Anti-Psoriasis Agents from Natural Plant Sources

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The user has requested enhancement of the downloaded file. Send Orders for Reprints to [email protected] 1250 Current Medicinal Chemistry, 2016, 23, 1250-1267 Anti-Psoriasis Agents from Natural Plant Sources

M. Bonesi1, M.R. Loizzo1, E. Provenzano2, F. Menichini1 and R. Tundis1,*

1Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy; 2Operative Unit of Dermatology, A.O. of Cosenza, Italy

Please provide Abstract: Psoriasis is a chronic inflammatory immune-mediated skin disease. It affects most corresponding author(s) races, does not have any sexual predilections and can manifest at any age of life. Psoriasis is photograph more frequent in certain racial groups and geographical areas. For these reasons, both genetic and environmental factors could be considered. In this review, we discuss promising natural compounds, their molecular targets and mechanisms, which may help the further de- sign of new anti-psoriasis agents. Literature documents the widespread use of herbal remedies worldwide, and the presence of some phytochemicals supports the efficacy of some botanical treatments. The research on natural products has greatly contributed to the progress in the treatment of skin diseases such as psoriasis and many of these compounds are now being used. Understanding the mechanism of these molecules will contribute to the development of more specific preventive strategies for the treatment of psoriasis. Keywords: Psoriasis, skin, botanicals, medicinal plants, mechanism of action.

1. INTRODUCTION 30% of cases. About 70-80% of patients have mild psoriasis, controlled by topical therapies alone [6]. In addi- Psoriasis is a chronic inflammatory immune-media- tion to ethnicity, the prevalence of psoriasis may also ted skin disease. Both genetic and environmental fac- be affected by exposure to the sun and the climate. tors are involved in the etiology. Symptoms include the However, Jacobson et al. [7] in a recent study demon- presence of erythematous red patches covered with strated a weak correlation between latitude and psoria- scaly dry and whitish, pain, itchiness, and bleeding [1]. sis prevalence. This suggests that other factors, or In 2013, the Executive Board of World Health Organi- much more plausibly combinations of factors, might be zation (WHO) recommended a resolution that requests involved. to increase awareness of psoriasis as one of the main health problems worldwide [2]. People affected by psoriasis are most at risk of de- veloping other diseases including psoriatic arthritis, Psoriasis is one of the most common and frequent anxiety and depression, lymphoma, metabolic syn- skin diseases. Its estimated prevalence in the world’s drome, cardiovascular disorders, and Crohn’s disease. population is about 2%, but there are many geographic Mild trauma, sunburn or chemical irritants can provoke and ethnic differences so that it can swing widely be- psoriasis. There are drugs such as non-steroidal anti- tween 0.5 and 4%. Psoriasis is more common in colder inflammatory agents, β-blockers, lithium and antima- northern climates than in the tropical regions [3]. Sev- larials that can aggravate the disease. eral studies suggested that Caucasians are more affected than other races [4,5]. The incidence seems to be Plants and their secondary metabolites demonstrated the same in the sexes, but some authors identify preva- an important role in the discovery of new potential lence in males. Psoriasis can make its debut at all ages anti-psoriasis agents [8]. Interestingly, in America and of life, being able to be present in newborns as in the Europe about 50% subjects affected by psoriasis use elderly, with a peak incidence in the range 20-30 years complementary and alternative medicine, including and 50-60 years. Particularly severe forms affect about plant-based medicines [9-12]. 10% of patients; psoriatic arthritis can be present in 20- The interest in plant-based medicines used for the treatment of psoriasis is evident analising the literature *Address correspondence to this author at the Department of Phar- [8,12-21]. The aim of this review is to report the most macy, Health and Nutritional Sciences, University of Calabria, recent works on plant extracts and pure compounds for 87036 Rende (CS), Italy; E-mail: [email protected]

