biomedicines

Review New Herbal Biomedicines for the Topical Treatment of Dermatological Disorders

Julia Hoffmann, Fabian Gendrisch, Christoph Mathis Schempp and Ute Wölfle * Research Center Skinitial, Department of Dermatology, Medical Center, University of Freiburg, Hauptstr. 7, D-79104 Freiburg, Germany; julia.hoff[email protected] (J.H.); [email protected] (F.G.); [email protected] (C.M.S.) * Correspondence: ute.woelfl[email protected]; Tel.: +49-0761-27068250; Fax: +49-0761-27068290



Received: 8 January 2020; Accepted: 6 February 2020; Published: 8 February 2020


Abstract: Herbal extracts and isolated plant compounds play an increasing role in the treatment of skin disorders and wounds. Several new herbal drugs, medicinal products and cosmetic products for the treatment of various skin conditions have been developed in recent years. In this nonsystematic review, we focus on herbal drugs that were tested in controlled clinical studies or in scientifically sound preclinical studies. The herbal biomedicines are intended to treat atopic dermatitis (St. John’s wort, licorice, tormentil, bitter substances, evening primrose), psoriasis (araroba tree, lace flower, barberry bark, indigo, turmeric, olibanum, St. John’s wort), actinic keratosis (birch bark, petty spurge), herpes simplex (lemon balm, sage and rhubarb), rosacea (green tea, licorice, tormentil) and acne vulgaris (tea tree oil, green tea, hop), or to improve photo protection (green tea, Dyer’s weed, cocoa tree, carotinoids, licorice), aesthetic dermatology (licorice, pine bark, gotu kola) and wound healing (birch bark, onion).

Keywords: atopic dermatitis; acne; actinic keratoses; psoriasis; rosacea; wound healing

1. Introduction Herbal therapies have been used for the treatment of skin conditions for centuries. Several plant compounds are still used in topical treatments, such as salicylic acid from willow bark from Salix spp. (for desquamation), 8-methoxypsoralen from Ammi visnaga (L.) Lam. (for photochemotherapy), and tannins from oak bark, black tea or hamamelis bark (for oozing eczema). Traditionally used medical plants were evaluated and documented in 300 monographs by Commission E at the German institute for drugs and medicinal products (BfArm) between 1976 and 1993. About 30% of these plants received a negative evaluation. The positive monographs contained 25 plants with relevance for dermatological treatments. They include well-known medical plants such as chamomile, which hazel and marigold. However, most of these plants only achieved a low level of evidence for their efficacy, because only a few high quality clinical studies have been performed [1,2]. During the last years the therapeutic potential of medical plants traditionally used in dermatology has been explored, and some of them have been developed and approved as drug or medical device for the treatment of skin disorders. Furthermore, an increasing number of herbal products have been developed in the field of medical cosmetics, often called “cosmeceuticals”. This review highlights the most exciting new experimental and clinical studies with herbal drugs and cosmeceuticals for skin disorders. Literature was searched in actual plant reviews focusing on special skin diseases. We focused predominantly on controlled clinical studies with a sufficiently high level of evidence. However, this is not purely a systematic evidence based review, because we have also included scientifically confirmed effects of plant extracts with promising new treatment options for dermatologists. In this way we could point to new auspicious treatment strategies, although clinical studies are still missing or under preparation. The quality of the

Biomedicines 2020, 8, 27; doi:10.3390/biomedicines8020027 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, 27 2 of 21 clinical studies was classified as “levels of evidence” (LOE) A to D according to the proposal of the UK National Health Service [3]. Level A represents the highest level with randomized, controlled clinical studies and cohort studies. Level B includes conclusive retrospective or analytical cohort studies, research results, and case control studies, as well as follow-up studies of level A. Level C includes case reports or follow-up studies of level B and level D is assigned to expert opinions without scientific background, pure laboratory research or mechanisms of action. The outline of the paper is arranged according to dermatological conditions and at the end of this article, the main findings are summarized.

2. Atopic Dermatitis Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease. Dermatologists often prescribe glucocorticoids to the patients, but patients and parents of children with AD worry about the side effects of glucocorticoids, especially in long term therapy. They ask for herbal therapies because they expect similar effectivity and fewer side effects. A comprehensive, evidence-based review on clinical studies with herbal products for AD has been published recently [4]. Some of the studies are highlighted here.

2.1. St. John’s Wort (Hypericum perforatum (L.)) St. John’s wort is traditionally used as hypericum oil for the treatment of wounds and burns. The lipophilic phloroglucin derivative hyperforin displays antibacterial, anti-inflammatory and keratinocyte differentiation-promoting properties [5]. The efficacy of a hyperforin-rich ointment standardized to 1.5% hyperforin has been investigated in a randomized, placebo-controlled half side comparison pilot study in 21 AD patients. The treatment was performed twice daily over a period of 4 weeks [6] (LOE-A).

2.2. Licorice (Glycyrrhiza glabra (L.)) The anti-inflammatory effect of licorice (Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisch. ex DC.) is well studied and summarized in an actual review [7]. Most studies were performed with the triterpenes glycyrrhizin and glycyrrhetinic acid of licorice on skin [7–10]. However, other ingredients, such as the flavonoid isoliquiritigenin [11] and the chalcone licochalcone A [12–14] display also anti-inflammatory effects. A hydrophilic ointment with 2% glycyrrhetinic acid as the main active ingredient was tested in a randomized, placebo-controlled study on 281 adult subjects with mild to moderate AD. The application was performed three times daily in the affected areas. After five weeks the verum was significantly superior to the vehicle (placebo) (80% vs 10% improvement) [15] (LOE-A). In a placebo controlled study with 26 adults a cream with Licochalcone A as anti-inflammatory ingredient showed anti-inflammatory effects superior to placebo [16] (LOE-A). Furthermore it has been shown that a herbal composition with glycyrrhizinic acid (0.6%) and licorice extract (0.1% Glycyrrhiza uralensis root extract) as main active ingredients displays anti-inflammatory effects in a placebo-controlled double-blind UV-erythema test study 48 h after irradiation and cream application. The licorice-based product was as effective as 1% hydrocortisone acetate [17]. Besides, it reduced the severity score in 10 patients with AD treated twice daily over 2 weeks in a non-interventional pilot study [17] (LOE-B).

2.3. Tormentil (Potentilla erecta (L.)) Tannins from black tea (Camellia sinensis (L.) Kuntze), witch hazel (Hamamelis virginiana L.) and oak bark (Quercus spp.) have been empirically used in dermatology since ancient times. Tannins are used as wet-lipid wraps or local baths for the treatment of acute, oozing eczema. A cream containing 2% tannins from the rhizome of tormentil (Potentilla erecta (L.) Raeusch.) displayed a corticoid-like vasoconstrictive effect in an occlusive patch test after 48 h [18]. It also displayed placebo-controlled anti-inflammatory properties comparable to hydrocortisone in the UV-erythema test (LOE-A) and Biomedicines 2020, 8, 27 3 of 21 was effective in the treatment of 24 patients suffering from mild to moderate AD. The application was performed twice daily over 2 weeks, and was not placebo controlled [19] (LOE-B).

2.4. Bitter Substances Bitter substances have been used as appetizing and digestion promoting agents since Ayurvedic medicine 5000 years ago. Only recently the molecular structure of bitter taste receptors (TAS2Rs) has been elucidated, and it was shown that TAS2Rs are also expressed in human epidermis [20]. Bitter compounds such as salicin from willow bark (from Salix spp.) and amarogentin from Gentiana lutea (L.) bind to the bitter taste receptors of the skin, eventually leading to calcium influx and the enhanced expression of skin barrier-constituting proteins such as filaggrin [20]. Bitter compounds also stimulated the synthesis of lipids in keratinocytes. In a placebo-controlled, double-blind half-side comparison with 33 volunteers 5% gentian extract significantly increased the lipid content of the epidermal stratum corneum on the volar forearm. In this body region skin lipids are nearly exclusively produced by keratinocytes [21]. The application occurred twice a day for 4 weeks. After 2 weeks of treatment, a significant increase in the lipid content could already be observed (LOE-B). Interestingly, the predilection sites of AD (flexures of the arms and knees) correspond to skin regions in which the lipids are exclusively formed by keratinocytes and not by sebaceous glands. Therefore, topical treatment with bitter agents is especially helpful in dry and atopic skin with reduced synthesis of epidermal lipids.

2.5. Evening Primrose (Oenothera biennis (L.)) The oil obtained from evening primrose seeds is beneficial for AD due to its high content of γ-linolenic acid. It is used both internally and in topical products. Only a few high-quality studies have investigated the effect of evening primrose oil in AD. A recent meta-analysis of the existing literature concludes that there is a moderate effect of evening primrose oil on itching, scaling and crusting in AD [22] (LOE-A).

3. Psoriasis Vulgaris Herbal products are also used for the topical treatment of psoriasis. Psoriasis is a chronic, immune-mediated skin disease that shows red and scaly patches on the skin that itch or burn. Three systematic reviews have evaluated the use of herbal therapies in psoriasis [23–25].

