multiple cutaneous functions, including epidermal proliferation, differentiation, lipid production, cytokine expression, as well as innate immunity.1 Moreover, studies have revealed that epidermal permeability barrier function plays a critical role in the development of contact dermatitis2 and atopic dermatitis (AD).3 Furthermore, a link between permeability barrier status and cutaneous antimicrobial defense and oxidative stress4 has been established. Enhancement of permeability barrier does not only improve atopic dermatitis, but also delays the relapse of AD in humans.5 Therefore; researchers have been searching for products that can enhance the permeability barrier. Although both stratum corneum (SC) lipids, ligands
of peroxisome proliferator-activated receptors (PPARs), and liver X receptor (LXR) can improve the permeability barrier,6,7 clinical use of either SC lipids or PPAR/LXR ligands often requires special preparation. For example, a proper molar ratio of SC lipids is required for maximum benefits,6 and both lipids and certain PPAR/ LXR ligands, such as T 0901317 and farnesol, only dissolve in solvents. Thus, they are not readily available worldwide. However, studies have shown that herbal medicines benefit the epidermal permeability barrier. Here, we review the beneficial effects of herbal medicines on the permeability barrier and their mechanisms. Effects on barrier function Normal skin
Conflicts of interest: The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in this article. * Corresponding author. Dermatology (190), 4150 Clement Street, San Francisco, CA 94121, USA. ** Corresponding author. School of Basic Medical Sciences, Tianjing Medical University, Tianjing 300070, PR China. E-mail addresses: [email protected] (L. Hu), [email protected] (M.-Q. Man). a Both authors contributed equally.
Although the beneficial effects of herbs on skin have been known for years, their effects on epidermal permeability barrier have not been well appreciated until recently. Several studies showed that topical herbal medicines accelerated barrier recovery although they did not affect basal permeability barrier. For instance, topical applications of extracts of a herbal mixture twice daily for 7 days significantly accelerated barrier recovery at both 2 hours and 4 hours after barrier disruption in a normal murine skin without
http://dx.doi.org/10.1016/j.dsi.2015.04.009 1027-8117/Copyright © 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
changing either baseline transepidermal water loss rates (TEWL), skin surface pH, or SC hydration.8 Similarly, topical applications of 2% hesperidin, a main constituent of citrus, twice daily for 6 days also only enhanced barrier recovery without altering basal TEWL, skin surface pH, and SC hydration in a normal murine model.9 Whereas topical applications of 0.1% apigenin, an ingredient from chrysanthemum, twice daily for 9 days induced a significant acceleration in barrier recovery only 4 hours after barrier disruption, and a reduction in SC hydration in normal murine skin.10 Moreover, topical application of herbal extracts to barrier damaged skin also accelerated barrier recovery.11e13 These results indicate that the influences of topical herbal medicines on permeability homeostasis vary with the ingredient. In addition to murine models, clinical studies have also demonstrated beneficial effects of herbal medicines on epidermal permeability barrier in normal humans. Rasul and Akhtar14 reported that topical applications of 3% basil extract to the cheek once daily for 2 weeks lowered TEWL and increased SC hydration. More significant improvements in both TEWL and SC hydration were observed 12 weeks after topical applications of basil extract. Likewise, topical applications of Lithospermum erythrorhizon extract at concentrations ranging from 1% to 5% for 7 days significantly lowered TEWL and increased SC hydration.15 Again, a further improvement in both TEWL and SC hydration were observed 28 days after applications. In comparison to vehicle alone, cream containing10% Laminaria japonica markedly decreased TEWL and increased SC hydration 8 hours after application.16 Moreover, topical 4% Foeniculum vulgare extract also improved both TEWL and SC hydration in normal humans.17 Some herbal medicines not only affect barrier function and SC hydration, but also influence melanin and sebum content. For example, in addition to the decrease in TEWL, a remarkable reduction in melanin index was seen after topical applications of a cream containing 5% Terminalia chebula extract for 1 week while skin surface sebum content and SC hydration were increased. A more profound improvement was observed 6 weeks after applications.18 Furthermore, topical applications of 0.25% extract of Terminalia arjuna extract for 8 weeks reduced TEWL in aged humans.19 Finally, improvement of barrier function by oral herbal extracts has also been demonstrated in both young and aged humans.20,21 Herbal medicines that benefit barrier function are listed in Table 1. Diseased skin Studies have shown that herbal medicines are effective in treating and preventing some skin disorders accompanied by an abnormal permeability barrier.22,23 Herbal medicines can also improve permeability barrier function in some dermatoses, such as AD, acne, and glucocorticoid-damaged skin. (1) Atopic dermatitis Both humans and murines with AD exhibit a higher TEWL.24 Herbal medicines not only improve AD, but also prevent the development of AD. In a 2,4-dinitrochlorobenzene (DNCB)-induced murine AD model, topical applications of Bambusae caulis in liquamen prevented the expected increase in TEWL during the development of AD.25 Similarly, topical applications of 0.1% apigenin lowered both TEWL and skin surface pH, and elevated SC hydration in an oxazolone-induced murine AD like model.26 A number of studies have demonstrated that oral administration of herbal extracts could also prevent the increase in TEWL, and the development of AD symptoms in murine AD models.27e32 Clinically, there were two separate studies showing that topical applications of borage oil, a constituent of herbal medicines such as