0929-8673/16 $58.00+.00 © 2016 Bentham Science Publishers Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1251 the treatment of psoriasis and to discuss their mecha- dermal keratinocytes. Moreover, inflammation, ob- nisms of action. As reported, in many cases it is observed in psoriatic lesions, leads to induction and acti- served a greater activity of plant extracts and/or pure vation of several pro-angiogenic factors. constituents in comparison to conventional drugs, such Regulatory T cells affect the vascular endothelial as corticosteroids. Aloe vera, Boswellia serrata, Cur- growth factor (VEGF)-related angiogenic microenvi- cuma longa, Hypericum perforatum, Indigo naturalis, ronment and contribute to some psoriasis features. Mahonia aquifolium, and Viola tricolor and their main Therapies able to target leukocytes recruitment and/or active constituents boswellic acids, curcumin, hy- vascular functions are a promising approach for the pericin, hyperforin, indirubin, and berberine can be treatment of psoriasis. considered the most promising agents for future me- nagement of psoriasis. Five types of psoriasis have been described. Plaque psoriasis, also known as psoriasis vulgaris, is the most 2. PATHOGENESIS AND CLINICAL MANIFES- common form of the disease (about 85% of cases). Dis- TATIONS tinctive characters are monomorphic demarcated erythematous plaques covered by silvery lamellar Psoriasis is a skin disease with an etiology involving scales. These are mainly found on the scalp, knees, el- both genetic and environmental factors. The causes are bows, legs, and sacral area, but may be present on any still unidentified. Now the role of the immune system is part of the body in the most advanced states of the dis- widely accepted and, consequently, the genetic predis- ease. The other types are: a) guttate or eruptive psoria- positions of psoriasis with respect to immune genes and sis; b) inverse psoriasis, also called intertriginous or their encoded pathways in the pathogenesis [22,23]. flexural psoriasis; c) pustular psoriasis or generalised The immune genes are responsible for several func- pustular psoriasis; and d) erythrodermic psoriasis. tions that involve innate immunity, antigen presenta- tion, the interleukin (IL)-23 axis, and T-cell develop- Guttate psoriasis presents small lesions over the up- ment and polarization. In recent years, the contribution per trunk and proximal extremities and is frequent of some of these gene products to psoriasis has been among young adults. Inverse psoriasis shows up as proved targeting of some key immune components, very red lesions in is found in the armpits, groin, under namely IL-23, tumor necrosis factor alpha (TNF-α), the breasts and in other skin folds on the body. It is and the Th17/IL-23 axis [24]. Psoriasis involves kerati- common in overweight people. nocytes, antigen-presenting cells, neutrophilic granulo- Pustular psoriasis is characterized by white coalesc- cytes, vascular endothelial cells, and the cutaneous ing pustules (blisters of non-infectious pus) and often nervous system [25]. At onset of psoriasis, activated appears in patients with existing or previous psoriasis dendritic cells produce different mediators including vulgaris while erythrodermic psoriasis is a severe and TNF-α and IL-23. rare complication of psoriasis. TNF-α is a pro-inflammatory cytokine, produced by different cell types including lymphocytes, keratino- 3. CONVENTIONAL THERAPIES cytes, endothelial cells, and macrophages, which am- The conventional therapies for the treatment of mild plifies inflammation response through several path- disease are generally topical drugs such as glucocorti- ways. The IL-23/Th17 axis could be a novel targeted costeroids and vitamin D derivatives, or their combina- therapy for the treatment of psoriasis [26]. Th17 cells tions. Topical calcineurin inhibitors, such as tacrolimus are a subset of T-lymphocytes that express IL17, dif- and pimecrolimus, are used for the treatment of diffi- ferent from the classical Th17 cells that have a signifi- cult-to-treat parts, such as the intertriginous areas or the cant role in the pathogenesis of inflamatory disorders face. Mason et al. [27] showed that a combination of including psoriasis. corticosteroids and vitamin D3 was the most effective Expansion and survival of these cells depend on treatment for the scalp. Unfortunately, convenience, myeloid cell-produced IL-23, which determine the time needed for the treatment, and adverse effects limit Th17 cells differentiation. Other cytokines including the use of these topical drugs. Patients affected by IL-9 might support Th17-related inflammation. After moderate and severe psoriasis generally use a combina- activation, Th17 cells produce several mediators that tion of phototherapy and systemic therapy. Acitretin, induce keratinocyte proliferation and other psoriasis ciclosporin, and methotrexate have been approved for features. TNF-α and IL23/Th17 axis pathways affect the treatment of psoriasis as systemic drugs. Apremilast the proliferation and production of cytokines by epi- has been approved in