3.1. Araroba Tree (Vataireopsis araroba (Aguiar) Ducke) The most potent topical treatment for psoriasis is the anthracen derivative dithranol (synonym: anthralin). It was obtained from chrysarobin, extracted from the bark of the araroba tree that grows in the rain forests of the Amazon. Dithranol inhibits the release of pro-inflammatory cytokines and the proliferation of keratinocytes. A randomized controlled multicenter study on 106 psoriasis patients with chronic psoriasis plaques demonstrated significant better therapeutic effectivity for dithranol short contact treatments (15–45 min) with stepwise increasing concentrations of dithranol (up to 5%) once daily for 12 weeks as compared to the standard treatment calcipotriol ointment (50 µg/g twice daily) [26] (LOE-A).

3.2. Lace Flower (Ammi majus(L.) and Ammi visnaga (L.)) The furanocoumarins 8-methoxypsoralen (8-MOP) and 5-methoxypsoralen (5-MOP) are isolated for therapeutic use from Ammi majus (L.) and Ammi visnaga (L.) Lam. The psoralens are phototoxic substances that are photo-activated by long-wave ultraviolet A (UVA) radiation and may cause severe phototoxic skin reactions. In the therapeutic setting of PUVA therapy (psoralen plus UVA) they inhibit keratinocyte proliferation and display immunosuppressive effects that are used to treat severe inflammatory skin conditions, i.e., psoriasis. Several clinical studies confirmed the efficacy of systemic Biomedicines 2020, 8, 27 4 of 21

PUVA [27] (LOE-A), bath PUVA [28] (LOE-A) and cream PUVA therapy (0.1% 8-MOP) [29] in psoriasis (LOE-A).

3.3. Barberry Bark (Mahonia aquifolium (Pursh) Nutt.) The barberry Mahonia aquifolium is a shrub indigenous to Northern America. It was used for centuries by Native Americans to treat psoriasis. Tinctures and ointments from Mahonia bark are available as traditional drugs in Northern America and Europe. Recently, a randomized placebo-controlled double-blind study in 200 psoriasis patients demonstrated the efficacy and safety of a 10% Mahonia ointment in the treatment of psoriasis. The application was done twice daily for 12 weeks [30] (LOE-A).

3.4. Indigo (Baphicacanthus cusia, Brem.) ‘Indigo naturalis‘ is an important remedy in Traditional Chinese Medicine (TCM). It is a blue powder obtained from the plant Baphicacanthus cusia by grinding, fermentation and addition of lime. In a randomized placebo-controlled study 42 patients suffering from chronic plaque psoriasis were treated once daily with a 10% indigo containing ointment for 12 weeks. The indigo naturalis used contained 1.4% indigo and 0.16% indirubin. Treatment with indigo improved symptoms by 81%, while the improvement with placebo was only 26% [31] (LOE-A). As a side effect, four patients showed itching. Because Indigo naturalis causes long lasting blue staining of skin and clothes, Taiwanese researchers developed a patented uncolored Indigo naturalis extract [32]. Several studies with Indigo extract have been performed in psoriasis. A recently published randomized, double-blind, placebo-controlled study in 100 psoriasis patients showed a dose-dependent efficacy of Indigo extract applied twice a day over 8 weeks. Indigo extract (200 µg/g) reduced the PASI by 70%, and Indigo extract (50 µg/g) reduced the PASI by 50%. Side effects in some patients were nasopharyngitis, infections of the upper respiratory tract and local erythema. Severe side effects were not observed [33] (LOE-A). Punch biopsies obtained before treatment and after 8 weeks of treatment revealed a normalization of skin morphology and downregulation of the pro-inflammatory key cytokine in psoriasis, IL-17 [33]. All studies with Indigo extract were performed on Asian patients. Whether the effect of Indigo naturalis is comparable in Caucasians cannot be assessed.

3.5. Turmeric (Curcuma longa (L.)) Turmeric plays an important role in TCM and in Aryuvedic Medicine. In vitro, turmeric and its major active ingredient curcumin display anti-inflammatory, antimicrobial and anti-oxidative properties [34]. During the last years some laboratory and clinical studies have investigated the therapeutic potential of curcumin in psoriasis. Curcumin may improve psoriasis by inhibition of phosphorylase kinase [35,36], downregulation of pro-inflammatory cytokines such as IL-17 and TNF-α, as well as improvement of the epidermal barrier by inducing the expression of involucrin and filaggrin in vitro [37]. However, randomized placebo-controlled studies with turmeric and curcumin in psoriasis are missing so far [38].

3.6. Olibanum (Boswellia Serrata, Triana & Planch.) Olibanum containing ointments were recommended in the Greco-Roman period by Hippocrates, Galen and Dioscorides for the treatment of various skin disorders such as psoriasis, burns, warts, bleeding and wounds. Recently, 200 patients with mild to moderate psoriasis were treated three times daily for 12 weeks with an olibanum ointment containing 5% 3-O-Acetyl-11-keto-β-boswellic acid in an open label application study. The PASI was significantly reduced, as well as serum biomarkers such as leukotrien B4, TNF-α, VEGF and PGE2 (LOE-B). Thirteen patients (6.5%) developed contact dermatitis [39]. Biomedicines 2020, 8, 27 5 of 21

3.7. St. John’s Wort (Hypericum perforatum (L.)) Psoriatic keratinocytes show increased cell proliferation, disturbed cell differentiation, an inflammatory phenotype and reduced expression of cationic channels such as TRPC6. Hyperforin—the major lipophilic active ingredient of St. John’s wort—displays in vitro pronounced anti-inflammatory effects and stimulates calcium influx into psoriasis keratinocytes, activates TRPC6 expression, reduces cell proliferation and promotes proper cell differentiation [40]. A placebo-controlled single-blind pilot study with 5% St. John’s wort extract on 10 psoriasis patients revealed a significant improvement of the erythema, extension and thickness of the psoriasis plaques. The treatment was performed twice daily [41] (LOE-B). Similarly, a recently published placebo-controlled, double-blind half-side comparison in 20 patients with mild to moderate plaque psoriasis with 5% St. John’s wort extract showed a significant reduction of the PASI and the lesional TNF-α expression [42] (LOE-B).

4. Herpes Simplex The herpes simplex virus (HSV) can cause blisters and sores in almost any part of the skin. These sores usually occur either around the mouth and nose, or on the genitals and buttocks. Several extracts were described with antiviral activity [43] including licorice extract [44] and Boswellia serrata oleo gum [45]. However clinical studies using these plant products are still missing. Here, we focused on plants with clinical evidence against herpes simplex infection.

4.1. Lemon Balm (Melissa officinalis (L.)) Lemon balm cream was tested in 66 patients with recurrent herpes simplex labialis in a randomized double-blind, placebo-controlled study. The application of the test cream (1% dried Melissa officialis extract) was four times daily for 5 days. The lesions cleared significantly faster with lemon balm cream, and the patients had less blisters and pain [46] (LOE-A).

4.2. Sage (Salvia officinalis (L.)) and rhubarb (Rheum palmatum (L.)) A randomized, placebo-controlled study investigated the combination of sage and rhubarb extract in 149 patients with herpes simplex labialis. The patients were treated topically with either acyclovir (50 mg/g), sage extract (23 mg/g), or the combination of sage and rhubarb extract (23 mg/g each). The combined sage-rhubarb cream was superior to sage alone, and was as effective as acyclovir [47] (LOE-A).

5. Actinic Keratosis Actinic keratoses (AK) represent in situ squamous cell carcinomas that form on sun-damaged skin and appear clinically as thick, scaly or crusty skin. Several plant extracts were tested against actinic keratosis; however, the results were mostly not promising (e.g., for St John’s wort [48].

5.1. Birch Bark (Betula spp.) Birch bark contains 87% triterpenes, mainly betulin. A betulin oleogel is produced by mixing a standardized dry extract from birch bark with vegetable oil. In a multicenter, placebo-controlled, randomized study with betulin oleogel, 165 patients were treated topically for 3 months and showed no positive effect. However, two thirds of the patients had actinic keratosis grade 3 [49] (LOE-A). In contrast in a non-randomized, non-placebo controlled study with 28 patients with actinic keratosis grade 1 or 2 it could be demonstrated that a therapy with betulin cream (betulin oleogel with additional water) was as effective as cryotherapy [50] (LOE-B). The same result was achieved with betulin oleogel in a prospective, randomized, monocentric study with 45 patients with early grades of AK [51] (LOE-B). Histological and experimental studies suggest a differentiation-promoting effect as main mechanism of action of betulin in early grades of actinic keratosis [51,52]. Biomedicines 2020, 8, 27 6 of 21

5.2. Petty Spurge (Euphorbia peplus (L.)) The latex of the lactiferous petty spurge contains toxic diterpene esters such as ingenol mebutate. A randomized double-blind, placebo-controlled study evaluated the efficacy of 0.025% and 0.05% ingenol mebutate gel compared to placebo in 200 patients with actinic keratoses. The topical products were applied once daily for three days. Both ingenol mebutate concentrations were highly effective (75% and 100% clearing, versus 0% clearing with placebo). Ingenol mebutate induces a localized necrosis of the treated skin, followed by an inflammatory response, crusting and subsequent clearing of the treated area. Scar formation was not observed [53] (LOE-A). These results were confirmed in another randomized double-blind, placebo-controlled study [54] (LOE-A). Ingenol mebutate gel was approved in 2013 as a prescription drug (150 µg/g gel and 500 µg/g gel).