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Borago officinalis, for 2 weeks or 4 weeks significantly improved clinical symptoms and TEWL in AD children.33,34 Xue and Tan35 reported that oral loratadine in combination with herbal bathing one to two times daily for 4 weeks lowered TEWL readings from 38.12 ± 5.56 to 13.45 ± 2.91 in AD patients in addition to an overall 65% reduction in AD severity scores. By contrast, loratadine in combination with topical petrolatum only lowered TEWL readings from 37.72 ± 5.23 to 22.12 ± 3.91 and had a 56% reduction in AD severity scores. Another study showed that oral herbal medicines once daily for 4 weeks also significantly reduced TEWL (from 36.54 ± 4.04 to 17.15 ± 3.77) in AD patients in comparison to loratadine alone (from 36.01 ± 3.49 to 26.59 ± 3.09).36 These studies reveal that either topical herbal medicines or oral herbal medicines improve epidermal barrier function in both murine AD models and AD in humans. (2) Glucocorticoid-treated skin Glucocorticoids (GC) are among the most common medications used for various disorders. Our prior studies have demonstrated that either topical or systemic applications of GC compromise epidermal permeability barrier.37 In a murine model, either psychological stress, which elevates GC levels in serum or saliva, or systemic administrations of GC significantly increased basal TEWL levels. In addition to stratum corneum lipids, PPAR and LXR activators, herbal medicines are also effective in overcoming GC-induced epidermal barrier abnormalities. Following each psychological stress, inhalation of rose essential oil for 2 hours prevented the expected increase in TEWL in psychological stressed rat and humans.38 In humans, topical applications of GC raise TEWL.39 Qi et al40 reported that topical skin care products containing Prinsepia utilis and purslane in combination with zinc oxide ointment for 1 month significantly reduced TEWL in patients with glucocorticoid dependent dermatitis as compared with zinc oxide ointment alone. Moreover, other clinical studies showed that systemic administrations of herbal medicines markedly lowered TEWL and improved dermatitis scores in patients with glucocorticoid dependent dermatitis.41e43 These results indicate that herbal medicines can effectively overcome epidermal barrier abnormalities induced by either topical or systemic glucocorticoids. (3) Others Following UVB irradiation, defective permeability barrier function is commonly seen in both human and murine skin. Studies indicate that either topical or oral herbal extracts can prevent UVB irradiation-induced increase in TEWL. For example, rats irradiated with UVB three times per week for 8 weeks caused a significant elevation of TEWL. Rats prefed with ()-epigallocatechin-3-gallate (EGCG) prevented the increase in both TEWL and epidermal thickness in addition to the inhibition of the development of clinical scores.44 Human studies revealed that topical 0.1% oleuropein emulsion 30 minutes prior to UVB irradiation induced a 22% reduction in erythema, and 35% reduction in TEWL.45 Skin with acne vulgaris exhibits a higher level of TEWL. Two separate clinical studies demonstrated that either topical or oral herbal extracts improved barrier function in acne patients. For example, topical applications of a formulation containing extracts of Prinsepia utilis and purslane to acne sites twice daily for 30 days caused a 43% reduction in TEWL while formulations without herbal extract only induced a 10% reduction in TEWL.46 Du et al47 reported that oral Callicarpa nudiflora tablets in combination with a blue-red light induced further improvements in both clinical
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Table 1 List of herbal medicines that benefit epidermal permeability barrier. Species/models
Treatment
Number of subjects
Basal TEWL
Barrier Recovery
Radix Paeoniae rubra, Cat Nut, Phellodenron, Rhizoma Alismatis, Angelica sinensis, & Glabrous Greenbrier Hesperidin Apigenin Ursolic acid & oleanolic acid
Normal mice
Topically applied to intact skin for 7 d
5
()
[
8
Normal mice Normal mice Normal mice
[ [ [
Normal humans
10 12 30 Not indicated 18
() () N/D
Eucalyptus
Y
N/D
9 10 11 12 13
Basil leaves & flowers Lithospermum erythrorhizon Terminalia chebula Terminalia arjuna Borage oil
Normal Normal Normal Normal Normal
N/D N/D N/D N/D N/D
Mouse dermatitis-induced by topical DNCB Mouse dermatitis-induced by topical oxazolone Mouse dermatitis-induced by topical TNCB Mouse dermatitis-induced by topical oxazolone Dermatitis in NC/Nga mice Dermatitis in NC/Nga mice
11 30 11 15 15 29 Not indicated
Y Y Y Y Y
Bambusae caulis in Liquamen
Topically applied to intact skin for 6 d Topically applied to intact skin for 9 d Topically applied to tape-stripped skin once Topically applied to acetone-treated skin once Topically applied to acetone/diethylether-treated skin for 4 d Topically applied to intact skin for 84 d Topically applied to intact skin 28 d Topically applied to intact skin 56 d Topically applied to intact skin 56 d Orally given for 84 d Orally given for 60 d Topically applied for 35 d
Y
N/D
14 15 18 19 20 21 25
Topically applied for 7 d
24
Y
N/D
26
Orally given for 5 d prior to TNCB application
5
Y
N/D
27
Orally given for 13 d after starting oxazolone challenge Orally given for 28 d Orally given for 42 d
4-8
Y
N/D
28
5 5
Y Y
N/D N/D
29 30
Orally given for16 d
2-7
Y
N/D
31
Atopic dermatitis humans
Orally given for 56 d Wearing borage oil-coated undershirt for 28 d Wearing borage oil-coated undershirt for 14 d Topically applied for 28 d
8 26 16 32
Y Y Y Y
N/D N/D N/D N/D
32 33 34 35
Atopic dermatitis humans
Not indicated
30
Y
N/D
36
PS rats
6
Y
N/D
38
GC-treated humans GC-treated humans
Rats were stressed 8 h/d for 14 d. Rose essential oil was given 2 h/d during stress Given rose essential oil for 13 d while participants were under stress Topically applied for 30 d Orally given for 30 d
30 38
Y Y
N/D N/D
40 41
GC-treated humans
Orally given for 28 s
68
Y
N/D
42
Apigenin Red ginseng Lithospermum erythrorhizon Persimmon leaves Atractylodes lancea rhizome, Hoelen, Cnidium rhizome, Japanese Angelica root, Bupleurum root, Glycyrrhiza root, & Uncaria thorn Actinidia arguta Beta vulgaris Borage oil Squama manis, cortex moutan, cortex albiziae, cortex lycii, periostracum cicadae, periostracum serpentis, pericarpium citri reticulatae, oriental variegated coralbean bark, cortex dictamni, & cortex phellodendri Radix Astragali, Radix Polygoni multiflori, fructus tribuli, rhizoma atractylodis macrocephalae, radix angelicae sinensis, radix saposhnikoviae, & scolopendra Rose essential oil
humans humans humans humans humans
Dermatitis in magnesium deficient rats Dermatitis in low fat diet mice Atopic dermatitis humans
PS humans Prinsepia utilis & purslane Flos chrysanthemi, flos sophorae, flos carthami, flos rosae rugosae, radix rehmanniae, flos Celosia cristata, radix glycyrrhizae, & Herba Artemisiae annuae Radix scutellariae, rhizoma coptidis, Herba Taraxaci, flos campsis, Flos Lonicerae, cortex moutan, radix arnebiae radix lithospermi, rhizoma imperatae, rhizoma anemarrhenae, radix ophiopogonis, radix rehmanniae, & Flos Celosia cristata
Permeability barrier
Refs
14
a
b
b
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
Herbal extracts
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efficacy and TEWL in patients with acne as compared with bluered light alone.
44 45 46 47
43
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
N/D
N/D N/D N/D N/D
Y
Y Y Y Y
Mechanisms Although studies have demonstrated that herbal medicines improve barrier function, the exact mechanisms remain unclear. Some evidence suggests the effects of herbal extracts on barrier function could be via multiple mechanisms, including the upregulation of keratinocyte differentiation, proliferation, lipid production and/or transportation, innate immunity, as well as antioxidation.
DNCB ¼ 2,4-dinitrochlorobenzene; EGCG ¼ epigallocatechin gallate; GC ¼ glucocorticoids-treated skin; PS ¼ psychological stress; TNCB ¼ trinitrochlorobenzene. a Acetone/diethylether-induced dry skin b Aged human.