the USA and Europe. Photoche- 1252 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al. motherapy or PUVA (Psoralen Plus Ultraviolet Light sis. The role of oxidative stress in the pathogenesis of Therapy) is a combination of ultraviolet A (UVA) light psoriasis makes to study the possible benefit of an en- therapy and a psoralen medication. Unfortunately, the riched diet or of a therapeutic supplementation of natu- carcinogenic effects of PUVA limit its long-term use. ral antioxidants. In recent years, several biologics such as TNF-α inhibitors (adalimumab, etanercept, and infliximab) and in- 5. NATURAL PRODUCTS hibitors of interleukin 12 and 23 (ustekinumab) have 5.1. Acanthus Mollis been approved for the treatment of psoriasis. Biologics have shown a good safety profile and no cumulative Acanthaceae family comprises of 250 genera and toxicity. TNF-α inhibitors are generally used when about 2500 species. Among them, Acanthus mollis is a conventional systemic therapies have either have plant used in traditional medicine in southern Italy for failed, were not tolerated or were contraindicated and the treatment of skin disorders including psoriasis [30]. after phototherapy. This is due in part to the high costs. Eicosanoids play a very important role in inflammatory processes of the skin, therefore, also in the course of 4. OXIDATIVE STRESS AND PSORIASIS psoriasis and dermatitis atypical. Neutrophils migrate into the epidermis quickly inflamed and come into Although endogenous antioxidants may attenuate close contact with the keratinocytes, releasing leukot- the damaging effects of reactive oxygen species (ROS), riene A4 in the extracellular space. From this substrate, increased and/or prolonged presence of free radicals the production of leukotriene B4 starts. can override ROS defense mechanisms and mediate several cellular responses that contribute to the devel- 12(S)-Hydroxy-5Z,8Z,10E,14Z-tetraenoico acid opment of a variety of skin disorders, including psoria- (12(S)-HETE) is one of the most widely eicosanoids sis [28]. Zhou et al. [28] reviewed studies that demon- produced by the epidermis, and is found in large quan- strated the role of oxidative stress in the pathogenesis tities in psoriatic plaques [31]. The activity of A. mollis of psoriasis. ROS influence the cellular signal transduc- extracts seems partly due to inhibition of direct and tion pathways such as pro-inflammatory signaling indirect enzyme responsible for the synthesis of ei- pathways and modulate the expression of numerous cosanoids. Moreover, in vitro studies have shown that genes [29]. The most important effects are observed in A. mollis extracts are able to inhibit cyclooxygenase the mitogen-activated protein kinase/activator protein 1 (COX), lipoxygenase (LOX), and redox-sensitive en- (MAPK/AP-1), nuclear factor κB, and Janus kinase- zymes, and affect the release of LTB4, eicosanoid and signal transducers and activators of transcription path- activation of nuclear factor NF-kB (Table 1) [32,33]. ways, which have been considered as initial events in The methanol extract of A. mollis was assessed for its inflammatory disorders such as psoriasis. Moreover, in vitro effects against COX-1, 5-, 12- and 15-LOX the high level of polymorphonuclear leukocytes (PMN) enzymes, and NF-κB activation [34-38]. A. mollis in- in psoriatic lesions leads to the release of ROS pro- hibited both COX-1 and 5-LOX (at a concentration of duced via NADPH-dependent oxidase/myelo-peroxi- 200 µg/ml). No inhibitory activity on 12-LOX was ob- dase and proteolytic enzymes, leading to lipid peroxi- served. dation and oxidative damage of skin cells. In particular, the decrease of membrane fluidity caused by lipid per- 5.2. Aloe Vera L. oxidation products is observed in association with the Aloe vera (Asphodelaceae) has been used for more exacerbation of the disease. Fatty acids and their oxida- than 2000 years in the treatment of dermatological dis- tion products can bind the peroxisome proliferator- orders [39-41]. Different studies investigated products activated receptor PPARδ, that controlling lipid and obtained by A. vera for the treatment of psoriasis. Syed lipoprotein metabolism, cell proliferation, differentia- et al. [42] in a study that involved sixteen patients with tion, and apoptosis of keratinocytes, is a major event in mild to moderate psoriasis evaluated an A. vera cream psoriasis, contributing to the hyperproliferative pheno- demonstrating that the treatment effect of A. vera was type by induction of heparin-binding EGFlike growth significantly superior than that to placebo. Succes- factor, known to induce epidermal hyperplasia and be sively, Paulsen et al. [43] conducted a randomized, overexpressed in psoriasis. double-blind, placebo-controlled, study with fourteen Although the molecular mechanism of the regula- patients. tion of ROS-mediated pathways is still unknown, anti- The Psoriasis Area Severity Index (PASI) scores oxidants may be beneficial for the treatment of psoria- decreased by 72.5% of the A. vera-treated sites com- Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1253