6. Photoprotection and Esthetic Dermatology Numerous plants contain photo-protective antioxidants and ultraviolet (UV) absorbing polyphenols (catechins and flavonoids), and carotinoids. These compounds may protect the skin from sunburn, skin ageing and the development of skin cancer, that are at least in part mediated by reactive oxygen species (ROS). A systematic review from 2014 summarizes topically and orally provided plant compounds for improved protection from sunlight [55]. Plant extracts are also used for multiple cosmetic indications. A review published in 2010 highlights controlled clinical studies for different cosmetic indications as well as for photo protection [2].

6.1. Green Tea (Non-Fermented Camellia sinensis (L.)) Green tea extracts contain high amounts of oligomeric proanthocyanidins such as catechin, epicatechin and epigallocatechin-3-gallate, that are potent antioxidants with photo-protective properties. They reduce oxidative stress induced by UV radiation and inhibit various cytokines and mediators involved in skin carcinogenesis [56] (LOE-D). Some studies have shown that green tea extract may prevent UV-induced inflammation when applied topically or systemically [57]. However, in vivo studies confirming that green tea may prevent skin cancer are still missing.

6.2. Dyer’s Weed (Reseda luteola (L.)) Flavonoids such as quercetin, rutin and luteolin are potent antioxidants. Dyer’s weed (is particularly rich in luteolin. It has been shown that Dyer’s weed extracts and luteolin display prominent anti-oxidant and anti-inflammatory effects in skin cells [58]. Additionally, luteolin absorbs UVA radiation and protects skin cells from UVB-induced DNA -damage [59,60]. In a randomized, placebo-controlled, double-blind study with 40 healthy volunteers a Dyer’s weed extract containing 2.5% luteolin reduced UVB-induced erythema to a similar extent as 1% hydrocortisone [61] (LOE-A). It has been recently shown that oxidative stress also plays a critical role in the induction of irritant and allergic contact dermatitis [62]. An ointment containing a combination of luteolin, tocopherol and ubichinone with a high radical protecting factor may protect the skin from skin irritation induced by alkali, acid, alcohol, soap, detergents and disinfection. This protective effect has been proven in the repetitive washing test in a placebo-controlled, double-blind study with 25 volunteers. As active ingredients, the antioxidant cream contained 0.1% Dyer’s weed extract, 0.1% tocopherol and 0.05% ubiquinone. 15 min prior to the washings, 200 µL of the test ointment was applied. The test was performed 3 times daily on 7 consecutive days. The antioxidant ointment significantly reduced erythema and transepidermal water loss and improved skin hydration in the washing test [63] (LOE-A).

6.3. Cocoa Tree (Theobroma cacao (L.)) Cocoa powder contains a mixture of flavanols and tannins, mainly catechin and epicatechin. In a randomized comparative double-blind study the photo-protective effect of cocoa consumption Biomedicines 2020, 8, 27 7 of 21 on UV-induced skin erythema was assessed in 24 female volunteers. The volunteers ingested cocoa with a high (326 mg/d) or a strongly reduced flavanol content (27 mg/d) dissolved in 100 mL water over 12 weeks. Subsequently, a UV-erythema test was performed in all subjects. It was shown that only the flavanol-rich cocoa preparation reduced the UV-erythema. Moreover, the consumption of the flavanol-rich cocoa drink significantly increased skin firmness and hydration [64] (LOE-A).

6.4. Carotinoids The effect of the plant-derived carotinoids β-carotene and lycopene on UV-induced skin erythema was assessed in a randomized placebo-controlled, double-blind parallel group study with 36 volunteers. On a daily basis, the subjects orally received either 24 mg β-carotene, or a carotinoid mix with 8 mg of β-carotene, lutein and lycopene respectively, or placebo. Skin erythema was measured at the beginning, after 6 weeks and after 8 weeks. Both the carotinoid mix and β-carotene significantly reduced UV-erythema after 8 weeks compared to the placebo [65] (LOE-A). Similarly, a controlled study with lycopene showed a significant reduction of the UV-erythema after 12 weeks [66] (LOE-B). A diet supplementation with a tomato paste containing high concentration in lycopene (16 mg lycopene) was tested in 20 women for 12 weeks in a randomized, controlled, single-blinded study. The assessing investigator was unaware of supplement allocation. A reduced UV-induced MMP-1 (Matrix-Metallo-Proteinase-1) production and protection from mitochondrial DNA-damage was shown in skin samples [67] (LOE-B).

6.5. Citrus Fruits (Citrus spp.) A case-control study with 470 participants showed that the consumption of citrus peel was associated with a lower risk to develop squamous cell carcinoma (SCC) (LOE-C) [68].

6.6. Coffee Plants (Coffea spec.) A prospective observatory study from the “Nurses’ Health Study and Health professionals” with 173229 patients showed that those patients with the highest quintile of caffeine intake compared with those in the lowest quintile had reduces Basal Cell Carcinoma (BCC) risk [69] (LOE-B). A case-control study compared 166 patients with BCC to 158 patients not showing BCC. No significant effect of coffee drinking could be shown on BCC risk [70] (LOE-B).

6.7. Licorice (Glycyrrhiza glabra (L.)) The root of licorice contains many different biologically active compounds [7]. The steroid saponin β-glycyrrhetinic acid is the best studied anti-inflammatory compound of licorice. In a randomized, placebo-controlled, double-blind intra-individual comparison study, the effect of an ointment with 2.5% β-glycyrrhetinic acid on the subcutaneous fat tissue of the thigh was investigated in 18 female volunteers. When applied twice daily over 4 weeks, the ointment with β-glycyrrhetinic acid significantly reduced the circumference of the thigh compared to the non-treated or placebo-treated contralateral thigh. The authors hypothesized that topically applied β-glycyrrhetinic acid is absorbed by the skin and may reduce subcutaneous depots of fat tissue through interaction with the local 11-hydroxysteroid dehydrogenase, eventually inhibiting adipocyte growth and maturation [71] (LOE-A). Licorice extracts are also traditionally used for depigmentation purposes. It has been shown that the lipophilic compound glabridin inhibits the enzyme tyrosin kinase and melanogenesis in melanocytes in animal experiments. The application of an ointment with 0.5% glabridin reduced UVB-induced pigmentation on guinea pig skin [72] (LOE-D). Some studies have investigated the photo-protective properties of the flavonoid licochalcone A present in licorice roots. In HaCaT keratinocytes licochalcone A upregulated various anti-inflammatory and cyto-protective enzymes [13]. UVA-treated human dermal fibroblasts containing licochalcone A showed higher glutathion levels and a reduced concentration of UV-generated reactive oxygen species [12] (LOE-D). These in vitro data are supported by a double-blind, placebo-controlled in vivo Biomedicines 2020, 8, 27 8 of 21 study with 22 healthy volunteers that were treated with either licochalcone A or the vehicle on their volar forearms twice daily for two weeks. The test areas were then irradiated with UVA, and luminescence of the skin was measured with ultra-weak photon emission detection. In the licochalcone A treated skin area, the generation of UVA-induced photons was significantly lower than on the placebo-treated area [12] (LOE-A).

6.8. Pine Bark (Pinus pinaster, Ailton) A standardized polyphenol extract obtained from the bark of Pinus pinaster (Syn.: P. maritima) with antioxidant properties has potent photo-protective and pigmentation modulating properties [73]. The effect of pine bark extract on melasma hyperpigmentation was investigated in an open label clinical study on 30 women with melasmatic hyperpigmentations. The subjects received 25 mg pine bark extract three times daily over four weeks. The degree and area of pigmentation was reduced in 80% of the test persons [74] (LOE-B).

6.9. Gotu Kola (Centella asiatica (L.) Urban) Centella asiatica contains a variety of pentacyclic triterpenoids, including asiaticoside, brahmoside, asiatic acid, and madecassic acid. Other constituents include centellose, centelloside, and madecassoside. A cream with Centella asiatica-extract, tocopherol and a collagen-elastin hydrolysate was tested in a randomized placebo-controlled, double-blind study on 80 pregnant women. The cream was applied daily from the end of the 12th week of pregnancy until delivery. The active cream was significantly superior to the placebo with regard to the number and severity of stretch marks [75] (LOE-A). Another vehicle-controlled half-side comparison study investigated the effect of a cream containing 0.1% asiaticoside on periocular wrinkles in 27 women. The women applied the creams twice daily over 12 weeks. Silicone imprints revealed a significantly superior reduction of the crow’s feet wrinkles with the asiaticoside cream compared to placebo [76] (LOE-B).

7. Wound Healing Wound healing is a natural physiological response to tissue injury and involves a complex interplay between numerous cell types (keratinocytes, fibroblasts and immune cells), cytokines and the vascular system to stop bleeding, kill bacteria and initiate re-epithelialization. Most herbal remedies traditionally used for wound healing have not been investigated in controlled clinical studies [77]. In contrast, the wound-healing properties of a betulin rich extract from the bark of white birches have been thoroughly investigated. This extract allows the production of a solid phase stabilized emulsion without conventional emulsifiers or preservatives [78] and will be described in more detail.

7.1. Birch Bark (Betula spp.) The wound healing properties of betulin have been elucidated at the molecular level and positively affect all three phases of wound healing (the inflammatory phase as well as migration and differentiation phase of keratinocytes) [79]. The first clinical evidence for the wound healing properties of betulin was achieved in a split thickness wound study with the topical application of a water-free betulin oleogel [80]. Subsequently, several multicentric, controlled, randomized clinical studies on superficial wounds and second degree burns were performed with betulin oleogel [81–83] (LOE-A). In 2016, the European Medical Agency (EMA) approved betulin oleogel as a drug for the topical treatment of superficial wounds and burns [84].