Orally given while they were irradiated for 56 d Topically applied 30 min prior to UVB irradiation Topically applied for 30 d Orally given for 28 d UVB-irradiated rats UVB-irradiated humans Humans with acne Humans with acne
5 10 43 90
Orally given for 30 d
Radix rehmanniae, radix scrophulariae, radix ophiopogonis, poria, rhizoma dioscoreae, fructus corni, rhizoma alismatis, radix Paeoniae alba, & cortex moutan Epigallocatechin gallate Oleuropein Prinsepia utilis & purslane Callicarpa nudiflora
GC-treated humans
50
Epidermal differentiation and proliferation Expression of epidermal differentiation-related proteins, such as filaggrin, loricrin, and involucrin, are required for permeability barrier formation.1 The regulatory roles of some herbal medicines on barrier function are via the upregulation of the expression of epidermal differentiation-related proteins. It is reported that oleanolic acid upregulated expression of filaggrin, involucrin, loricrin, and stimulated cornified envelope formation in keratinocyte cultures via enhancing expression and activation of peroxisome proliferator-activated receptor a (PPARa).11,12 The latter is known as a critical regulator for keratinocyte differentiation and proliferation. Likewise, hesperidin increased epidermal filaggrin and loricrin expression, and keratinocyte proliferation in a murine model8 while topical apigenin only unregulated epidermal filaggrin and its mRNA expression.10 Moreover, studies indicate that hesperidin increased PPARg and its mRNA expression in NALM-6 cells and human preadipocytes. Our prior study showed that activation of PPARg upregulated epidermal differentiation, resulting in improvement of barrier function.48 Furthermore, another barrier enhancer, EGCG, stimulates keratinocyte differentiation via the upregulation of activator protein 1 expression.49 These studies suggest that at least some herbal medicines induce improvement of barrier function through the stimulation of epidermal differentiation and proliferation. Lipid production and transportation Epidermal lipid production is crucial for permeability barrier homeostasis.1 Our prior studies showed that topical applications of herbal extract increased epidermal lipid content6 and the expression of mRNA for lipid synthetic enzymes.8,10 Topical applications of either 1% ursolic acid or 1% oleanolic acid for 3 days significantly increased epidermal ceramide content.12 Ishikawa et al13 reported that both macrocarpal A and extract of Eucalyptus globulus increased ceramide production and expression of mRNA for ceramide synthetic enzyme. Additionally, formation of the epidermal permeability barrier function requires not only the synthesis of lipids, but also the formation and secretion of lamellar bodies as a means to deliver lipids to the SC. Studies show that some herbal medicines improve barrier function via the stimulation of lamellar body formation and secretion. For example, either topical apigenin or hesperidin accelerated lamellar body formation and secretion.9,10 It is known that formation of a lamellar body requires ATPbinding cassette transporter 12 (ABCA12), a transmembrane glycosylceramide transporter. Topical applications of certain herbal extracts elevated epidermal ABCA12 mRNA expression.8,10 Thus, stimulation of epidermal lipid production and transportation could account for another potential mechanism whereby herbal extracts improve epidermal permeability barrier function.
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Table 2 Mechanisms by which herbal medicines benefit epidermal permeability barrier. Herbal extracts
Radix Paeonlae rubra, cat nut, Phellodendron, Rhizoma Alismatis, Angelica sinensis, & Glabrous greenbrier Hesperidin Apigenin Ursolic acid & oleanolic acid Terminalia arjuna Red ginseng Rose essential oil
Mechanisms
Others
Keratinocyte differentiation
Lipid production
Lamellar body formation
Antimicrobial peptides
N/D
[
[
[
[ [ [ [ N/D N/D N/D
[ [ N/D [ N/D N/D N/D
[ [ N/D N/D N/D N/D N/D
[ [ N/D N/D N/D N/D N/D
Refs
8
[proliferation, [antioxidation, YpH YInflammation [proliferation, [PPARa activity [PPARa activity [VEGF expression YInflammation, [antioxidation YPlasma corticosterone
9,52 10,26 11 12 19 a 27,51 38
PPAR ¼ peroxisome proliferator activated receptor. a Aged human.
Antioxidant Nowadays the association of oxidative stress and skin barrier function is greatly appreciated.4 Several in vivo studies have demonstrated the beneficial effects of antioxidants on skin barrier function in both normal and diseased skin.43,44 Some herbal extracts that improve barrier function exhibit potent antioxidant property. In vitro studies showed that ginseng extract decreased reactive oxygen species, and increased both glutathione content and superoxide dismutase activity in keratinocytes.50,51 Although some studies showed that EGCG could cause oxidative damages to cells, numerous studies have demonstrated that it inhibited H2O2 production and lipid peroxidation in UVB or UVA irradiated keratinocytes. Moreover, EGCG inhibited the expression of inducible nitric oxide synthase mRNA, nitric oxide production, as well as IL-6 secretion in keratinocytes via inhibition of UVB-induced activation and translocation of NF-kappaB. The antioxidant properties of other barrier enhancing herbal extracts are also well demonstrated. For example, rats fed with hesperidin for 4 weeks displayed lower levels of serum thiobarbituric acid-reactive substances, product of lipid peroxidation, and higher levels of serum antioxidant capacity. Similarly, oral hesperidin or ginseng or their combination significantly reduced serum malondialdehyde levels and increased total superoxide dismutase activity in chickens. Likewise, orally given hesperidin lowered serum malondialdehyde and nitrite levels, and increased the activity of serum antioxidant enzymes, including catalase and superoxide dismutase in pentylenetetrazole-treated mice. Hence, the antioxidant properties of herbal extracts can be attributed to the improvement of barrier function.
Innate immunity Prior studies showed that epidermal antimicrobial peptides are also required for epidermal permeability barrier function. At least two epidermal antimicrobial peptides, CAMP (LL-37) and mBD3 (hBD2), are packaged and secreted by lamellar body and regulated in parallel with changes in permeability barrier function.6 Our previous studies revealed that extract of a herbal mixture increased both epidermal CAMP and mBD3 expression in addition to improving barrier function in vivo 8 In addition, the same extract upregulated the expression levels of mBD3 mRNA in vivo, and induced a dosedependent increase in LL-37 and hBD2 mRNA expression in cultured human keratinocytes. Moreover, as stated above, topical apigenin improved barrier function in both normal and diseased skin.10,26 We have demonstrated that topical applications of apigenin twice daily for 9 days markedly increased epidermal CAMP and mBD3 expression in mice.10 Therefore, the upregulation of
antimicrobial peptide expression could be an additional potential mechanism for herbal extract-induced improvement of barrier function. The potential mechanisms whereby herbal medicines benefit epidermal permeability barrier are summarized in Table 2. Conclusion Epidermal permeability barrier function has a significant impact on cutaneous functions. Improvement of skin barrier function is becoming a valuable approach to prevent and treat some skin disorders. Evidence indicates that herbal medicines benefit barrier function in both normal and diseased skin with fewer adverse effects and lower cost. Thus, herbal medicines could be used as an optional alternative for preventing and treating certain dermatoses accompanied by epidermal permeability barrier abnormalities. Acknowledgments This work was partially supported by grants (National Institutes of Health (NIH) AR061106, Veterans Affairs (VA) Merit-1 101BX000608, National Eczema Association Grant, and Natural Science Foundation of China (NSFC) 81301360). References 1. Elias PM, Feingold KR. Coordinate regulation of epidermal differentiation and barrier homeostasis. Skin Pharmacol Appl Skin Physiol 2001;14:28e34. 2. Smith HR, Rowson M, Basketter DA, McFadden JP. Intra-individual variation of irritant threshold and relationship to transepidermal water loss measurement of skin irritation. Contact Dermatitis 2004;51:26e9. 3. Darlenski R, Kazandjieva J, Tsankov N, Fluhr JW. Acute irritant threshold correlates with barrier function, skin hydration and contact hypersensitivity in atopic dermatitis and rosacea. Exp Dermatol 2013;22:752e3. 4. Man MQ, Elias PM. Influences of antioxidants on epidermal permeability barrier function. Chin J Dermatovenereol 2013;27:722e4. n K, Nohlgård C, Nyberg F, et al. Treatment with a barrier-strengthening 5. Wire moisturizing cream delays relapse of atopic dermatitis: a prospective and randomized controlled clinical trial. J Eur Acad Dermatol Venereol 2009;23: 1267e72. 6. Man MQM, Feingold KR, Thornfeldt CR, Elias PM. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol 1996;106:1096e101. 7. Man MQ, Choi EH, Schmuth M, et al. Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: liposensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing. J Invest Dermatol 2006;126:386e92. 8. Man M, Hupe M, Mackenzie D, et al. A topical Chinese herbal mixture improves epidermal permeability barrier function in normal murine skin. Exp Dermatol 2011;20:285e8. 9. Hou M, Man M, Man W, et al. Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol 2012;21:337e40. 10. Hou MH, Xun R, Hupe M, et al. Topical apigenin improves epidermal permeability barrier homeostasis in normal murine skin by divergent mechanisms. Exp Dermatol 2013;22:210e5.