Table 1. Plant extracts for the treatment of psoriasis.

Species Family Parts Study Ref.

Acanthus mollis Acanthaceae Leaves In vitro [28] Aloe vera Asphodelaceae Leaves In vivo [36-39] Astragalus sinicus Fabaceae Dried roots or stems In vitro and in vivo [42] Boswellia serrata Burseraceae Resin In vivo [47, 48, 50-54] Caesalpinia bonduc Caesalpiniaceae Leaves In vitro and in vivo [59] Curcuma longa Zingiberaceae Rizhome In vivo [62-67, 74-76, 78] Dodoneae polyandra Sapindaceae Leaves In vitro and in vivo [79-82] Hypericum perforatum Hypericaceae Flowers/Fruits In vitro and in vivo [90-97] Illicium verum Illiciaceae Fruits In vitro [102-104] Indigo naturalis Leaves* In vitro and in vivo [106-111] Mahonia aquifolium Berberidaceae Bark In vivo [113-120] Memecylon malabaricum Melastomataceae Leaves In vitro and in vivo [121-122] Picea mariana Pinaceae Bark In vitro [124] Viola tricolor Violaceae Leaves and flowers In vitro [139] *Leaves of Baphicacavthus cusia, Isatis indigotica, Indigofera tinctoria, and Polygonum tinctorium. pared with 82.5% of the placebo-treated areas after 4 5.3. Astragalus sinicus L. weeks of treatment. However, no difference in efficacy Astragalus sinicus (Fabaceae) (known as Chinese between A. vera and the placebo was evidenced after milkvetch) is a perennial legume that growth in Korea, 12 weeks. In contrast to these results, A. vera cream Japan, and central and southern China. The main iden- was more effective than 0.1% triamcinolone acetonide tified classes of constituents are alkaloids, flavonoids, cream after 8 weeks [44]. The improvement in the and triterpene glycosides [46,47]. PASI was about 66.1% in the A. vera group and 60.1% in the triamcinolone acetonide group. No complete re- In a recent study, the dried roots or stems of A. sini- mission was observed in either of the groups. The im- cus were extracted with methanol and dichloro- pact of psoriasis on the quality of life was investigated methane. The extracts were partitioned into water and using the e Dermatology Life Quality Index (DLQI). n-butanol, and the latter fraction was repartitioned into This index decreased in both groups throughout the aqueous methanol and n-hexane [48]. Among fractions course of the study. No significant difference between obtained from the aqueous methanol layer, rf3 and rf4 the 2 groups was found after 8 weeks of treatment. showed the most interesting anti-inflammatory and antioxidant effects. A. vera cream showed mild side effects. A 95% ethanolic extract of the gel of A. vera leaf has recently In particular, rf3 and rf4 exerted an effect on the been studied using a mouse-tail model of psoriasis JAK/STAT (Janus kinase/signal transducer and activa- [45]. This extract made significative differentiation in tor of transcription) signaling cascade with possible the epidermis as seen from its degree of orthokeratosis inhibitory effects in cytokine-induced keratinocytes. (85.07%), equivalent to the effect of the positive con- Both fractions inhibited Th2 and Th17 cells differentia- trol tazarotene (0.1%) gel, which showed a 90.03% tion and enhanced Treg-cell differentiation. Besides degree of orthokeratosis. JAK/STAT signaling pathways, both fractions, but in particular rf4, inhibited the activation of nuclear factor A. vera leaf gel extract also increased relative epi- kappa B (NF-κB) by inhibiting a) the phosphorylation dermal thickness, whereas tazarotene did not produced and degradation of IκBα protein, b) the phosphoryla- any change. Unfortunately, until now results on the tion of NF-κB p65, and c) the nuclear translocation of effectiveness of A. vera are contradictory [40]. the activated NF-κB p65 subunit. Overall, these effects

1254 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al. resulted in the inhibition of the expression and produc- is attributed to the ability of both compounds to bind tion of pro-inflammatory mediators. A. sinicus fractions the 5-lipoxygenase enzyme at a selective site for penta- were also in vivo studied. Topical application of rf3 and cyclic triterpenes that is different from the arachidonate rf4 was able to suppress ear thickness and psoriasis substrate-binding site [54]. The analysis of structure- progression. activity relationships (SARs) revealed that the penta- cyclic triterpene ring system is crucial for binding to 5.4. Boswellia serrata Roxb. ex Colebr. the highly selective effector site, whereas the keto Boswellia serrata (Burseraceae) is a moderate to function in addition to a hydrophilic group on C4 of large sized branching tree that grows in dry mountain- ring A are essential for the 5-lipoxygenase inhibitory ous regions of India, Northern Africa and the Middle activity of boswellic acids [55]. More recently, Alt- East. Since ancient times, three of these species have mann et al. [56] have demonstrated that boswellic acids been considered as “true Frankincense” producing trees at low concentrations inhibited the activation of mito- [49]. gen-activated protein kinases (MAPK) signaling and significantly suppressed the PAF-induced Ca2+ mobili- The gum-resins of trees was mentioned in Ayurve- zation. Moreover, boswellic acid inhibited leukocyte dic and Unani texts as an effective remedy for diar- elastase, released in inflammatory reactions and hyper- rhoea, dysentery, fevers, cardiovascular diseases, sensitivity, underscoring its antiphlogistic effects [57]. mouth sores, bad throat, bronchitis, asthma, cough, vaginal discharges and skin diseases [50]. Several stud- The 3-acetyl-11-keto-β-boswellic acid (4) also ies support the use of this species as antiarthritic, anti- caused inhibition of nuclear factor NF-κB and then a inflammatory, antihyperlipidemic, antiatherosclerotic down-regulation of the expression of TNF-α through and analgesic agent [51]. its direct inhibition of IKK (beta kinase K) [58]. Hu- man psoriatic skin lesions exhibited strong activation The resinous part of B. serrata contains α-thujene, of transcription factor NF-κB. incensole, incensole oxide, iso-incensole oxide, serra- tol, α- and β-amyrins, boswellic acids and tirucall- Based on this observation, Wang et al. [59] investi- 8,24-dien-21-oic acids as main constituents [52]. Bos- gated the in vivo effect of 3-acetyl-11-keto-β-boswellic wellic acids, a natural mixture of four major penta- acid (4) by using a mouse model of psoriasis. After cyclic triterpene acids, namely β-boswellic acid (1), 11- treatment with compound 4, NF-κB signaling and NF- keto-β-boswellic acid (2), 3-acetyl-β-boswellic acid κB-dependent cytokine production was strongly sup- (3), and 3-acetyl-11-keto-β-boswellic acid (4), is re- pressed. Moreover, the application of 3-acetyl-11-keto- ported to be effective as anti-inflammatory, immuno- β-boswellic acid (4) led to resolution of the abundant modulatory, antitumor, anti-asthmatic agents (Fig. 1). immune cell infiltrates, counteracted the expression of This mix of compounds exerted the anti-inflammatory IL-12, IL-23, and MCP-1 in lesional areas, and reduced activity by the inhibition of leukotrienes via 5- the proliferation of keratinocytes. lipoxygenase inhibitory effect (Table 2). Singh et al. Successively, Togni et al. [60] described the results [53] investigated the anti-inflammatory activity of of the application for 30 days of novel boswellic acid boswellic acids. The results of the study revealed that formulation (Bosexil®). The size and irritation of le- topical application of boswellic acids in both acute and sions were classified as absent, moderate, severe or chronic models exerted leukotriene inhibitory activity. very severe. The efficacy of treatment was evaluated The anti-inflammatory activity of boswellic acid (1) according to the “change of conditions” of patients, and its derivative 3-acetyl-11-keto-β-boswellic acid (4) according to the following scale: a) in remission: when