7.2. Onion (Allium cepa (L.)) A systematic review published in 2017 on anti-scarring agents mentions many positive outcomes in scarring management with onion extract [85]. Biomedicines 2020, 8, 27 9 of 21

In a randomized placebo controlled study on 58 subjects that underwent small surgical procedures of the skin, such as excision of skin tumors or punch biopsies, the effect of onion extract on scar formation was investigated. After initial primary wound healing for three weeks, the patients received onion extract or placebo twice daily for 10 weeks. Onion extract significantly improved redness, smoothness, texture and general appearance of the scars compared to placebo [86] (LOE-A).

8. Rosacea Rosacea is an inflammatory skin disease of the face affecting both sebaceous glands and small superficial skin vessels. Different clinical forms of rosacea include an erythematous, papulopustulous and telangiectatic variant. A recent systematic review analyzed the efficacy of herbal medicinal products for the treatment of rosacea [87].

8.1. Green Tea (Non-Fermented Camellia sinensis (L.)) Green tea extract contains high amounts of oligomeric proanthocyanidins such as epigallocatechin- 3-gallate (EGCG)—a potent antioxidant with photo-protective properties. It has been shown that EGCG inhibits the expression of the vascular endothelial growth factor VEGF and the hypoxia-induced factor 1α (HIF-1α) that both stimulate angiogenesis in the skin. In a very small randomized, double blind, vehicle controlled split face trial four volunteers used a 2.5% EGCG containing cream twice daily over 6 weeks. However, no reduction in skin erythema could be detected, neither clinically nor histologically [88] (LOE-D). However, larger clinical studies are needed to determine if EGCG has a clinically relevant effect. As sun exposure is a trigger factor of rosacea, green tea products might have a relevant therapeutic role via their photo-protective effects.

8.2. Licorice Root (Glycyrrhiza inflata, Batalin) An open label study with 62 volunteers showed that licochalcone A, a flavonoid from licorice root, incorporated in different vehicles significantly reduces erythema in rosacea when applied once daily over 8 weeks. When combined topically with the antibiotic metronidazole it was also well tolerated in 25 patients [89] (LOE-B). The combination of licochalcone A with trans-4-t-butylcyclohexanol, an inhibitor of the cation channel TRPV1, was also investigated. The TRPV1 channel in the skin is known to mediate sensation of pain, itch and warmth. In keratinocytes stimulation of TRPV1 results in increased Ca2+-influx, which induces finally cell death and disruption of the epidermal barrier [90]. In an open, not placebo controlled, international multi-center study 1221 patients with sensitive skin prone to redness and rosacea were treated with this combination. An improvement of the studied symptoms (e.g., redness and erythema) could be shown after 4 weeks with applications twice a day [90] (LOE-B). The product was well tolerated. However the used concentration of trans-4-t-butylcyclohexano and licochalcone A was not mentioned in the publication.

8.3. Bitter Wood (Simarouba amara Aubl.) In a recent review on herbal products for rosacea [87] a 4% extract from Simarouba amara was the only herbal product that reduced telangiectasia. In a study with 30 patients suffering from rosacea a topical gel with Simarouba amara-extract was applied twice daily over 6 weeks. All clinical parameters such as flush, erythema, telangiectasia, papules and pustules were significantly reduced after 6 weeks. No side effects such as pruritus, edema or stinging were observed. The clinical overall improvement was similar to conventional standard treatments such as metronidazole or azelaic acid. However, no control group was included in this study [91] (LOE-B).

8.4. Tormentil (Potentilla erecta (L.)) Although no clinical trials with tormentil have been conducted in rosacea, recent studies point to a potent vasoconstrictory effect of tormentil that might be useful in treating telangiectasia in rosacea. Biomedicines 2020, 8, 27 10 of 21

In a randomized, prospective, placebo controlled double blind patch test with 40 healthy volunteers 1% hydrocortisone and a tormentil extract containing the ellagitannin agrimoniin displayed both a similar blanching effect, that means a paling of the skin [18] (LOE-B). The exact mechanism responsible for the blanching effect is not entirely clear, but local vasoconstriction of smooth muscle cells and consecutive blood flow reduction seem to be involved in this phenomenon [92]. Tormentil-extract displays this vasoconstrictive property at least partly by radical scavenging of NO, an important vasodilator of dermal blood vessels and by inhibition of the endothelial NO-syntase (eNOS) that is constitutively active. Because of its vasoconstrictive effect PE might be beneficial to treat rosacea erythematosa (LOE-C). Facial reddening in rosacea is at least partly mediated by formation of NO via iNOS that is induced by endogenous or exogenous factors such as demodex mites. Sauermann and colleagues showed that the treatment of rosacea with the topical NO inhibitor L-NAME (1% L-NAME cream, applied twice daily for 3 weeks) resulted in a significant reduction of erythema in rosacea patients [93] (LOE-B). However, a clinical study to prove that tormentil extract indeed reduces the facial reddening in rosacea is still missing.

9. Acne Vulgaris Acne vulgaris is characterized by hyperactive sebaceous glands, epidermal hyperproliferation and perifollicular inflammation. The most important pathogens linked to acne-prone skin are for example Propionibacterium acnes (P. acnes) and Staphylococcus aureus (S. aureus). Botanical and phytochemical options for acne vulgaris therapy are summarized in a systematic review published in 2014 [94].

9.1. Tea Tree (Melaleuca alternifolia (Maiden & Betche) Cheel) In a single-blind, randomized study 5% tee tree oil was compared to 5% benzoyl peroxide on 124 acne patients in topical application. After 3 months of treatment signs and symptoms had markedly improved with both preparations. There were no differences between the two therapies [95] (LOE-B). A vehicle-controlled, randomized, double-blind study with 60 acne patients confirmed the efficacy of a gel containing 5% tea tree oil when applied twice daily over 45 days [96] (LOE-A).

9.2. Green Tea (non-fermented Camellia sinensis (L.)) It could be shown that epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, displays apoptotic, sebosuppressive and anti-inflammatory effects on human sebocytes. Furthermore it displays antibacterial effects on P. acnes [97]. EGCG significantly improved acne in an 8-week randomized, split-face, clinical trial with 35 patients that were treated with 1% or 5% EGCG solution twice daily [97] (LOE-A). The efficacy of a lotion with 2% green tea extract was demonstrated in a prospective, non-randomized study on 20 patients with acne using the preparation twice daily for 6 weeks [98] (LOE-B).

9.3. Hop (Humulus lupulus (L.)) Hop extract shows anti-oxidative and anti-inflammatory effects. In the microdilution test hop extract inhibited the growth of P. acnes and S. aureus already at a concentration of 3.1 and 9.4 µg/mL respectively. In addition, a gel formulation with 0.3% hop extract (w/w) showed antibacterial activity in the agar diffusion test against P. acnes and S. aureus (inhibition zone value: 5.5 mm and 3 mm, respectively) (LOE-C). Therefore, hop extract might be an alternative treatment option for acne-prone skin [99] and should be tested in clinical studies.

10. Conclusions Botanical compounds such as salicylic acid, methoxsalen and chrysarobin have been traditionally used and still play an important role in the treatment of psoriasis. Recently, the alkaloid indirubin from indigo has been shown to be effective against psoriasis in randomized clinical trials. Glycyrrhetinic acid Biomedicines 2020, 8, 27 11 of 21 and licochalcone A from licorice have been shown to be effective in the treatment of atopic dermatitis. The toxicBiomedicines diterpene 2019 ester, 7, x FOR ingenol PEER REVIEW mebutate from petty spurge has been approved as a highly11 eff ofective 23 prescription drug for the treatment of superficial epithelial skin cancer (actinic keratoses). Only recently, betulin-oleogel obtained from birch bark has been approved as a drug for the topical treatmentL R of superficialDisease wounds and burns.Plant These examplesCompound illustrate thatTreatment botanical compounds and extractsO e that Biomedicines 2019, 7, x FOR PEER REVIEW 11 of 23 are summarized in Table1 have a great potential to be developed as prescription or over-the-counterE f drugs inBiomedicines dermatology. 2019, 7, x FOR PEER REVIEW Hyperforin L 11 ofR 23 Disease Plant Compound Treatment O e TableSt. 1. John’sSummary wort of herbal compounds for the treatment- Ointment of with skin 1.5% diseases. L R E f Disease (HypericumPlant Compound Treatmenthyperforin twice daily for 4 OA e6 Hyperforin L Disease perforatumPlant (L.)) Compound weeks Treatment E O f Ref E St. John’s wort Hyperforin - Ointment with 1.5% Hyperforin (Hypericum hyperforin twice daily for 4 A 6 St. John’s wort Glycyrrhetinic acid - -Ointment Hydrophilic with ointment 1.5% with St. John’sperforatum wort (L.)) weeks- Ointment with 1.5% (Hypericum(Hypericum perforatum hyperforin2%hyperforin glycyrrhetinic twice twice daily acid daily for three for 4 AA A 615 [ 6] perforatum(L.)) (L.)) weekstimes4 weeks daily for 5 weeks