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95 11. Lim SW, Hong SP, Jeong SW, et al. Simultaneous effect of ursolic acid and oleanolic acid on epidermal permeability barrier function and epidermal keratinocyte differentiation via peroxisome proliferator-activated receptor-alpha. J Dermatol 2007;34:625e34. 12. Lee HK, Nam GW, Kim SH, Lee SH. Phytocomponents of triterpenoids, oleanolic acid and ursolic acid, regulated differently the processing of epidermal keratinocytes via PPAR-alpha pathway. Exp Dermatol 2006;15:66e73. 13. Ishikawa J, Shimotoyodome Y, Chen S, et al. Eucalyptus increases ceramide levels in keratinocytes and improves stratum corneum function. Int J Cosmet Sci 2012;34:17e22. 14. Rasul A, Akhtar N. Formulation and in vivo evaluation for anti-aging effects of an emulsion containing basil extract using non- invasive biophysical techniques. Daru 2011;19:344e50. 15. Chang MJ, Huang HC, Chang HC, Chang TM. Cosmetic formulations containing Lithospermum erythrorhizon root extract show moisturizing effects on human skin. Arch Dermatol Res 2008;300:317e23. 16. Choi JS, Moon WS, Choi JN, et al. Effects of seaweed Laminaria japonica extracts on skin moisturizing activity in vivo. J Cosmet Sci 2013;64:193e205. 17. Rasul A, Akhtar N, Khan BA, Mahmood T, Uz Zaman S, Khan HM. Formulation development of a cream containing fennel extract: in vivo evaluation for antiaging effects. Pharmazie 2012;67:54e8. 18. Akhtar N, Khan AB, Muhammad S, et al. Formulation and characterization of a cream containing Terminalia chebula extract. Forsch Komplementmed 2012;19: 20e5. € hler T, Schild J, et al. Pentacyclic triterpenes from Terminalia 19. Farwick M, Ko arjuna show multiple benefits on aged and dry skin. Skin Pharmacol Physiol 2013;27:71e81. 20. De Spirt S, Stahl W, Tronnier H, et al. Intervention with flaxseed and borage oil supplements modulates skin condition in women. Br J Nutr 2009;101: 440e5. 21. Brosche T, Platt D. Effect of borage oil consumption on fatty acid metabolism, transepidermal water loss and skin parameters in elderly people. Arch Gerontol Geriatr 2000;30:139e50. 22. May BH, Zhang AL, Zhou W, Lu CJ, Deng S, Xue CC. Oral herbal medicines for psoriasis: a review of clinical studies. Chin J Integr Med 2012;18:172e8. 23. Man W, Man M, Hupe M, et al. Topical herbal extract (Huangdang mixture) exhibits both preventive and therapeutic effects in murine acute irritant contact dermatitis. Int J Dermatol 2011;50:1421e7. 24. Elias PM, Eichenfield LF, Fowler Jr JF, Horowitz P, McLeod RP. Update on the structure and function of the skin barrier: atopic dermatitis as an exemplar of clinical implications. Semin Cutan Med Surg 2013;32:S21e4. 25. Qi XF, Kim DH, Yoon YS, et al. Effects of Bambusae caulis in Liquamen on the development of atopic dermatitis-like skin lesions in hairless mice. J Ethnopharmacol 2009;123:195e200. 26. Man MQ, Hupe M, Sun R, Man G, Mauro TM, Elias PM. Topical apigenin alleviates cutaneous inflammation in murine models. Evid Based Complement Alternat Med 2012;2012:1e7. 27. Cho E, Cho SH. Effects of Korean red ginseng extract on the prevention of atopic dermatitis and its mechanism on early lesions in a murine model. J Ethnopharmacol 2013;145:294e302. 28. Lee JH, Jung KM, Bae IH, et al. Anti-inflammatory and barrier protecting effect of Lithospermum erythrorhizon extracts in chronic oxazolone-induced murine atopic dermatitis. J Dermatol Sci 2009;56:64e6. 29. Matsumoto M, Kotani M, Fujita A, et al. Oral administration of persimmon leaf extract ameliorates skin symptoms and transepidermal water loss in atopic dermatitis model mice, NC/Nga. Br J Dermatol 2002;146:221e7. 30. Funakushi N, Yamaguchi T, Jiang J, et al. Ameliorating effect of Yokukansan on the development of atopic dermatitis-like lesions and scratching behavior in socially isolated NC/Nga mice. Arch Dermatol Res 2011;303:659e67. 31. Choi JJ, Park B, Kim DH, et al. Blockade of atopic dermatitis-like skin lesions by DA-9102, a natural medicine isolated from Actinidia arguta, in the Mgdeficiency induced dermatitis model of hairless rats. Exp Biol Med (Maywood) 2008;233:1026e34.