H H O O H H O O HO HO O O H H H H O O O O OH OH OH OH

1 2 3 4 Fig. (1). Chemical structure of boswellic acids 1-4. Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1255

Table 2. Pure compounds and their potential mechanism of action for the treatment of psoriasis.

Compound Species Potential mechanism of action Ref.

Boswellic acids (1- Boswellia serrata Inhibition of 5-lipoxygenase, activation of MAPK signaling and [48, 50-54] 4) suppression of PAF-induced Ca2+ mobilization, inhibition of leukocyte elastase; inhibition of NF-κB; down-regulation of the expression of TNF-α through inhibition of IKK. Curcumin (5) Curcuma longa reduction of IL-17A, IL-17F, IL-22, IL-1β, IL-6 and TNF-α cytoki- [62-67, 74-76, nes expression; inhibition of the activation of NF-kB 78] Polyandric acid A Dodoneae polyandra Anti-inflammatory activity in the TPA-induced mouse ear oedema [80, 81] (6) model; inhibition of IL-1β production; reduction of ear thickness and myeloperoxidase accumulation; reduction of IL-6 secretion. Polyandric acid B Dodoneae polyandra anti-inflammatory activity in the TPA-induced mouse ear oedema [80] (7) model Hypericin (8) Hypericum perfora- Inhibition of IL-12 production in lipopolysaccharide-activated mouse [92] tum macrophages Hyperforin (9) Hypericum perfora- radical scavenging properties in human HaCaT keratinocytes; inhibi- [90, 93-95] tum tion of COX-1, 5-lipoxygenase, and PGE2 production p-Anisaldehyde (10) Illicium verum Inhibition of IFN-γ-induced ICAM-1 expression and regulatory [104] mechanisms in the HaCaT cell line trans-Anethole (11) Illicium verum Inhibition of IFN-γ-induced ICAM-1 expression and regulatory [104] mechanisms in the HaCaT cell line Indirubin (12) Indigo naturalis Down-regulation of the expression of CDC25B at both the mRNA [110-111] and protein levels; inhibition of the activation of EGF receptor highly expressed in psoriatic lesions. Berberine (13) Mahonia aquifolium Inhibition of COX-2, lipoxygenase and NO release; reduction of [113-116] TNF-α, IFN-γ and IL-1α). p-Coumaric acid Picea mariana Inhibition of NO production through the inhibition of the expression [125-127] (14) of iNOS mRNA Pinoresinol (15) Picea mariana Inhibition of NO production through the inhibition of the expression [125-127] of iNOS mRNA Resveratrol (16) Picea mariana Inhibition of NO production through the inhibition of the expression [125-127] of iNOS mRNA subjects have no more injuries; b) improvement: sub- including a small number of patients. In addition to jects with very severe injuries to moderate or severe to anti-inflammatory effects, as already reported, these moderate; c) equality: when subjects did not undergo molecules have the capacity to restore and protect in improvements; d) worsened: when subjects have dete- the time the barrier function of the skin, which is made riorated. Generally, there were no significant differ- weaker by the same psoriatic plaques. It is thought to ences between individuals of different sex or age in the also increase the time between periods of remission studied groups. Results clearly evidenced that the when the disease takes over the patient’s skin. In addi- treatment with Bosexil® formulation improved scales tion to serving for the treatment of psoriasis and ec- and erythema without any case of worsening. Bosexil® zemas, the formulations investigated can also be ap- formulation improved both erythema and itchiness plied for other inflammatory disorders of the skin, in- without any case worsening. In conclusion, Bosexil®, cluding contact, atopic, and seborrhoeic dermatitis. formulated according to the Phytosome® delivery system, could be proposing for the treatment of psoriatic 5.5. Caesalpinia bonduc (L.) Roxb. and eczematous symptoms. This study has shown that Caesalpinia bonduc (Caesalpiniaceae), known as through topical administration, twice a day for thirty Kat Karanj in Hindi, is traditionally used in the Mala- days resulted in an actual improvement of the disease. bar region, Karnataka, India, to treat inflammation and However, the study was carried out for a short period, 1256 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al. skin diseases, such as psoriasis [61]. Phytochemical ethanol (96%) 17 g, and distilled water q.s. to 100 g) screening reported cassane furanoditerpenes from dif- strongly inhibited psoriasis-like inflammation in an ferent parts of the plant [62-64]. A decoction and a hy- animal model, the development of which is based on droalcoholic extract of C. bonduc leaves were prepared the IL-23/IL-17A axis. Real-time PCR analysis re- and studied for their potential anti-psoriasis effects by vealed that the