Glycyrrhetinic acid -- HydrophilicCream with ointment0.6% with 2%glycyrrhizinic glycyrrhetinic acid acid and three A 15 - Hydrophilic ointment with GlycyrrhetinicGlycyrrhetinic acid acid - Hydrophilic ointment with timeslicorice2% glycyrrhetinicdaily extract for 5(0.1% weeks acid three A [ 15] 2%times glycyrrhetinic daily for 5acid weeks three A 15 Licorice -Glycyrrhiza Cream with uralensis 0.6% root times- Cream daily with for 5 0.6% weeks (Glycyrrhiza glycyrrhizinicextract)glycyrrhizinic twice dailyacid acid and for and 2 licorice B 17 - Cream with 0.6% licoriceweeksextract extract (0.1% (0.1%Glycyrrhiza B [17] Licoriceglabra (L.)) glycyrrhizinicuralensis root acid extract) and twice Licochalcone A (GlycyrrhizaLicorice glabra (L.)) Glycyrrhizadaily for 2uralensis weeks root licorice extract (0.1% Atopic Licochalcone A extract) twice daily for 2 B 17 Atopic (Glycyrrhiza Licorice Glycyrrhiza uralensis root dermatitisdermatitis weeks- Cream with < 1% glabra (L.)) - Cream with < 1% (Glycyrrhiza extract) twice daily for 2 BA A 1716[ 16 ] Licochalcone A licochalconelicochalcone A A glabra (L.)) weeks Atopic Licochalcone A dermatitis - Cream- Cream with with < 1% 2% tannins from Atopic A 16 Biomedicines 2019, 7, x FOR PEER REVIEW licochalcone- Creamthe rhizome with A of2% tormentil tannins from for 48 BB 1218 [of18 23] dermatitis Tormentil - Creamh in an with UV-erythema < 1% test Tannins (Potentilla erecta (L.)) the rhizome of tormentil for 48 A 16 licochalcone- Cream with A 2% tannins from Tormentil h thein an rhizome UV-erythema of tormentil test twice B [ 19] Evening daily for 2 weeks (Potentilla erecta Tannins - Cream with 2% tannins from B 18 Atopic primrose - -Meta-analysis Cream with 5% for gentain the use of (L.)) Primrose oil the- Creamextract rhizome with twice of 2% dailytormentil tannins for 4 for weeksfrom 48 A 22 dermatitisBitter substances(Oenothera Gentian extract - primroseCreamincreases with oil in 2% volunteers tannins from B B 18[ 21] Tormentil hthe in rhizomean UV-erythema of tormentil test twice biennis (L.)) theepidermal rhizome of lipids tormentil that are for 48 (Potentilla erecta Tannins dailyreduced for 2 inweeks atopic dermatitis B 19 Tormentil h in an UV-erythema test Atopic Evening primrose - Meta-analysis for the use of (L.)) Primrose oil - Cream with 2% tannins from A [22] dermatitis (Oenothera(Potentilla biennis erecta(L.)) Tannins - Creamprimrose with oil 5% gentain Dithranol the rhizome of tormentil twice Dithranol - Daily short treatments (15 - (L.)) - extractCream twicewith 2%daily tannins for 4 weeksfrom Araroba tree daily- Daily for 2 short weeks treatments (15 - B 19 Bitter substances Gentian extract theincreases45 rhizomemin) with in of volunteers dithranol tormentil cream twice B 21 Araroba(Vataireopsis tree 45 min) with dithranol cream Psoriasis (Vataireopsis araroba daily-epidermalof Creamof stepwise stepwisefor 2with weeks lipids rising rising5% gentainthat are BA A 1926[ 26 ] vulgaris (Aguiar)araroba Ducke) (Aguiar) concentrations up to 5% for extractreducedconcentrations twice in atopic daily up dermatitis forto 5% 4 weeks for 12 Ducke) 12 weeks - Cream with 5% gentain Bitter substances Gentian extract increasesweeks in volunteers B 21 extract twice daily for 4 weeks epidermal lipids that are Bitter substances 8-methoxypsoralen Gentian extract increases in volunteers BA 2127 reduced- Oral 8-MOP in atopic PUVA dermatitis (0.6 (8-MOP) epidermal lipids that are mg/kg) twice per week reduced in atopic dermatitis - Bath PUVA with 5 mg/l A 28 8-MOP 4 times per week

Lace flower - Cream PUVA with 0.1%

(Ammi majus (L.) 8-MOP 12 treatments and A 29 Ammi visnaga 5-methoxypsoralen (L.)) (5-MOP) Psoriasis - Oral 5-MOP PUVA (1.2 vulgaris A 27 mg/kg) twice per week

Barberry bark (Mahonia - 10% Mahonia ointment twice Mahonia ointment A 30 aquifolium daily for 12 weeks (Pursh) Nutt.)

Indigo naturalis containing indigo and indirubin Indigo - 10% indigo ointment (1.4%

(Baphicacanthus indigo and 0.16% indirubin) A 31 cusia Brem.) daily for 12 weeks Biomedicines 2019, 7, x FOR PEER REVIEW 12 of 23

Evening Atopic primrose - Meta-analysis for the use of Primrose oil A 22 dermatitis (Oenothera primrose oil Biomedicines 2019, 7,biennis x FOR PEER(L.)) REVIEW 12 of 23

Biomedicines 2019, 7, x FOR PEER REVIEW 12 of 23 Dithranol Evening - Daily short treatments (15 -

Atopic Ararobaprimrose tree - Meta-analysis for the use of Primrose oil 45 min) with dithranol cream A 22 dermatitis (Vataireopsis(OenotheraEvening primrose oil of stepwise rising A 26 Atopic ararobabiennisprimrose (Aguiar) (L.) ) - Meta-analysis for the use of Primrose oil concentrations up to 5% for 12 A 22 dermatitis (OenotheraDucke) primrose oil weeks biennis (L.)) Dithranol - Daily short treatments (15 - 8-methoxypsoralen A 27 Araroba tree - Oral 8-MOP PUVA (0.6 (8-MOP)Dithranol 45 min) with dithranol cream (Vataireopsis mg/kg) twice per week -of Daily stepwise short rising treatments (15 - A 26 Araroba tree araroba (Aguiar) - Bath PUVA with 5 mg/l 45concentrations min) with dithranol up to 5% cream for 12 Biomedicines 2020, 8, 27 (Vataireopsis A 2812 of 21 Ducke) 8-MOP 4 times per week ofweeks stepwise rising A 26 ararobaLace flower (Aguiar) - concentrationsCream PUVA withup to 0.1% 5% for 12 (AmmiDucke majus) (L.) 8-methoxypsoralenTable 1. Cont . 8-MOPweeks 12 treatments A 27 and - Oral 8-MOP PUVA (0.6 A 29 (8-MOP) L Ammi visnaga 5-methoxypsoralen mg/kg) twice per week Disease Plant 8-methoxypsoralenCompound Treatment AO 27Ref - Oral 8-MOP PUVA (0.6 (L.)) (5-MOP) - Bath PUVA with 5 mg/l E (8-MOP) A 28 Psoriasis mg/kg) twice per week 8-methoxypsoralen (8-MOP) - 8-MOPOral- Oral 5-MOP 8-MOP4 times PUVA PUVAper week (1.2 A [ 27] vulgaris Lace flower - (0.6Bath mg PUVA/kg) twicewith 5 per mg/l week A 27 mg/kg)- Cream twice PUVA per with week 0.1% - Bath PUVA with 5 mg/L A 28 (Ammi majus (L.) 8-MOP 412 times treatments per week A [28] 8-MOP 4 times per week A 29 Laceand flower - Cream PUVA with 0.1% Lace flower - Cream PUVA with 0.1% 5-methoxypsoralen A [ 29] (Ammi(AmmiAmmi majus majus visnaga(L.) (L.) 8-MOP8-MOP 12 12 treatments treatments and A 29 (L.))and 5-methoxypsoralen(5-MOP) (5-MOP) Ammi visnaga (L.)) Psoriasis 5-methoxypsoralen BarberryAmmi visnaga bark - Oral 5-MOP PUVA (1.2 vulgaris (5-MOP) - Oral 5-MOP PUVA (1.2 A 27 (Mahonia(L.)) - mg/kg)10% Mahonia twice per ointment week twice A [27] mg/kg) twice per week Psoriasis Mahonia ointment A 30 aquifolium daily- Oral for 5-MOP 12 weeks PUVA (1.2 Biomedicinesvulgaris 2019, 7, x FOR PEER REVIEW A 13 27of 23 (Pursh) Nutt.) mg/kg) twice per week Barberry bark - 10% Mahonia ointment twice Biomedicines( Mahonia2019, 7, x aquifoliumFOR PEER REVIEW Mahonia ointment A 13 of[30 23] Indigo naturalis containing daily for 12 weeks (Pursh)Barberry Nutt.) bark - Indigo ointment (50 µg/g Indigoindigo naturalis and indirubin containing (Mahonia and- 10% 200 Mahonia µg/g indigo ointment extract) twice Indigo indigoIndigo and extract indirubin - 10% indigo ointment (1.4% A 33 Mahonia ointment A 30 Barberryaquifolium bark applied-daily Indigo for twiceointment 12 weeks daily (50 over µg/g 8 (Baphicacanthus indigo- 10% and indigo 0.16% ointment indirubin) (1.4% A 31 (Pursh)(Mahonia Nutt.) weeksand- 10%indigo 200 Mahonia µg/g and 0.16%indigo ointment indirubin) extract) twice A [31] cusia Brem.) MahoniaIndigo extractointment dailydaily for for 12 12weeks weeks AA 3330 Indigoaquifolium applieddaily for twice 12 weeks daily over 8 (Baphicacanthus cusia (Pursh) Nutt.) weeks Psoriasis Brem.) Indigo naturalisCurcumin containing vulgaris - Indigo ointment (50 µg/g and indigo and indirubin - No randomized 200 µg/g indigo extract) TurmericIndigo Indigo extract - 10% indigo ointment (1.4% A [33] Indigo naturalisCurcumin containing placebo-controlledapplied twice daily studies over ((CurcumaBaphicacanthus longa indigo8 weeks and 0.16% indirubin) A 31 indigo and indirubin available,- No randomized only in vitro studies TurmericIndigo(L.)) Curcumin - 10%- No indigo randomized ointment (1.4% cusia Brem.) ordaily in vivo for studies12 weeks using mice Curcuma placebo-controlled studies Turmeric((CurcumaBaphicacanthus ( longa indigoplacebo-controlled and 0.16% indirubin) studies A 31 Psoriasis longa (L.)) available,available, only only inin vitro vitro studiesstudies cusia(L.)) Brem.) dailyor in for vivo 12 studiesweeks using mice vulgaris 3-O-Acetyl-11-keto- or in vivo studies using mice 3-O-Acetyl-11-keto- - Olibanum ointment Psoriasis β-boswellic-boswellic acid acid Olibanum containing- Olibanum 5% ointment vulgaris 3-O-Acetyl-11-keto- Olibanum containing 5% (Boswellia serrata, 3-O-Acetyl-11-keto-- Olibanum ointmentβ-boswelli B 39 (Boswellia serrata, β-boswellic acid 3-O-Acetyl-11-keto-β-boswellic B [39] TrianaTriana &Olibanum Planch) & Planch) ccontaining acidacid three three 5% times daily for 12