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32. Kawano K, Umemura K. Oral intake of beet extract provides protection against skin barrier impairment in hairless mice. Phytother Res 2013;27:775e83. 33. Kanehara S, Ohtani T, Uede K, Furukawa F. Undershirts coated with borage oil alleviate the symptoms of atopic dermatitis in children. Eur J Dermatol 2007;17:448e9. 34. Kanehara S, Ohtani T, Uede K, Furukawa F. Clinical effects of undershirts coated with borage oil on children with atopic dermatitis: a double-blind, placebocontrolled clinical trial. J Dermatol 2007;34:811e5. 35. Xue S, Tan J. Effects of “shi-pi-tang” on skin barrier function in patients with atopic dermatitis. Chin J Exp Tradit Med Form 2011;17:282e3. 36. Yang X, Ye j, Li Q. The effects of the clinical efficacy of method of strengthening spleen and enriching blood eliminating wind in treatment of chronic atopic dermatitis. J Yunan University Tradit Chin Med 2009;32:5e7. 37. Kao JS, Fluhr JW, Man MQ, et al. Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol 2003;120:456e64. 38. Fukada M, Kano E, Miyoshi M, Komaki R, Watanabe T. Effect of “rose essential oil” inhalation on stress-induced skin-barrier disruption in rats and humans. Chem Senses 2012;37:347e56. 39. Chen S, Song W, Du X, Han C. Analysis of transepidermal water loss and skin hydration in patients with facial steroid dermatitis. Chin J Dermatol 2008;41: 473e5. 40. Qi Y, Pang Q, Tu Y, et al. Clinical observation on the efficacy of skin care product containing Prinsepia utilis and purslane on skin barrier in patients with glucocorticoid dependent dermatitis. Chin J Clin Dermatol 2012;41: 119e21. 41. Chen SY, Song WM, Du XH. Effect of modified wuhua decoction on skin barrier function in facial corticosteroid addictive dermatitis patients. Zhongguo Zhong Xi Yi Jie He Za Zhi 2008;28:410e3. 42. Du XH, Song WM, Xu AE. Clinical effect of treatment for clearing heat, detoxicating and nourishing Yin on patients with glucocorticosteroid induced facial dermatitis and its effect on skin barrier function. Zhongguo Zhong Xi Yi Jie He Za Zhi 2006;26:46e8. 43. Peng HH. Clinical research on mechanism of “Jia-Jian Xiao-Yao Powder” improving facial skin barrier function of hormone-dependent dermatitis patients. World Sci Technol-Modern Tradit Chin Med 2013;3:539e42. 44. Jeon HY, Kim JK, Kim WG, Lee SJ. Effects of oral epigallocatechin gallate supplementation on the minimal erythema dose and UV-induced skin damage. Skin Pharmacol Physiol 2009;22:137e41. 45. Perugini P, Vettor M, Rona C, et al. Efficacy of oleuropein against UVB irradiation: preliminary evaluation. Int J Cosmet Sci 2008;30:113e20. 46. Pang Q, Tu Y, He L. Clinical study on effects of skin care products containing extract of Prinsepia utilis and purslane in the treatment of acne vulgaris. J Clin Dermatol 2012;41:380e2. 47. Du D, Lu Q, Guo Q. The observation of effect of Callicarpa nudiflora tablet combined with red-blue light on patients with acne. Chin Med Herald 2012;9: 61e5. 48. Mao-Qiang M, Fowler AJ, Schmuth M, et al. Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J Invest Dermatol 2004;123:305e12. 49. Balasubramanian S, Efimova T, Eckert RL. Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factordependent involucrin gene expression in normal human keratinocytes. J Biol Chem 2002;277:1828e36. 50. Kim MR, Lee HS, Choi HS, Kim SY, Park Y, Suh HJ. Protective effects of ginseng leaf extract using enzymatic extraction against oxidative damage of UVA-irradiated human keratinocytes. Appl Biochem Biotechnol 2014;173: 933e45. 51. Hong CE, Lyu SY. Anti-inflammatory and Anti-oxidative effects of Korean red ginseng extract in human keratinocytes. Immune Netw 2011;11:42e9. 52. Man G, Mauro TM, Zhai Y, et al. Topical hesperidin enhances epidermal function in an aged murine model. J Invest Dermatol 2015;135:1184e7.
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Dermatologica Sinica journal homepage: http://www.derm-sinica.com
INVITED ARTICLE
Herbal medicines that benefit epidermal permeability barrier function Lizhi Hu 1, a, **, Huibin Man 2, a, Peter M. Elias 3, 4, Mao-Qiang Man 3, 4, * 1
School of Basic Medical Sciences, Tianjing Medical University, Tianjing, PR China Wendeng Central Hospital, Shandong, PR China 3 Dermatology Service, Veterans Affairs Medical Center, San Francisco, CA, USA 4 Department of Dermatology, University of California San Francisco, San Francisco, CA, USA 2
a r t i c l e i n f o
a b s t r a c t
Article history: Received: Apr 21, 2014 Revised: Mar 19, 2015 Accepted: Apr 19, 2015
Epidermal permeability barrier function plays a critical role in regulating cutaneous functions. Hence, researchers have been searching for effective and affordable regimens to enhance epidermal permeability barrier function. In addition to topical stratum corneum lipids, peroxisome proliferator-activated receptor, and liver X receptor ligands, herbal medicines have been proven to benefit epidermal permeability barrier function in both normal and diseased skin, including atopic dermatitis, glucocorticoid-induced skin damage, and UVB-damaged skin. The potential mechanisms by which herbal medicines improve the permeability barrier include stimulation of epidermal differentiation, lipid production, antimicrobial peptide expression, and antioxidation. Therefore, utilization of herbal medicines could be a valuable alternative approach to enhance epidermal permeability barrier function in order to prevent and/or treat skin disorders associated with permeability barrier abnormalities. Copyright © 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
Keywords: dermatitis herbal medicines permeability barrier skin
Introduction Epidermal permeability barrier function influences multiple cutaneous functions, including epidermal proliferation, differentiation, lipid production, cytokine expression, as well as innate immunity.1 Moreover, studies have revealed that epidermal permeability barrier function plays a critical role in the development of contact dermatitis2 and atopic dermatitis (AD).3 Furthermore, a link between permeability barrier status and cutaneous antimicrobial defense and oxidative stress4 has been established. Enhancement of permeability barrier does not only improve atopic dermatitis, but also delays the relapse of AD in humans.5 Therefore; researchers have been searching for products that can enhance the permeability barrier. Although both stratum corneum (SC) lipids, ligands
of peroxisome proliferator-activated receptors (PPARs), and liver X receptor (LXR) can improve the permeability barrier,6,7 clinical use of either SC lipids or PPAR/LXR ligands often requires special preparation. For example, a proper molar ratio of SC lipids is required for maximum benefits,6 and both lipids and certain PPAR/ LXR ligands, such as T 0901317 and farnesol, only dissolve in solvents. Thus, they are not readily available worldwide. However, studies have shown that herbal medicines benefit the epidermal permeability barrier. Here, we review the beneficial effects of herbal medicines on the permeability barrier and their mechanisms. Effects on barrier function Normal skin
Conflicts of interest: The authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in this article. * Corresponding author. Dermatology (190), 4150 Clement Street, San Francisco, CA 94121, USA. ** Corresponding author. School of Basic Medical Sciences, Tianjing Medical University, Tianjing 300070, PR China. E-mail addresses: [email protected] (L. Hu), [email protected] (M.-Q. Man). a Both authors contributed equally.