treatment with curcumin (5) determined using a mouse-tail test [65]. a reduction of IL-17A, IL-17F, IL-22, IL-1β, IL-6 and C. bonduc decoction was fractionated with water TNF-α cytokines expression similarly to clobetasol, a saturated n-butanol to give a butanol and a water frac- glucocorticoid largely used for psoriasis treatment. tion decoction. Hydroalcoholic extract was fractionated IL-17A induces the activation of the NF-κB and with chloroform and water saturated n-butanol to give JUN amino-terminal kinase (JNK) signaling pathways chloroform, n-butanol and water fraction of hydroalco- and synergizes with other cytokines namely IL-1β, IL-6 holic extract. and TNF-α that promote the activation of tissue- In the mouse-tail test, the most active fractions were infiltrating neutrophils. Curcumin (5) significantly re- n-butanol and water fraction of hydroalcoholic extract duced the increased expression of IL-17A and IL-17F by producing remarkable orthokeratosis in comparison induced by imiquimod (IMQ). The receptor RORγ, with the control. Moreover, the water fraction of hy- activated by IL-6 and TGF-β, is necessary for the ex- droalcoholic extract also exhibited significant modifi- pression of IL-17A. Because there are no evidences of cation in epidermal thickness. C. bonduc decoction and the influence of curcumin (5) on the expression of the other fractions did not produce significant or- RORγ, it can be deduced that compound 5 down- thokeratosis but determined important changes in epi- regulated the expression of IL-17A/IL-22 by inhibiting dermal thickness. the production of IL-1β/IL-6. The expression of IL-22 was also significantly down-regulated by 5 in IMQ- Taking into account the role of LOX catalysed oxy- induced psoriasis-like inflammation. genation products in the development of psoriasis, extracts and fractions were also tested for their ability to Moreover, curcumin (5) enhanced the proliferation inhibit the enzyme. The most active fraction was the of epidermis γδ T cells but inhibit dermal γδ T cell pro- water fraction of decoction with an IC50 value of liferation. In mouse skin cells γδ T type are very abun- 164.71 µg/ml, followed by decoction (IC50 value of dant, and act in order to monitor local immune. IL-23, 291.65 µg/ml). The water fraction of decoction showed in turn, is essential for the maintenance of homeostasis, antiproliferative activity against HaCaT cell line. and cell differentiation γδ-T. Curcumin (5) demonstrated to stimulate the prolif- 5.6. Curcuma longa L. eration of γδ T cells [70]. The increased skin thickness Curcuma longa (Zingiberaceae) is a perennial plant and inflammation in IMQ-treated mouse ear skin was with characteristic odour and slightly pungent bitter in inhibited by curcumin (5) [71]. An improved level of taste. The rhizome contains three main curcuminoids, activation of signal transducer and activator of tran- namely curcumin (5) (Fig. 2), demethoxycurcumin, and scription 3 (STAT3) was found in human psoriatic le- bisdemethoxycurcumin, as well as volatile oils (tumer- sions [72]. Curcumin (5) also suppressed the phos- one, atlantone, and zingiberone). C. longa is largely phorylation of STATs. STAT3 alters the proliferation used in traditional medicine especially in Ayurvedic and differentiation of keratinocytes, and induced in- medicine for its analgesic, antibacterial, antioxidant, flammatory molecules [73]. expectorant, and anti-inflammatory properties [66,67]. In psoriatic lesions, STAT3 activation was pro- Curcumin (5) demonstrated to be a highly plei- moted by increased levels of cytokines and growth fac- otropic molecule able to interact with numerous mo- tors. For example, IL-22 strongly triggers STAT3. In lecular targets involved in inflammation [68]. IL-23, fact, it inhibited both IL-6-induced STAT3 and IFN-α- IL-17A, and IL-17F and cytokines play a critical role in induced STAT1 phosphorylations [74]. Therefore, cur- the pathogenesis of psoriasis [69]. Curcumin (5) exerts cumin (5) inhibits inflammatory factors that contribute its beneficial effect in psoriatic patients since it acts in to inflammation and the proliferation of keratinocytes keratinocytes as an anti-inflammatory agent by inhibit- in psoriatic patients. ing the expression of several pro-inflammatory cytokines. The topical use of a curcumin (5) gel formulation Moreover, curcumin (5) has shown its inhibitory ef- (curcumin 1 g, azone 1 g, hydroxypropyl cellulose 3 g, fect on NF-kB, MAPK and cytokines [75]. NF-κB me- Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1257 diates several gene expressions, critical for the regula- associated with phototherapy demonstrating