12 weeks (Boswellia serrata, weeks3-O-Acetyl-11-keto- β-boswelli B 39 Triana & Planch) c acid three times daily for 12 - 5% St. John’s wort extract St. John’s wort weeks B [41] (Hypericum perforatum St. John’s wort extract - 5%twice St. dailyJohn’s for wort 4 weeks extract B 41 (L.)) - 5% St. John’s wort extract St. John’s wort twice daily for 4 weeks B [42] once daily for 4 weeks (Hypericum St. John’s wort extract - 5% St. John’s wort extract B 41 - Cream containing 1% dried Lemon balm perforatumSt. John’s wort(L.)) Lemon balm extract -twice 5%Melissa St. daily John’s offi forcialis wort4 weeksextract extract applied A [46] (Melissa officinalis (L.)) 4 times daily for 5 days (Hypericum St. John’s wort extract once daily for 4 weeks B 42 - Treatment with cream Herpes perforatum (L.)) - 5%containing St. John’s sage wort extract extract (23 Sage simplex mg/g) or combination of sage (Salvia officinalis (L.)) once daily for 4 weeks B 42 Sage and rhubarb extract and rhubarb extract (23 mg/g A [47] and Rhubarb each) until healing (7.6 days (Rheum palmatumLemon balm(L.)) - Cream containing 1% dried with sage and 6.7 with (Melissa Lemon balm extract Melissacombination) officialis extract applied A 46 officinalisLemon balm (L.)) 4- Creamtimes daily containing for 5 days 1% dried (Melissa Lemon balm extract Melissa officialis extract applied A 46 Herpes officinalis (L.)) 4 times daily for 5 days - Treatment with cream simplex Sage containing sage extract (23 Herpes (Salvia officinalis mg/g)- Treatment or combination with cream of sage simplex (L.))Sage and Sage and rhubarb extract andcontaining rhubarb sage extract extract (23 (23mg/g A 47 (SalviaRhubarb officinalis each)mg/g) until or combination healing (7.6 of days sage (L.))(Rheum and Sage and rhubarb extract withand rhubarb sage and extract 6.7 with (23 mg/g A 47 palmatumRhubarb (L.)) combination)each) until healing (7.6 days (Rheum with sage and 6.7 with palmatum (L.)) combination) Biomedicines 2019, 7, x FOR PEER REVIEW 14 of 23

Betulin - Treatment with betulin oleogel for 3 months without A 49 Birch bark effect in high grade actinic BiomedicinesBiomedicines2020, 8, 272019, 7, x FOR PEER REVIEW B 1450 of13 23 of 21 (Betula spp.) keratoses- Birch bark ointment Biomedicines 2019, 7, x FOR PEER REVIEW B 1451 of 23 Betulin (betulin- Treatment oleogel) with for betulin 2 months- Table 1. Cont. Betulin Betulinoleogel- Treatment oleogelfor 3 withmonths for betulin 3 months without Actinic A 49 Birch bark effectoleogel in forhigh 3 monthsgrade actinic without L keratoses Ingenol mebutate - Gel with 0.025% or 0.05% Disease Plant Compound Treatment ABA O 535049Ref BiomedicinesBiomedicines 2019( BetulaBirch2019, 7,, x7, FOR xbarkspp FOR PEER.) PEER REVIEW REVIEW ingenolkeratoses-effect in mebutate high Birch grade bark daily actinic ointment for 314 of 14 23 of 23 B E 5150 Petty(Betula spurge spp.) Betulin days(betulinkeratoses-- Treatment oleogel) Birch with barkfor betulin 2 ointmentmonths- Betulin - Treatment- Treatment with with betulin betulin B 51 Betulinoleogel oleogel for 3 monthsfor 3 months without (Euphorbia peplus oleogeloleogel-(betulin Gel for withfor 3 months3 oleogel) months 0.0025%, without without for 0.01% 2 months- or A [49] Actinic effect in high grade actinicA A49 49 (L.))Birch bark effect0.05%Betulin in high ingenol oleogelgrade actinic mebutate for 3 months on Birch bark Ingenol mebutate effect- Gelkeratoses in withhigh grade0.025% actinic or 0.05% B 50 keratosesActinicBirch bark (Betula(Betula spp .)spp.) keratoses- Birch bark ointment B 50A 53 (Betula spp.) keratoses-two- Birchconsecutive Birch bark bark ointment daysointment or (betulinon B 51 Ingenol mebutate ingenol- Gel with mebutate 0.025% dailyor 0.05% for 3B 51 B [50] keratoses (betulin oleogel) for 2 months- AA 5453 (betulindayoleogel) 1 oleogel)and day for for 28 months2 months- Actinic Petty spurge Betulindaysingenol oleogel mebutate for 3 months daily for 3 Actinic Betulin- Betulin oleogel oleogelfor 3 months for 3 months B [51] keratoses Actinic( EuphorbiaPetty spurge peplus Epigallocatechin-3-gallateIngenol mebutate - Gel-days Gelwith with0.025% 0.0025%, or 0.05% 0.01% or keratoses Ingenol mebutate - Gel with 0.025% or 0.05%A 53 keratoses Ingenol mebutate - Gel with 0.025% or 0.05% (Euphorbia(L.)) peplus ingenol0.05%- Gelingenol mebutate with ingenol mebutate0.0025%, daily mebutate for 3 0.01% daily on foror A 53 A [53] Green tea ingenol- 1 mg/cm mebutate2 skin daily of for 3 Petty spurgePetty spurge days 3 days (L.))Petty spurge daystwo0.05% consecutive ingenol mebutate days or on (Euphorbia(Camellia peplus(Euphorbia sinensis(L.)) peplus - Gelepigallocatechin-3-gallate with- Gel 0.0025%, with 0.0025%,0.01% or 0.01% or DA 5654 day 1 and day 8 (Euphorbia(L.)) peplus 0.05%- Geltwo 0.05%ingenol with consecutive 0.0025%, ingenolmebutate 0.01% mebutateondays or or on on (L.)) before UV exposure AA 54[ 54] (L.)) Epigallocatechin-3-gallate two0.05%day consecutivetwo ingenol 1 and consecutive daysdaymebutate or8 on days on or on day 1 and day 8 A 54 Epigallocatechin-3-gallate daytwo 1 andconsecutive day 8 days or on Epigallocatechin-3-gallate A 54 Green tea Epigallocatechin-3-gallate day- 1 1 mg/cm and day2 8skin of Luteolin (CamelliaGreen sinensis tea Epigallocatechin-3-gallate epigallocatechin-3-gallate- 1 mg/cm2 skin of D 56 Green tea - 1 mg/cm- 1 mg2 skin/cm of 2 skin of Green tea (Camellia(L.)) sinensis beforeepigallocatechin-3-gallateepigallocatechin-3-gallate UV exposure DD 56[ 56] (Camellia sinensis(CamelliaGreen(L.)) tea sinensis epigallocatechin-3-gallate- 1 mg/cm2 skin of D 56 (L.)) before- Dyer’sbefore UV exposure weed UV exposure extract (Camellia(L.)) sinensis epigallocatechin-3-gallatebefore UV exposure D 56A 61 (L.)) beforecontaining UV exposure 2.5% luteolin Luteolin Photo- LuteolinLuteolin Dyer’s weed protection Luteolin (Reseda luteola Luteolin and esthetic - Dyer’s- Dyer’s weed weedextract extract - Dyer’s weed extract A 61 (L.)) containing 2.5% luteolin A A 61[ 61] dermatology containing- Dyer’scontaining weed 2.5% 2.5% extract luteolin luteolin - Dyer’s- Cream weed with extract 0.1% Dyer's Photo-Dyer’s weed A 61A 61 Photo- Reseda luteolaDyer’s weed containingcontaining 2.5% 2.5% luteolin luteolin (protection (L.)) weed extract, 0.1% tocopherol Dyer’s( Resedaweed luteola Dyer`s weed extract A 63 protectionPhoto- Photo-and esthetic and 0.05% ubiquinone three (ResedaDyer’sDyer’s luteolaweed(L.)) weed - Cream with 0.1% Dyer’s Biomedicinesprotectiondermatology 2019, 7 , x FOR PEER REVIEW 15 of 23 andprotection esthetic - Creamtimesweed with daily extract,0.1% for Dyer's 7 0.1%days tocopherol (Reseda(L.))(Reseda luteola luteola Dyer’s weed extract A [63] dermatologyand esthetic weed extract,and 0.05% 0.1% tocopherol ubiquinone three and esthetic (L.)) Dyer`s weed extract - Cream with 0.1% Dyer'sA 63 dermatology (L.)) β-carotene and 0.05%times ubiquinone daily for three 7 days dermatology - Cream with 0.1% Dyer's Biomedicines 2019, 7, x FOR PEER REVIEW FlavanolFlavanol weed- Cream extract, with 0.1% tocopherolDyer's 15 of 23 Dyer`s weed extract timesweed daily extract, for 7 0.1%days tocopherol A 63 Dyer`s weed extract andweed 0.05% extract, ubiquinone 0.1% tocopherol threeA 63 Photo- and- -Ingestion 0.05%24 mg ubiquinone β-carotene of cocoa three withorally high daily Cocoa tree Dyer`sβ -caroteneweed extract - Ingestion of cocoa with high A 63 protection Flavanol timestimesand daily 0.05% daily for ubiquinone 7for days 7 days three A 65 Cocoa tree (326for(326 upmg/d) mg to /8 d)or weeks orlow low (27 (27 mg/d) mg/ d) and esthetic (Theobroma cacao A A 64[ 64] (Theobroma cacao (L.)) - Ingestiontimesflavanol ofdaily cocoa content for with 7 dayshigh in water over dermatology Cocoa tree flavanol content in water over Biomedicines 2019, 7, x FOR(L.)) PEER REVIEW (326 -mg/d) 1224 weeksmg or lowβ-carotene (27 mg/d) orally daily 15 of 23 (Theobroma cacao FlavanolFlavanol 12 weeks A 64 flavanol content in water over A 65 (L.)) - Ingestionfor up toof 8cocoa weeks with high Carotinoids Flavanol 12 weeks- Ingestion of cocoa with high Cocoa tree βLycopene-carotene Cocoa tree β-carotene (326- 10mg/d) mg or lycopene low (27 mg/d) daily for 12 (Theobroma cacao (326- Ingestion mg/d) orof cocoalow (27 with mg/d) highA 64 B 66 (Theobroma cacao flavanolweeks- 24 content mg β-carotene in water over orally daily A 64 Cocoa tree(L.)) A [65] Carotinoids 12flavanol(326 -weeks 24for mgmg/d) up βcontent to-carotene 8or weeks low in (27 waterorally mg/d) over daily (Theobroma(L.)) cacao A 64 Lycopene - 10 mg lycopene daily for 12 A 65 12flavanolfor weeks up to content 8 weeks in water over Carotinoids(L.)) - -Tomato 10 mg lycopenepaste containing daily for 16 B 66 Lycopene B [66] 12weeks12 weeks weeks mg lycopene daily for 12 - Tomato paste containing 16 B 67 weeksmg lycopene daily for B [ 67] Carotinoids - Tomato paste containing 16 Lycopene 12 weeks Limonene -mg 10 lycopenemg lycopene daily daily for 12for 12 Limonene B 6667 weeks - Regular citrus fruit Citrus fruits - Regular citrus fruit Citrus fruits Limonene -consumption Tomatoconsumption paste with withcontaining or or without without 16 CC 68[68 ] (Citrus(Citrusspp.) spp.) peelpeel mg- Regular lycopene citrus daily fruit for 12 Photo- Citrus fruits B 67 weeksconsumption with or without C 68 protection (Citrus spp.) peel and esthetic LimoneneCaffeine Photo- dermatology protection - Regular citrus fruit Citrus fruits and esthetic Coffee plants Caffeine consumption- Observatory with studies or without on CB 6869 (Citrus spp.) dermatology (Coffea spec.) peelcaffeine intake B 70 Photo- Coffee plants - Observatory studies on B 69 protection (Coffea spec.) caffeine intake B 70 and esthetic β-glycyrrhetinicCaffeine acid dermatology Coffee plants - ObservatoryOintment with studies 2.5% on B 69 β-glycyrrhetinic acid (Coffea spec.) caffeineβ-glycyrrhetinic intake acid twice AB 7071