Although the beneficial effects of herbs on skin have been known for years, their effects on epidermal permeability barrier have not been well appreciated until recently. Several studies showed that topical herbal medicines accelerated barrier recovery although they did not affect basal permeability barrier. For instance, topical applications of extracts of a herbal mixture twice daily for 7 days significantly accelerated barrier recovery at both 2 hours and 4 hours after barrier disruption in a normal murine skin without
http://dx.doi.org/10.1016/j.dsi.2015.04.009 1027-8117/Copyright © 2015, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
changing either baseline transepidermal water loss rates (TEWL), skin surface pH, or SC hydration.8 Similarly, topical applications of 2% hesperidin, a main constituent of citrus, twice daily for 6 days also only enhanced barrier recovery without altering basal TEWL, skin surface pH, and SC hydration in a normal murine model.9 Whereas topical applications of 0.1% apigenin, an ingredient from chrysanthemum, twice daily for 9 days induced a significant acceleration in barrier recovery only 4 hours after barrier disruption, and a reduction in SC hydration in normal murine skin.10 Moreover, topical application of herbal extracts to barrier damaged skin also accelerated barrier recovery.11e13 These results indicate that the influences of topical herbal medicines on permeability homeostasis vary with the ingredient. In addition to murine models, clinical studies have also demonstrated beneficial effects of herbal medicines on epidermal permeability barrier in normal humans. Rasul and Akhtar14 reported that topical applications of 3% basil extract to the cheek once daily for 2 weeks lowered TEWL and increased SC hydration. More significant improvements in both TEWL and SC hydration were observed 12 weeks after topical applications of basil extract. Likewise, topical applications of Lithospermum erythrorhizon extract at concentrations ranging from 1% to 5% for 7 days significantly lowered TEWL and increased SC hydration.15 Again, a further improvement in both TEWL and SC hydration were observed 28 days after applications. In comparison to vehicle alone, cream containing10% Laminaria japonica markedly decreased TEWL and increased SC hydration 8 hours after application.16 Moreover, topical 4% Foeniculum vulgare extract also improved both TEWL and SC hydration in normal humans.17 Some herbal medicines not only affect barrier function and SC hydration, but also influence melanin and sebum content. For example, in addition to the decrease in TEWL, a remarkable reduction in melanin index was seen after topical applications of a cream containing 5% Terminalia chebula extract for 1 week while skin surface sebum content and SC hydration were increased. A more profound improvement was observed 6 weeks after applications.18 Furthermore, topical applications of 0.25% extract of Terminalia arjuna extract for 8 weeks reduced TEWL in aged humans.19 Finally, improvement of barrier function by oral herbal extracts has also been demonstrated in both young and aged humans.20,21 Herbal medicines that benefit barrier function are listed in Table 1. Diseased skin Studies have shown that herbal medicines are effective in treating and preventing some skin disorders accompanied by an abnormal permeability barrier.22,23 Herbal medicines can also improve permeability barrier function in some dermatoses, such as AD, acne, and glucocorticoid-damaged skin. (1) Atopic dermatitis Both humans and murines with AD exhibit a higher TEWL.24 Herbal medicines not only improve AD, but also prevent the development of AD. In a 2,4-dinitrochlorobenzene (DNCB)-induced murine AD model, topical applications of Bambusae caulis in liquamen prevented the expected increase in TEWL during the development of AD.25 Similarly, topical applications of 0.1% apigenin lowered both TEWL and skin surface pH, and elevated SC hydration in an oxazolone-induced murine AD like model.26 A number of studies have demonstrated that oral administration of herbal extracts could also prevent the increase in TEWL, and the development of AD symptoms in murine AD models.27e32 Clinically, there were two separate studies showing that topical applications of borage oil, a constituent of herbal medicines such as
91
Borago officinalis, for 2 weeks or 4 weeks significantly improved clinical symptoms and TEWL in AD children.33,34 Xue and Tan35 reported that oral loratadine in combination with herbal bathing one to two times daily for 4 weeks lowered TEWL readings from 38.12 ± 5.56 to 13.45 ± 2.91 in AD patients in addition to an overall 65% reduction in AD severity scores. By contrast, loratadine in combination with topical petrolatum only lowered TEWL readings from 37.72 ± 5.23 to 22.12 ± 3.91 and had a 56% reduction in AD severity scores. Another study showed that oral herbal medicines once daily for 4 weeks also significantly reduced TEWL (from 36.54 ± 4.04 to 17.15 ± 3.77) in AD patients in comparison to loratadine alone (from 36.01 ± 3.49 to 26.59 ± 3.09).36 These studies reveal that either topical herbal medicines or oral herbal medicines improve epidermal barrier function in both murine AD models and AD in humans. (2) Glucocorticoid-treated skin Glucocorticoids (GC) are among the most common medications used for various disorders. Our prior studies have demonstrated that either topical or systemic applications of GC compromise epidermal permeability barrier.37 In a murine model, either psychological stress, which elevates GC levels in serum or saliva, or systemic administrations of GC significantly increased basal TEWL levels. In addition to stratum corneum lipids, PPAR and LXR activators, herbal medicines are also effective in overcoming GC-induced epidermal barrier abnormalities. Following each psychological stress, inhalation of rose essential oil for 2 hours prevented the expected increase in TEWL in psychological stressed rat and humans.38 In humans, topical applications of GC raise TEWL.39 Qi et al40 reported that topical skin care products containing Prinsepia utilis and purslane in combination with zinc oxide ointment for 1 month significantly reduced TEWL in patients with glucocorticoid dependent dermatitis as compared with zinc oxide ointment alone. Moreover, other clinical studies showed that systemic administrations of herbal medicines markedly lowered TEWL and improved dermatitis scores in patients with glucocorticoid dependent dermatitis.41e43 These results indicate that herbal medicines can effectively overcome epidermal barrier abnormalities induced by either topical or systemic glucocorticoids. (3) Others Following UVB irradiation, defective permeability barrier function is commonly seen in both human and murine skin. Studies indicate that either topical or oral herbal extracts can prevent UVB irradiation-induced increase in TEWL. For example, rats irradiated with UVB three times per week for 8 weeks caused a significant elevation of TEWL. Rats prefed with ()-epigallocatechin-3-gallate (EGCG) prevented the increase in both TEWL and epidermal thickness in addition to the inhibition of the development of clinical scores.44 Human studies revealed that topical 0.1% oleuropein emulsion 30 minutes prior to UVB irradiation induced a 22% reduction in erythema, and 35% reduction in TEWL.45 Skin with acne vulgaris exhibits a higher level of TEWL. Two separate clinical studies demonstrated that either topical or oral herbal extracts improved barrier function in acne patients. For example, topical applications of a formulation containing extracts of Prinsepia utilis and purslane to acne sites twice daily for 30 days caused a 43% reduction in TEWL while formulations without herbal extract only induced a 10% reduction in TEWL.46 Du et al47 reported that oral Callicarpa nudiflora tablets in combination with a blue-red light induced further improvements in both clinical
