Anti-Psoriatic Effects of Antimony Compounds In Vitro.

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and a pro-inflammatory milieu in the skin. While patients with moderate to severe psoriasis are treated using targeted therapies (small molecules and monoclonal antibodies), patients suffering from milder forms are still in need of effective topical products without adverse effects. Antimony compounds (ACs) are regularly used as anti-inflammatory compounds in traditional and anthroposophic medicine and as antiprotozoan drugs. Here, we examined the effect of metallic antimony, natural antimony(III) sulfide and potassium antimonyl(III) tartrate in vitro on psoriasis-like keratinocytes and the human dendritic cell line THP-1 using qPCR, immunocytochemistry, ELISA and flow cytometry. In psoriatic keratinocytes, ACs inhibited the overexpression of the antimicrobial peptide ß-defensin 2 and glucose transporter 1, as well as the hyperproliferation marker keratin 17. Furthermore, ACs mediated anti-inflammatory effects by reducing nuclear translocation of the p65 subunit of NF-κB and pSTAT3 and inhibited pro-inflammatory cytokine secretion by keratinocytes. In addition, ACs displayed anti-psoriatic effects by reducing the activation of IFN-α-treated THP-1 cells as well as the expression of the psoriasis-promoting master cytokine IL-23 by these cells. While all ACs showed anti-psoriatic effects, the most prominent results were seen with potassium antimonyl(III) tartrate. In summary, ACs display numerous anti-psoriatic effects in vitro at subtoxic concentrations. We conclude that ACs are interesting compounds for the topical treatment of psoriasis that warrant further investigation in clinical studies.

The Effect of Herbal Medicinal Products on Psoriasis-Like Keratinocytes.

Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation of keratinocytes and expression of pro-inflammatory cytokines in the epidermis. New biological drugs were developed for the systemic treatment of moderate to severe psoriasis. However, products for the topical treatment of mild psoriasis are still required. Here, we examined the effect of natural compounds on psoriasis-like keratinocytes in vitro and ex vivo. Psoriasis-like keratinocytes were generated by treating human primary keratinocytes with the psoriasis-associated cytokines IL-17A, TNF-α and IL-22. Initially, 10 botanical extracts from Ayurvedic Medicine, Traditional Chinese Medicine, Northern American traditional medicine and Occidental Monastic Medicine were investigated using BrdU assays and IL-6 and IL-8 ELISAs. Curcuma amada, Humulus lupulus and Hypericum perforatum turned out to be the most effective plant extracts. In vitro, the plant extracts inhibited the expression of anti-microbial peptides (ß-defensin 2), the hyperproliferation marker keratin 17, the glucose transporter 1 and downregulated the nuclear translocation of NF-κB and pSTAT3. In an ex vivo psoriasis model, Humulus lupulus displayed the most prominent anti-proliferative and anti-inflammatory effect. In conclusion, among the plant extracts investigated, Humulus lupulus showed the most promising anti-psoriatic effect. It is an interesting candidate for topical psoriasis treatment that should be further studied in clinical trials.

Gentiana lutea Extract Modulates Ceramide Synthesis in Primary and Psoriasis-Like Keratinocytes.

Gentiana lutea is a bitter herb that is traditionally used to improve gastric disorders. Recently, we have shown that Gentiana lutea extract (GE) also modulates the lipid metabolism of human keratinocytes in vitro and in vivo. In the present study, we investigated the role of GE on ceramide synthesis in human primary keratinocytes (HPKs) and psoriasis-like keratinocytes. We could demonstrate that GE increased the concentrations of glucosylceramides and the ceramide AS/AdS subclass without affecting the overall ceramide content in HPKs. The expression of ceramide synthase 3 (CERS3) and elongases (ELOVL1 and 4) was reduced in psoriasis lesions compared to healthy skin. Psoriasis-like HPKs, generated by stimulating HPKs with cytokines that are involved in the pathogenesis of psoriasis (IL-17, TNF-α, IL-22 and IFN-γ) showed increased levels of IL-6, IL-8 and increased expression of DEFB4A, as well as decreased expression of ELOVL4. The treatment with GE partly rescued the reduced expression of ELOVL4 in psoriasis-like HPKs and augmented CERS3 expression. This study has shown that GE modulates ceramide synthesis in keratinocytes. Therefore, GE might be a novel topical treatment for skin diseases with an altered lipid composition such as psoriasis.