daily over 4 weeks - Ointment with 2.5% Licorice β-glycyrrhetinic acid twice A 71 (Glycyrrhiza daily over 4 weeks β-glycyrrhetinicGlabridin acid glabra (L.)) Licorice - Ointment with 2.5% (Glycyrrhiza Glabridin β- -glycyrrhetinicOintment with acid0.5% twice A 71 glabra (L.)) D 72 dailyglabridin over on 4 weeks guinea pig skin

Licorice - Ointment with 0.5% D 72 (Glycyrrhiza glabridin on guinea pig skin Glabridin glabra (L.))

- Ointment with 0.5% D 72 glabridin on guinea pig skin Biomedicines 2019, 7, x FOR PEER REVIEW 15 of 23

Biomedicines 2019, 7, x FOR PEER REVIEW β-carotene 15 of 23 Biomedicines 2019, 7, x FOR PEER REVIEW 15 of 23 β-carotene β-carotene - 24 mg β-carotene orally daily A 65 for up to 8 weeks - 24 mg β-carotene orally daily A 65 for- 24 up mg to β 8-carotene weeks orally daily A 65 for up to 8 weeks Carotinoids Lycopene - 10 mg lycopene daily for 12 Carotinoids B 66 Lycopene weeks Carotinoids - 10 mg lycopene daily for 12 Lycopene B 66 weeks- 10 mg lycopene daily for 12 - Tomato paste containing 16 B 66 weeks mg lycopene daily for 12 - Tomato paste containing 16 B 67 weeks mg- Tomato lycopene paste daily containing for 12 16 B 67 Limonene weeksmg lycopene daily for 12 B 67 weeks Limonene - Regular citrus fruit Citrus fruits Limonene consumption with or without C 68 Biomedicines 2020, 8, 27 (Citrus spp.) - Regular citrus fruit 14 of 21 Citrus fruits peel consumption- Regular citrus with fruit or without C 68 Photo- (CitrusCitrus fruitsspp.) peelconsumption with or without C 68 protection (Citrus spp.) Table 1. Cont. Photo- peel andPhoto- esthetic Caffeine protection L dermatology Diseaseandprotection esthetic Plant CompoundCaffeine Treatment O Ref E dermatologyand esthetic Coffee plants Caffeine - Observatory studies on B 69 Caffeine dermatology (Coffea spec.) caffeine intake B 70 Coffee plants - Observatory studies on B 69 Coffee plants - Observatory studies on B 69 Coffee(Coffea plants spec.) caffeine- Observatory intake studies on BB 70[69 ] (Coffea(Coffeaspec.) spec.) caffeinecaffeine intake intake BB 70[70 ] Biomedicines 2019, 7, x FOR PEER REVIEW β-glycyrrhetinic acid 16 of 23 Biomedicines 2019, 7, x FOR PEER REVIEW 16 of 23 β-glycyrrhetinic acid β-glycyrrhetinicLicochalcone A acid - Ointment with 2.5% β-glycyrrhetinicLicochalcone acidA -β 9-glycyrrhetinic µM Licochalcone acid A twice in in A 71 - Ointment with 2.5% D 12 - -9 Ointment µM Licochalcone with 2.5% A in in vitrodaily- Ointment experiments- over 4 with weeks 2.5% Ointment β-glycyrrhetinicβ-glycyrrhetinic acid acid twice twice AD A 7112[ 71 ] vitro experiments- Ointment Licorice containingβdaily-glycyrrhetinic over licochalcone 4 weeks acid twice A A 71 daily over 4 weeks A 12 twicecontaining daily forlicochalcone 2 weeks A (Glycyrrhiza daily over 4 weeks A 12 Licorice Glabridin glabra (L.)) twice daily for 2 weeks (GlycyrrhizaLicorice Glabridin Glabridin (glabraGlycyrrhiza (L.)) Licorice Glabridin - Ointment with 0.5% Photo- glabra (L.)) - Ointment with 0.5% D 72 (Glycyrrhiza glabra (L.)) D [72] protection Pine bark -glabridin Oralglabridin ingestion on on guinea guinea of 25 pig mg pig skin pine skin Biomedicines 2019, 7, x FOR PEER REVIEW - Ointment with 0.5% 16 of 23 and esthetic (PinusPine pinaster bark Pine bark extract bark- Oral extract ingestion three of times 25 mg daily pine DB 7274 dermatology glabridin- Ointment on with guinea 0.5% pig skin (Pinus pinaster PineLicochalcone bark extract A bark extract three times daily DB 7274 Ailton) forglabridin 30 days on guinea pig skin Photo- Licochalcone A - 9 µM Licochalcone A in Ailton) -for 9 µM 30 daysLicochalcone A in in D [12] Photo- in vitro experiments D 12 protection vitro experiments- Ointment protection and esthetic containing- Ointment licochalcone containing A dermatologyand esthetic licochalcone A twice daily for AA 12[12 ] -twice Cream2 weeks daily with for Centella 2 weeks asiatica dermatology extract- Cream applied with Centella daily from asiatica the - Oral ingestion of 25 mg pine Pine bark Gotu kola extract A 75 Pine bark extract endextractbark of extractthe applied 12th three week daily times offrom daily the B [74] (Pinus pinaster Ailton) Gotu kola extract A 75 for 30 days pregnancyend of the until12th weekdelivery of - Cream with Centella asiatica Gotu kola pregnancy until delivery Pine bark - extractOral ingestion applied of daily 25 mg from pine the Gotu kola extract A [75] (CentellaGotu asiaticakola end of the 12th week of (Pinus pinaster PineAsiaticoside bark extract bark extract three times daily B 74 (Centella asiatica pregnancy until delivery (L.)Ailton) Urban) for 30 days AsiaticosideAsiaticoside Photo- Gotu(L.) kola Urban) (Centella asiatica (L.) - Cream containing 0.1% protection Urban) asiaticoside- Cream containing twice daily 0.1% for 12 B 76 - Cream containing 0.1% and esthetic weeksasiaticosideasiaticoside twice twice daily daily for for 12 BB 76[76 ] dermatology -weeks 12Cream weeks with Centella asiatica extract applied daily from the Gotu kola extract A 75 Betulin end - Wounds of the 12thincluding week secondof BetulinBetulin - Wounds including second degreepregnancy- Wounds burns until including and delivery second Gotu kola split-thicknessdegreedegree burns burns and skin and graft Birch bark split-thickness skin graft Birch bark split-thickness skin graft (Centella asiatica woundswounds were were treated treated with with A [81] (Betula(BetulaBirchspp.) spp.)bark Asiaticoside A 81 Wound (L.) Urban) betulinwoundsbetulin oleogel oleogelwere treated(containing (containing with healing (Betula spp.) 10% betulin) till wound A 81 betulin oleogel (containing 10%- closureCream betulin) containing or up till to wound 28 0.1% days Wound closure10% betulin) or up totill 28 wound days asiaticoside- Onion extract twice twice daily daily for 12 for B 76 healingWound Onion Onion extract closure10 weeks or afterup to initial28 days primary A [86] (Allium cepa (L.)) weeks healing wound healing - Onion extract twice daily for Onion - Onion extract twice daily for OnionBetulin extract 10 - Woundsweeks after including initial primary second A 86 (AlliumOnion cepa (L.)) Onion extract wound10 weeks healing after initial primary A 86 (Allium cepa (L.)) degree burns and wound healing split-thickness skin graft Birch bark wounds were treated with (Betula spp.) A 81 betulin oleogel (containing 10% betulin) till wound Wound closure or up to 28 days healing