a reduction of inflammation and autoimmune diseases [76]. tion of human skin keratinocytes proliferation, induc- Recent studies demonstrated that the route of signal tion of apoptosis, inhibition of NF-κB activity and acti- transduction induced by IL-1 is a key step in the forma- vation of caspase-8 and caspase-9. tion of autoimmune diseases mediated by IL-17A, such 5.7. Dodoneae polyandra Merr. & L.M. Perry as psoriasis [77]. Consequently, the link between IL- 1R1 and IL-1β starts the process of signal transduction, Dodoneae polyandra (Sapindaceae) is an Australian culminating in the activation of NF-kB, JNK and p38 Northern Kaanju medicinal plant. D. polyandra leaf MAPK. NF-kB is closely related to the onset of psoria- extract showed anti-inflammatory effects in an acute sis, as it combines the action of keratinocytes and lym- mouse ear oedema model induced by croton oil and 12- phocytes [78]. Curcumin (5) can inhibit the activation O-tetradecanoylphorbol-13-acetate (TPA) [85]. Two of NF-kB inhibiting the phosphorylation of IκB. The furanoclerodane diterpenoids, namely polyandric acid nuclear receptor RORγ, which is activated by IL-6 and A (6) and B (7), were identified as main active compo- TGF-β is involved in the expression of IL-17A both in nents. vitro and in vivo [79]. In the pathogenesis of psoriasis, Both compounds demonstrated potent anti- phosphorylase kinase (PhK) increased activity has been inflammatory activity in the TPA-induced mouse ear demonstrated. oedema model [86]. Polyandric acid A (6) demon- Heng et al. [80] evaluated the effect of curcumin (5) strated to inhibit interleukin-1β production in an acute PhK suppression in patients with psoriasis. Forty pa- skin inflammation model, and to reduce ear thickness tients were distributed into four groups: untreated pso- and myeloperoxidase accumulation in a chronic model riasis; psoriasis treated by calcipotriol (a vitamin D3 [87]. A significant reduction of IL-6 secretion in pri- analogue and an indirect inhibitor of PhK); curcumin mary neonatal human keratinocytes was also observed. (5) (diferuloylmethane); non-psoriatic people. In pso- Recently, the D. polyandra leaves resin has been in- riasis treated with curcumin (5) and calcipotriol the serted in an oil-in-water cream formulation at strength lower level of PhK activity was found in association of 5% w/w [88]. Keratinocytes released high amounts with a decrease in keratinocyte transferrin receptor ex- of TNF-α and IL-1β, pro-inflammatory cytokines that pression and a reduction of the severity of parakerato- in turn initiate several inflammatory responses and ex- sis. The suppression of PhK activity by curcumin (5) is acerbation of the symptoms. D. polyandra cream sig- linked to the resolution of psoriatic plaque. In another nificantly reduced the production of IL-1β in the ear study, 20 patients with chronic plaque psoriasis re- tissue, inflammatory cell infiltration and ear oedema. ceived capsules with curcumin (5) 4.5 g every day for The release from the formulation of diterpenoids 6 and 12 weeks, followed by an observation period of 4 7 was studied by using an in vitro test using a Franz weeks [81]. At the end of the treatment only two pa- diffusion cell with a synthetic polyvinylidene difluoride tients showed 83-88% improvement. This study was (PVDF) membrane as a measure of batch consistency. limited by the small sample size and the lack of group However, the amounts released of both compounds control. In consequence, obtained results should be were low (approximately 4 and 2% after 8 hours for prudently evaluated. compounds 6 and 7, respectively). Many factors, including the physico-chemical properties of the sample, More recently, Carrion-Gutierrez et al. [82] have the composition of the vehicle and the interactions be- investigated the effect of oral administration of curcu- tween them, influence these results. min (5) together with real visible light phototherapy (VLRT) or simulated visible light phototherapy 5.8. Hypericum perforatum L. (VLST) in 21 patients with plaque psoriasis. In contrast to the patients treated with VSLT (30%), patients Hypericum perforatum L. (also known as St. John’s treated with VLRT showed a remission to moderate or wort) (Hypericaceae) is one of the most investigated severe plaques (81%). medicinal plants worldwide in the last two decades. H. perforatum is known for its antidepressant effects, but In another recent study, a microemulgel containing it is also traditionally used as oil and tincture for the curcumin (5) reduced the mean redness score and treatment of burns, cramps, decubitus, lumbago, and thickness after 9 weeks