New Herbal Biomedicines for the Topical Treatment of Dermatological Disorders.

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).

Hop Extract Acts as an Antioxidant with Antimicrobial Effects against Propionibacterium Acnes and Staphylococcus Aureus.

Acne is associated with hyperkeratosis, elevated levels of skin sebum and growth of Propionibacterium acnes (P. acnes) and Staphylococcus aureus (S. aureus). Furthermore, P. acnes promotes inflammation by inducing IL-6 production and oxidative stress. The aim of this study was to assess the antioxidant, anti-inflammatory and antibacterial potential of a hop-CO2-extract with 50% humulone and lupulone. The susceptibility of P. acnes and S. aureus to the hop extract was tested by using the broth microdilution technique. The minimal inhibitory concentrations (MIC) for P. acnes and S. aureus were 3.1 and 9.4 µg/mL, respectively. In addition, the hop extract showed an antioxidative effect with a half maximal inhibitory concentration (IC50) of 29.43 µg/mL as well as additional anti-inflammatory effects by reducing the IL-6 expression (IC50: 0.8 µg/mL). In addition, a gel formulation with 0.3% hop extract (w/w) had antibacterial activity against P. acnes and S. aureus (inhibition zone value: 5.5 mm and 3 mm, respectively) which was significantly superior to the placebo gel. The positive control (a gel with the antibiotic clindamycin) showed an inhibition zone of 9 mm. Due to its antioxidant, anti-inflammatory and antibacterial effects hop extract might be a treatment option for acne-prone skin.

Anti-Inflammatory Effect of a Novel Topical Herbal Composition (VEL-091604) Consisting of Gentian Root, Licorice Root and Willow Bark Extract.

The anti-inflammatory properties of the topical herbal composition VEL-091604 with gentian root, licorice root, and willow bark extract were assessed in a randomized, prospective, placebo-controlled, double-blind ultraviolet (UV)-erythema test study with 42 healthy volunteers in comparison to 1% hydrocortisone acetate. The efficacy and tolerability of VEL-091604 cream 2 times daily over 2 wk was evaluated in an open-label, prospective proof of concept study in 10 subjects with atopic dermatitis using a lesional SCORAD severity score. In the UV-erythema test VEL-091604 cream significantly reduced inflammation compared to placebo and was as effective as 1% hydrocortisone acetate. The clinical study with atopic subjects revealed a significant and rapid reduction of the lesional SCORAD severity score in the test areas after 1 and 2 wk. No adverse events were recorded. It is concluded that the herbal cream VEL-091604 with licorice root, willow bark, and gentian root extract display anti-inflammatory properties in vivo. It is a promising new treatment option for atopic dermatitis that warrants further investigation in controlled studies.

Effect of a botanical cleansing lotion on skin sebum and erythema of the face: A randomized controlled blinded half-side comparison.

BACKGROUND: Elevated levels of skin sebum are associated with the growth of Propionibacterium acnes. Intensive degreasing of the skin reduces Propionibacterium acnes but also may cause skin irritation. AIMS: We assessed the degreasing effect and skin tolerability of a botanical face cleanser with hops and willow bark extract and disodium cocoyl glutamate as mild cleansing agent compared to a standard face cleanser with sodium laureth sulfate (SLES). MATERIALS AND METHODS: A total of 21 healthy volunteers with normal to oily skin were enrolled in this study. Both cleansers were applied twice a day on the left or right side of the forehead for 15 days in a standardized manner. Bioengineering measurements were performed on day 8 and 15 and on day 17 after an application break of 48 hours. The sebum level was determined using a Sebumeter® , and skin redness was measured using a Mexameter® . RESULTS: The botanical face cleanser significantly reduced the sebum level (P < .01) in the test area on day 17. The SLES containing cleanser showed a statistically relevant degreasing effect already on day 15, but after the application break the sebum level increased again on day 17. None of the cleansers caused skin irritation as determined by skin redness measurements. CONCLUSIONS: In contrast to the SLES containing cleanser, the botanical skin cleanser with hops and willow bark extract had a continuous degreasing effect without reactive seborrhoe after the treatment break. Skin cleansing without SLES might be advantageous for sensitive skin.