92
Table 1 List of herbal medicines that benefit epidermal permeability barrier. Species/models
Treatment
Number of subjects
Basal TEWL
Barrier Recovery
Radix Paeoniae rubra, Cat Nut, Phellodenron, Rhizoma Alismatis, Angelica sinensis, & Glabrous Greenbrier Hesperidin Apigenin Ursolic acid & oleanolic acid
Normal mice
Topically applied to intact skin for 7 d
5
()
[
8
Normal mice Normal mice Normal mice
[ [ [
Normal humans
10 12 30 Not indicated 18
() () N/D
Eucalyptus
Y
N/D
9 10 11 12 13
Basil leaves & flowers Lithospermum erythrorhizon Terminalia chebula Terminalia arjuna Borage oil
Normal Normal Normal Normal Normal
N/D N/D N/D N/D N/D
Mouse dermatitis-induced by topical DNCB Mouse dermatitis-induced by topical oxazolone Mouse dermatitis-induced by topical TNCB Mouse dermatitis-induced by topical oxazolone Dermatitis in NC/Nga mice Dermatitis in NC/Nga mice
11 30 11 15 15 29 Not indicated
Y Y Y Y Y
Bambusae caulis in Liquamen
Topically applied to intact skin for 6 d Topically applied to intact skin for 9 d Topically applied to tape-stripped skin once Topically applied to acetone-treated skin once Topically applied to acetone/diethylether-treated skin for 4 d Topically applied to intact skin for 84 d Topically applied to intact skin 28 d Topically applied to intact skin 56 d Topically applied to intact skin 56 d Orally given for 84 d Orally given for 60 d Topically applied for 35 d
Y
N/D
14 15 18 19 20 21 25
Topically applied for 7 d
24
Y
N/D
26
Orally given for 5 d prior to TNCB application
5
Y
N/D
27
Orally given for 13 d after starting oxazolone challenge Orally given for 28 d Orally given for 42 d
4-8
Y
N/D
28
5 5
Y Y
N/D N/D
29 30
Orally given for16 d
2-7
Y
N/D
31
Atopic dermatitis humans
Orally given for 56 d Wearing borage oil-coated undershirt for 28 d Wearing borage oil-coated undershirt for 14 d Topically applied for 28 d
8 26 16 32
Y Y Y Y
N/D N/D N/D N/D
32 33 34 35
Atopic dermatitis humans
Not indicated
30
Y
N/D
36
PS rats
6
Y
N/D
38
GC-treated humans GC-treated humans
Rats were stressed 8 h/d for 14 d. Rose essential oil was given 2 h/d during stress Given rose essential oil for 13 d while participants were under stress Topically applied for 30 d Orally given for 30 d
30 38
Y Y
N/D N/D
40 41
GC-treated humans
Orally given for 28 s
68
Y
N/D
42
Apigenin Red ginseng Lithospermum erythrorhizon Persimmon leaves Atractylodes lancea rhizome, Hoelen, Cnidium rhizome, Japanese Angelica root, Bupleurum root, Glycyrrhiza root, & Uncaria thorn Actinidia arguta Beta vulgaris Borage oil Squama manis, cortex moutan, cortex albiziae, cortex lycii, periostracum cicadae, periostracum serpentis, pericarpium citri reticulatae, oriental variegated coralbean bark, cortex dictamni, & cortex phellodendri Radix Astragali, Radix Polygoni multiflori, fructus tribuli, rhizoma atractylodis macrocephalae, radix angelicae sinensis, radix saposhnikoviae, & scolopendra Rose essential oil
humans humans humans humans humans
Dermatitis in magnesium deficient rats Dermatitis in low fat diet mice Atopic dermatitis humans
PS humans Prinsepia utilis & purslane Flos chrysanthemi, flos sophorae, flos carthami, flos rosae rugosae, radix rehmanniae, flos Celosia cristata, radix glycyrrhizae, & Herba Artemisiae annuae Radix scutellariae, rhizoma coptidis, Herba Taraxaci, flos campsis, Flos Lonicerae, cortex moutan, radix arnebiae radix lithospermi, rhizoma imperatae, rhizoma anemarrhenae, radix ophiopogonis, radix rehmanniae, & Flos Celosia cristata
Permeability barrier
Refs
14
a
b
b
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
Herbal extracts
93
efficacy and TEWL in patients with acne as compared with bluered light alone.
44 45 46 47
43
L. Hu et al. / Dermatologica Sinica 33 (2015) 90e95
N/D
N/D N/D N/D N/D
Y
Y Y Y Y
Mechanisms Although studies have demonstrated that herbal medicines improve barrier function, the exact mechanisms remain unclear. Some evidence suggests the effects of herbal extracts on barrier function could be via multiple mechanisms, including the upregulation of keratinocyte differentiation, proliferation, lipid production and/or transportation, innate immunity, as well as antioxidation.
DNCB ¼ 2,4-dinitrochlorobenzene; EGCG ¼ epigallocatechin gallate; GC ¼ glucocorticoids-treated skin; PS ¼ psychological stress; TNCB ¼ trinitrochlorobenzene. a Acetone/diethylether-induced dry skin b Aged human.
Orally given while they were irradiated for 56 d Topically applied 30 min prior to UVB irradiation Topically applied for 30 d Orally given for 28 d UVB-irradiated rats UVB-irradiated humans Humans with acne Humans with acne
5 10 43 90
Orally given for 30 d
Radix rehmanniae, radix scrophulariae, radix ophiopogonis, poria, rhizoma dioscoreae, fructus corni, rhizoma alismatis, radix Paeoniae alba, & cortex moutan Epigallocatechin gallate Oleuropein Prinsepia utilis & purslane Callicarpa nudiflora
GC-treated humans
50
Epidermal differentiation and proliferation Expression of epidermal differentiation-related proteins, such as filaggrin, loricrin, and involucrin, are required for permeability barrier formation.1 The regulatory roles of some herbal medicines on barrier function are via the upregulation of the expression of epidermal differentiation-related proteins. It is reported that oleanolic acid upregulated expression of filaggrin, involucrin, loricrin, and stimulated cornified envelope formation in keratinocyte cultures via enhancing expression and activation of peroxisome proliferator-activated receptor a (PPARa).11,12 The latter is known as a critical regulator for keratinocyte differentiation and proliferation. Likewise, hesperidin increased epidermal filaggrin and loricrin expression, and keratinocyte proliferation in a murine model8 while topical apigenin only unregulated epidermal filaggrin and its mRNA expression.10 Moreover, studies indicate that hesperidin increased PPARg and its mRNA expression in NALM-6 cells and human preadipocytes. Our prior study showed that activation of PPARg upregulated epidermal differentiation, resulting in improvement of barrier function.48 Furthermore, another barrier enhancer, EGCG, stimulates keratinocyte differentiation via the upregulation of activator protein 1 expression.49 These studies suggest that at least some herbal medicines induce improvement of barrier function through the stimulation of epidermal differentiation and proliferation. Lipid production and transportation Epidermal lipid production is crucial for permeability barrier homeostasis.1 Our prior studies showed that topical applications of herbal extract increased epidermal lipid content6 and the expression of mRNA for lipid synthetic enzymes.8,10 Topical applications of either 1% ursolic acid or 1% oleanolic acid for 3 days significantly increased epidermal ceramide content.12 Ishikawa et al13 reported that both macrocarpal A and extract of Eucalyptus globulus increased ceramide production and expression of mRNA for ceramide synthetic enzyme. Additionally, formation of the epidermal permeability barrier function requires not only the synthesis of lipids, but also the formation and secretion of lamellar bodies as a means to deliver lipids to the SC. Studies show that some herbal medicines improve barrier function via the stimulation of lamellar body formation and secretion. For example, either topical apigenin or hesperidin accelerated lamellar body formation and secretion.9,10 It is known that formation of a lamellar body requires ATPbinding cassette transporter 12 (ABCA12), a transmembrane glycosylceramide transporter. Topical applications of certain herbal extracts elevated epidermal ABCA12 mRNA expression.8,10 Thus, stimulation of epidermal lipid production and transportation could account for another potential mechanism whereby herbal extracts improve epidermal permeability barrier function.