- Onion extract twice daily for Onion Onion extract 10 weeks after initial primary A 86 (Allium cepa (L.)) wound healing Biomedicines 2019, 7, x FOR PEER REVIEW 17 of 23

Epigallocatechin-3-gallate

Green - Cream containing 2.5% tea(Camellia epigallocatechin gallate twice D 88 sinensis (L.)) daily for 6 weeks

Licochalcone A - Licochalcone A in different B 89 vehicles applied daily for 8 weeks Biomedicines 2020, 8, 27 Licorice root 15 of 21 - Treatment with licochalcone (Glycyrrhiza A and inflata Batalin) Table 1. Cont. trans-4-t-butylcyclohexanol Biomedicines 2019, 7, x FOR PEER REVIEW 17 of 23 Biomedicines 2019, 7, x FOR PEER REVIEW (TRPV1 inhibitor) twice a day L 17 of 23 DiseaseRosacea Plant Compound for 4 weeks Treatment BO 90Ref Epigallocatechin-3-gallate E Epigallocatechin-3-gallate Epigallocatechin-3-gallate Green - Cream containing 2.5% Green - Cream containing 2.5% Bitter-wood - Gel containing 4% Simarouba tea(Camellia epigallocatechin- Cream containing gallate 2.5% twice D 88 Green tea(tea(CamelliaCamellia epigallocatechin gallate twice D 88 (Simarouba amara Bitter-wood extract amaraepigallocatechin extract twice gallate daily for twice 6 BD 91[88 ] sinensissinensis(L.)) (L.)) daily for 6 weeks sinensis (L.)) dailydaily for for 6 6weeks weeks Aubl.) weeks

Licochalcone A - Licochalcone A in different B 89 Licochalcone A - -Licochalcone Licochalcone A A in in different different B 89 Licochalcone A vehiclesvehicles applied applied daily daily for for 8 B [89] vehicles8 weeks applied daily for 8 Rosacea Licorice root weeks (GlycyrrhizaLicoriceTormentil inflata root - weeksTormentil- Treatment extract with licochalcone(5%) Licorice root - TreatmentA and with licochalcone Batalin)(Potentilla(Glycyrrhiza erecta Tormentil extract applied- Treatment topically with once licochalcone for 48 h C 18 (Glycyrrhiza A trans-4-t-butylcyclohexanoland B [90] inflata(L.)) Batalin) toA(TRPV1 volunteers and inhibitor) in a patch twice test a day inflata Batalin) trans-4-t-butylcyclohexanolfor 4 weeks trans-4-t-butylcyclohexanol Bitter-wood (TRPV1- Gel containing inhibitor) twice 4% Simarouba a day (Simarouba amara Bitter-wood extract (TRPV1amara extract inhibitor) twice twice daily a forday B [ 91] Rosacea for 4 weeks B 90 Rosacea Aubl.) - forGel6weeks 4 containing weeks 5% Melaleuca BB 9590 - Tormentil extract (5%) TormentilTea tree alternifolia oil applied topically Tormentil extract applied topically once for 48 h C [18] (Potentilla(Melaleuca erecta (L.)) for 3 months Bitter-wood - Gelto volunteers containing in 4% a patchSimarouba test Bitter-woodalternifolia Tea tree oil - -Gel Gel containing containing 4% 5% SimaroubaMelaleuca (Simarouba amara Bitter-wood extract amara extract twice daily for 6 B 91 Tea(Simarouba(Maiden tree amara& Bitter-wood extract - amaraGelalternifolia containing extractoil twice applied 5% Melaleucadaily topically for 6 BB 91 [95 ] (Melaleuca alternifoliaAubl.) weeksfor 3 months Betche)Aubl.) Cheel ) Tea tree oil alternifoliaweeks oil applied twice (Maiden & Betche) - Gel containing 5% Melaleuca Acne Cheel) dailyalternifolia for 45 daysoil applied twice AA 96[96 ] vulgaris daily for 45 days Epigallocatechin-3-gallate Epigallocatechin-3-gallate - Treatment with 1% or 5% TormentilGreen tea - Tormentil- Treatment extract with 1%(5%) or 5% epigallocatechin-3-gallate GreenTormentil tea - epigallocatechin-3-gallateTormentil extract (5%) Acne (Camellia(Potentilla sinensis erecta Tormentil extract applied topically once for 48 h CAA 1897[ 97] (Camellia(Potentilla sinensis (L.) erecta) Tormentil extract solutionappliedsolution twicetopically twice daily daily once for for for8 48 h C 18 vulgaris (L.))(L.)) to8 volunteers weeks in a patch test (L.)) weeksto volunteers in a patch test

- Lotion with 2% Camellia Green tea extract - Gelsinensis containingextract 5% twice Melaleuca daily for B B 95[ 98] - Gel containing 5% Melaleuca B 95 Tea tree alternifolia6 weeks oil applied topically Hop Tea tree alternifolia- 3.1 µg/mL oiland applied 9.4 µ topicallyg/mL of (Humulus(Melaleuca lupulus (L.) ) for 3 months (Melaleuca forHumulus 3 months lupulus extract alternifolia TeaHop tree extract oil in vitro C [99] alternifolia Tea tree oil (Maiden & - Gel- Gel containing containing 5% 0.3% MelaleucaHumulus (Maiden & - lupulusGel containingextract in5% vitro Melaleuca Betche) Cheel) alternifolia oil applied twice Acne Betche) Cheel) alternifolia oil applied twice Acne daily for 45 days A 96 vulgaris daily for 45 days A 96 Author Contributions:vulgaris Writing—originalEpigallocatechin-3-gallate draft preparation, review and editing (J.H., U.W.), writing—review and editing (F.G., C.M.S.), Table1 preparationEpigallocatechin-3-gallate (F.G.). All authors have read and agreed to the published version of the manuscript. - Treatment with 1% or 5% Green tea - Treatment with 1% or 5% Funding: Green tea epigallocatechin-3-gallate For this review(Camellia no external sinensis funding was received. epigallocatechin-3-gallate A 97 (Camellia sinensis solution twice daily for 8 A 97 Conflicts of Interest: U.W. and(L.)) C.S. hold a patent on the topical usesolution of bitter twice taste daily receptor for 8 agonist and have performed contract research for(L.) Birken) AG, Cassella Med, Weleda andweeks WALA. weeks Biomedicines 2020, 8, 27 16 of 21

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