The Herbal Bitter Drug Gentiana lutea Modulates Lipid Synthesis in Human Keratinocytes In Vitro and In Vivo.

Gentiana lutea is a herbal bitter drug that is used to enhance gastrointestinal motility and secretion. Recently we have shown that amarogentin, a characteristic bitter compound of Gentiana lutea extract (GE), binds to the bitter taste receptors TAS2R1 and TAS2R38 in human keratinocytes, and stimulates the synthesis of epidermal barrier proteins. Here, we wondered if GE also modulates lipid synthesis in human keratinocytes. To address this issue, human primary keratinocytes were incubated for 6 days with GE. Nile Red labeling revealed that GE significantly increased lipid synthesis in keratinocytes. Similarly, gas chromatography with flame ionization detector indicated that GE increases the amount of triglycerides in keratinocytes. GE induced the expression of epidermal ceramide synthase 3, but not sphingomyelinase. Lipid synthesis, as well as ceramide synthase 3 expression, could be specifically blocked by inhibitors of the p38 MAPK and PPARγ signaling pathway. To assess if GE also modulates lipid synthesis in vivo, we performed a proof of concept half side comparison on the volar forearms of 33 volunteers. In comparison to placebo, GE significantly increased the lipid content of the treated skin areas, as measured with a sebumeter. Thus, GE enhances lipid synthesis in human keratinocytes that is essential for building an intact epidermal barrier. Therefore, GE might be used to improve skin disorders with an impaired epidermal barrier, e.g., very dry skin and atopic eczema.

Anti-inflammatory and vasoconstrictive properties of Potentilla erecta - A traditional medicinal plant from the northern hemisphere.

ETHNOPHARMACOLOGICAL RELEVANCE: Potentilla erecta (L.) Raeusch is a medicinal plant of the Northern hemisphere belonging to the plant family of roses (Rosaceae). It has traditionally been used to treat inflammatory disorders of the skin and mucous membranes as well as chronic diarrhea. AIM OF THE STUDY: In the present study we analyzed the anti-inflammatory and vasoconstrictive effect of a Potentilla erecta extract (PE) and questioned if PE is similar effective as mild corticosteroids. Then we analyzed if PE acts in the skin via a similar mode of action as corticosteroids. MATERIAL AND METHODS: The anti-inflammatory effect of PE was analyzed in irradiated HaCaT keratinocytes by measuring the formation of IL-6 and PGE2. Additionally the effect of PE on TNF-α induced NF-κB activation was determined. As the anti-inflammatory effect of corticosteroids correlates with their vasoconstrictive properties we tested if PE displays also vasoconstriction. Therefore we performed an occlusive patch test and a collagen contraction assay. Furthermore the binding of PE to the glucocorticoid receptor was determined with stainings and reporter assays. The interaction of PE on the nitric oxide (NO) content was examined with radical scavenging and endothelial NO synthase (eNOS) reporter assays. RESULTS: In irradiated or TNF-α stimulated HaCaT cells the formation of IL-6 and PGE2 or NF-κB activation was strongly reduced by PE. Furthermore PE showed a blanching effect comparable to hydrocortisone. However, in contrast to glucocorticoids, PE did not cause nuclear translocation of the glucocorticoid receptor in HaCaT cells. The blanching effect of PE was at least partly attributable to a scavenging effect of NO and inhibition of eNOS. CONCLUSIONS: PE displays anti-inflammatory and vasoconstrictive effects and might therefore be beneficial for the topical treatment of inflammatory skin disorders.

Anti-Inflammatory Effects of Agrimoniin-Enriched Fractions of Potentilla erecta.