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Table 2 Mechanisms by which herbal medicines benefit epidermal permeability barrier. Herbal extracts
Radix Paeonlae rubra, cat nut, Phellodendron, Rhizoma Alismatis, Angelica sinensis, & Glabrous greenbrier Hesperidin Apigenin Ursolic acid & oleanolic acid Terminalia arjuna Red ginseng Rose essential oil
Mechanisms
Others
Keratinocyte differentiation
Lipid production
Lamellar body formation
Antimicrobial peptides
N/D
[
[
[
[ [ [ [ N/D N/D N/D
[ [ N/D [ N/D N/D N/D
[ [ N/D N/D N/D N/D N/D
[ [ N/D N/D N/D N/D N/D
Refs
8
[proliferation, [antioxidation, YpH YInflammation [proliferation, [PPARa activity [PPARa activity [VEGF expression YInflammation, [antioxidation YPlasma corticosterone
9,52 10,26 11 12 19 a 27,51 38
PPAR ¼ peroxisome proliferator activated receptor. a Aged human.
Antioxidant Nowadays the association of oxidative stress and skin barrier function is greatly appreciated.4 Several in vivo studies have demonstrated the beneficial effects of antioxidants on skin barrier function in both normal and diseased skin.43,44 Some herbal extracts that improve barrier function exhibit potent antioxidant property. In vitro studies showed that ginseng extract decreased reactive oxygen species, and increased both glutathione content and superoxide dismutase activity in keratinocytes.50,51 Although some studies showed that EGCG could cause oxidative damages to cells, numerous studies have demonstrated that it inhibited H2O2 production and lipid peroxidation in UVB or UVA irradiated keratinocytes. Moreover, EGCG inhibited the expression of inducible nitric oxide synthase mRNA, nitric oxide production, as well as IL-6 secretion in keratinocytes via inhibition of UVB-induced activation and translocation of NF-kappaB. The antioxidant properties of other barrier enhancing herbal extracts are also well demonstrated. For example, rats fed with hesperidin for 4 weeks displayed lower levels of serum thiobarbituric acid-reactive substances, product of lipid peroxidation, and higher levels of serum antioxidant capacity. Similarly, oral hesperidin or ginseng or their combination significantly reduced serum malondialdehyde levels and increased total superoxide dismutase activity in chickens. Likewise, orally given hesperidin lowered serum malondialdehyde and nitrite levels, and increased the activity of serum antioxidant enzymes, including catalase and superoxide dismutase in pentylenetetrazole-treated mice. Hence, the antioxidant properties of herbal extracts can be attributed to the improvement of barrier function.
Innate immunity Prior studies showed that epidermal antimicrobial peptides are also required for epidermal permeability barrier function. At least two epidermal antimicrobial peptides, CAMP (LL-37) and mBD3 (hBD2), are packaged and secreted by lamellar body and regulated in parallel with changes in permeability barrier function.6 Our previous studies revealed that extract of a herbal mixture increased both epidermal CAMP and mBD3 expression in addition to improving barrier function in vivo 8 In addition, the same extract upregulated the expression levels of mBD3 mRNA in vivo, and induced a dosedependent increase in LL-37 and hBD2 mRNA expression in cultured human keratinocytes. Moreover, as stated above, topical apigenin improved barrier function in both normal and diseased skin.10,26 We have demonstrated that topical applications of apigenin twice daily for 9 days markedly increased epidermal CAMP and mBD3 expression in mice.10 Therefore, the upregulation of
antimicrobial peptide expression could be an additional potential mechanism for herbal extract-induced improvement of barrier function. The potential mechanisms whereby herbal medicines benefit epidermal permeability barrier are summarized in Table 2. Conclusion Epidermal permeability barrier function has a significant impact on cutaneous functions. Improvement of skin barrier function is becoming a valuable approach to prevent and treat some skin disorders. Evidence indicates that herbal medicines benefit barrier function in both normal and diseased skin with fewer adverse effects and lower cost. Thus, herbal medicines could be used as an optional alternative for preventing and treating certain dermatoses accompanied by epidermal permeability barrier abnormalities. Acknowledgments This work was partially supported by grants (National Institutes of Health (NIH) AR061106, Veterans Affairs (VA) Merit-1 101BX000608, National Eczema Association Grant, and Natural Science Foundation of China (NSFC) 81301360). References 1. Elias PM, Feingold KR. Coordinate regulation of epidermal differentiation and barrier homeostasis. Skin Pharmacol Appl Skin Physiol 2001;14:28e34. 2. Smith HR, Rowson M, Basketter DA, McFadden JP. Intra-individual variation of irritant threshold and relationship to transepidermal water loss measurement of skin irritation. Contact Dermatitis 2004;51:26e9. 3. Darlenski R, Kazandjieva J, Tsankov N, Fluhr JW. Acute irritant threshold correlates with barrier function, skin hydration and contact hypersensitivity in atopic dermatitis and rosacea. Exp Dermatol 2013;22:752e3. 4. Man MQ, Elias PM. Influences of antioxidants on epidermal permeability barrier function. Chin J Dermatovenereol 2013;27:722e4. n K, Nohlgård C, Nyberg F, et al. Treatment with a barrier-strengthening 5. Wire moisturizing cream delays relapse of atopic dermatitis: a prospective and randomized controlled clinical trial. J Eur Acad Dermatol Venereol 2009;23: 1267e72. 6. Man MQM, Feingold KR, Thornfeldt CR, Elias PM. Optimization of physiological lipid mixtures for barrier repair. J Invest Dermatol 1996;106:1096e101. 7. Man MQ, Choi EH, Schmuth M, et al. Basis for improved permeability barrier homeostasis induced by PPAR and LXR activators: liposensors stimulate lipid synthesis, lamellar body secretion, and post-secretory lipid processing. J Invest Dermatol 2006;126:386e92. 8. Man M, Hupe M, Mackenzie D, et al. A topical Chinese herbal mixture improves epidermal permeability barrier function in normal murine skin. Exp Dermatol 2011;20:285e8. 9. Hou M, Man M, Man W, et al. Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol 2012;21:337e40. 10. Hou MH, Xun R, Hupe M, et al. Topical apigenin improves epidermal permeability barrier homeostasis in normal murine skin by divergent mechanisms. Exp Dermatol 2013;22:210e5.
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