Potentilla erecta (PE) is a small herbaceous plant with four yellow petals belonging to the Rosaceae family. The rhizome of PE has traditionally been used as an antidiarrheal, hemostatic and antihemorrhoidal remedy. PE contains up to 20% tannins and 5% ellagitannins, mainly agrimoniin. Agrimoniin is a hydrolyzable tannin that is a potent radical scavenger. In this study we tested the anti-inflammatory effect of four PE fractions with increasing amounts of agrimoniin obtained by Sephadex column separation. First, we analyzed in HaCaT keratinocytes the expression of cyclooxygenase-2 (COX-2) induced by ultraviolet-B (UVB) irradiation. As COX-2 catalyzes the metabolism of arachidonic acid to prostanoids such as PGE2, we also measured the PGE2 concentration in cell culture supernatants. PE inhibited UVB-induced COX-2 expression in HaCaT cells and dose-dependently reduced PGE2. The PE fraction with the highest agrimoniin amount (PE4) was the most effective in this experiment, whereas fraction PE1 containing mainly sugars had no effect. PE4 also dose dependently inhibited the phosphorylation of the epidermal growth factor receptor (EGFR) which plays a crucial role in UVB-mediated COX-2 upregulation. A placebo-controlled UV-erythema study with increasing concentrations of PE4 demonstrated a dose dependent inhibition of UVB-induced inflammation in vivo. Similarly, PE4 significantly reduced UVB-induced PGE2 production in suction blister fluid in vivo. In summary, PE fractions with a high agrimoniin content display anti-inflammatory effects in vitro and in vivo in models of UVB-induced inflammation.

Salicin from Willow Bark can Modulate Neurite Outgrowth in Human Neuroblastoma SH-SY5Y Cells.

Salicin from willow bark has been used throughout centuries in China and Europe for the treatment of pain, headache, and inflammatory conditions. Recently, it could be demonstrated that salicin binds and activates the bitter taste receptor TAS2R16. Studies on rodent tissues showed the general expression of bitter taste receptors (TAS2Rs) in rodent brain. Here, we demonstrate the expression of hTAS2R16 in human neuronal tissues and the neuroblastoma cell line SH-SY5Y. The functionality was analyzed in the neuroblastoma cell line SH-SY5Y after stimulation with salicin, a known TAS2R16 agonist. In this setting salicin induced in SH-SY5Y cells phosphorylation of ERK and CREB, the key transcription factor of neuronal differentiation. PD98059, an inhibitor of the ERK pathway, as well as probenecid, a TAS2R16 antagonist, inhibited receptor phosphorylation as well as neurite outgrowth. These data show that salicin might modulate neurite outgrowth by bitter taste receptor activation.

Topical application of St. John's wort (Hypericum perforatum).

St. John's wort (Hypericum perforatum) has been intensively investigated for its antidepressive activity, but dermatological applications also have a long tradition. Topical St. John's wort preparations such as oils or tinctures are used for the treatment of minor wounds and burns, sunburns, abrasions, bruises, contusions, ulcers, myalgia, and many others. Pharmacological research supports the use in these fields. Of the constituents, naphthodianthrones (e.g., hypericin) and phloroglucinols (e.g., hyperforin) have interesting pharmacological profiles, including antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. In addition, hyperforin stimulates growth and differentiation of keratinocytes, and hypericin is a photosensitizer which can be used for selective treatment of nonmelanoma skin cancer. However, clinical research in this field is still scarce. Recently, sporadic trials have been conducted in wound healing, atopic dermatitis, psoriasis, and herpes simplex infections, partly with purified single constituents and modern dermatological formulations. St. John's wort also has a potential for use in medical skin care. Composition and stability of pharmaceutical formulations vary greatly depending on origin of the plant material, production method, lipophilicity of solvents, and storage conditions, and this must be regarded with respect to practical as well as scientific purposes.

The photoprotective and antioxidative properties of luteolin are synergistically augmented by tocopherol and ubiquinone.

Ultraviolet radiation induces DNA damage and oxidative stress which can result in skin inflammation, photoaging, and photocarcinogenesis. The flavonoid luteolin that is present in high amounts in the dyers weld, Reseda luteola, is one of the most potent antioxidative plant metabolites and also has ultraviolet-absorbing properties.The aim of this study was to determine whether tocopherol and ubiquinone add synergistic antioxidative values to luteolin. None of the substances showed cytotoxic effects in concentrations from 0.25 to 4 µg/mL. The photoprotective and antioxidant effect of equivalent concentrations of luteolin, tocopherol, and ubiquinone and their combination in a ratio of 4 : 4 : 1 were studied in solar simulator irradiated human skin fibroblasts. Luteolin had a half-maximal radical scavenging concentration of 2 µg/mL, whereas tocopherol and ubiquinone were only effective at higher concentrations. None of the substances showed a phototoxic effect, and only luteolin had a moderate photoprotective effect at 2 µg/mL. The combination of luteolin, tocopherol, and ubiquinone exerted a synergistic radical scavenging effect already at a concentration of 0.25 µg/mL and a complete photoprotection at 2 µg/mL.In summary, our findings suggest that the potent antioxidant and photoprotective effect of flavonoids like luteolin may be further increased by the addition of low concentrations of other antioxidants such as tocopherol and ubiquinone.

In vivo photoprotective and anti-inflammatory effect of hyperforin is associated with high antioxidant activity in vitro and ex vivo.

Hyperforin, a major constituent of St. John's Wort (Hypericum perforatum, HP), provides anti-inflammatory, anti-tumor, and anti-bacterial properties. Previous studies have shown anti-oxidative properties of St. John's Wort extracts; however, its free radical scavenging activity in skin cells or skin has not been assessed in detail so far. Therefore, the free radical scavenging activity of hyperforin was tested in the H(2)DCFDA-assay in vitro in HaCaT keratinocytes irradiated with solar simulated radiation. Hyperforin (EC(50) 0.7 µM corresponding to 0.42 µg/ml) was much more effective compared to Trolox (EC(50) 12 µg/ml) and N-acetylcysteine (EC(50) 847 µg/ml) without showing phototoxicity. The radical protection factor of a cream containing 1.5%w/w of a hyperforin-rich HP extract was determined to be 200 × 10(14) radicals/mg, indicating a high radical scavenging activity. The cream was further applied ex vivo on porcine ear skin and significantly reduced radical formation after infrared irradiation. Finally, the UV-protective effect of the HP cream was tested on 20 volunteers in a randomized, double-blind, vehicle-controlled study. HP cream significantly reduced UVB-induced erythema as opposed to the vehicle. Occlusive application of HP cream on non-irradiated test sites did not cause any skin irritation. Taken together, these results demonstrate that hyperforin is a powerful free radical scavenger.

Which plant for which skin disease? Part 1: Atopic dermatitis, psoriasis, acne, condyloma and herpes simplex.

Plant extracts and isolated compounds are increasingly used in cosmetics and food supplements to improve skin conditions. We first introduce the positive plant monographs with dermatological relevance of the former German Commission E. Subsequently clinical studies with botanicals for atopic dermatitis, psoriasis, acne, condylomata acuminata and herpes simplex are discussed. The best studies have been conducted with atopic dermatitis and psoriasis patients. Mahonia aquifolium, Hypericum perforatum, Glycyrrhiza glabra and certain traditional Chinese therapies have been shown to be effective in the treatment of atopic dermatitis. Mahonia aquifolium, Indigo naturalis and Capsicum frutescens are effective treatments for psoriasis. Green tea extract and tea tree oil have been investigated in the treatment of acne. Podophyllin and green tea extract are effective treatments for condylomata acuminata. Balm mint and a combination of sage and rhubarb have been shown to be effective in the treatment of herpes simplex in proof of concept studies.

Which plant for which skin disease? Part 2: Dermatophytes, chronic venous insufficiency, photoprotection, actinic keratoses, vitiligo, hair loss, cosmetic indications.

This paper continues our review of scientifically evaluated plant extracts in dermatology. After plants effective against dermatophytes, botanicals with anti-edema effects in chronic venous insufficiency are discussed. There is good evidence from randomized clinical studies that plant extracts from grape vine leaves (Vitis vinifera), horse chestnut (Aesculus hippocastanum), sea pine (Pinus maritima) and butcher's broom (Ruscus aculeatus) can reduce edema in chronic venous insufficiency. Plant extracts from witch hazel (Hamamelis virginiana), green tea (Camellia sinensis), the fern Polypodium leucotomos and others contain antioxidant polyphenolic compounds that may protect the skin from sunburn and photoaging when administered topically or systemically. Extracts from the garden spurge (Euphorbia peplus) and from birch bark (Betula alba) have been shown to be effective in the treatment of actinic keratoses in phase II studies. Some plant extracts have also been investigated in the treatment of vitiligo, various forms of hair loss and pigmentation disorders, and in aesthetic dermatology.