of treatment. The microemulgel rheumatism. The European Medicines Agency accepts was remarkably more effective than the placebo in de- the use of H. perforatum for the symptomatic treatment creasing the the area of lesion and scaling lesions [83]. of skin inflammations and minor wounds [89,90]. Anti- Niu et al. [84] confirmed the effects of curcumin (5) 1258 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al. inflammatory, and antimicrobial properties, and stimu- scaling were evaluated in determining PASI. H. perfo- lation and differentiation of tissue growth have been ratum ointment applied twice daily produced a reduc- reported for H. perforatum and its constituents hy- tion of PASI scores in mild plaque-type psoriasis. H. pericin (8) and hyperforin (9), suggesting their poten- perforatum formulations were also studied for their tial benefits for the treatment of skin diseases including potential side effects. Adverse effects of H. perforatum psoriasis. H. perforatum extracts exhibited interesting application may be irritation and/or sensitization and antioxidant properties through different in vitro assays photosensitization. However, available clinical data [91-95]. suggests that the risk is low. In an irritation test, bath Hyperforin (9) has shown radical scavenging prop- oil with H. perforatum extract was administered to the erties in human HaCaT keratinocytes irradiated with surface of the arm of volunteers. The skin areas were solar-simulated radiation. A cream with compound 9 analysed for photometric measurements of erythema, significantly protected porcine ear skin after solar ra- and transepidermal water loss (TEWL). The bath oil diation [96]. with H. perforatum did not cause irritation [103]. Pre- viously, Schempp et al. [104] demonstrated that topical The anti-inflammatory activity of different H. per- application of H. perforatum oil or ointment on the foratum extracts and pure compounds were investi- forearms of volunteers caused no or only mild photo- gated in a mouse ear model [97]. In another study, hy- sensitization, respectively. Despite available clinical pericin (8) considerably inhibited IL-12 production in data demonstrated the low phototoxic potential of topi- lipopolysaccharide-activated mouse macrophages with cal hypericin (8) treatment, caution in the application an IC50 value of 1.45 µg/ml and the activation of the IL- of H. perforatum extracts should be used since higher 12 gene promoter, suggesting that hypericin (8) nega- penetration rates of compound 8 may occur in skin le- tively regulated IL-12 production at the transcription sions. Moreover, in fair-skinned people and after pro- level [98]. Different mechanisms such as inhibition of tracted solar irradiation, improved susceptibility to the COX-1, 5-lipoxygenase, and PGE2 production were photosensitizing effects of preparations containing hy- described for the anti-inflammatory activity of hyper- pericin (8) may occur. The synergism in the activity of forin (9) [99-101]. hypericin (8), hyperforin (9), and other constituents H. perforatum and hyperforin (9) demonstrated anti- may elucidate the interesting biological properties of H. inflammatory activity on T cells and stimulated kerati- perforatum. nocytes differentiation. In a recent study, H. perfora- H. perforatum oil is still recommended in traditional tum ointment was used to treat ten patients with medicine for treatment of burns and sunburns. How- plaque-type psoriasis [102]. Erythema, thickness, and ever, only a few clinical trials have been conducted

O O

O O OH H H HO O O O HO OH

OCH3 OCH3 O OH O OH

6 5 7 OH O OH OH O HO HO O

OH O OH

8 9 Fig. (2). Chemical structure of compounds 5-9. Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1259 which allow an estimation of its beneficial value in ap- treat more than 10,000 patients with psoriasis consid- plications relative to the treatment of other skin dis- erably improved skin psoriasis [112,113]. eases. Lin et al. [112] evaluated the effectiveness and safety of I. naturalis on treating plaque-type psoriasis 5.9. Illicium verum Hook. f. in fourteen patients affected by psoriasis. The his- Illicium verum (Illiciaceae) is a plant originally dis- tological change in skin tissues was also object of this tributed in most countries of Asia, commonly known as work. Patients were treated with I. naturalis ointment star anise. H. verum fruits are used in Eastern Asian or vehicle ointment for 8 weeks. traditional medicine for treating asthma, colic, stomach At the end of treatment, induration, scaling, ailments, skin inflammation, and rheumatic pain [105- erythema and clearing percentage were evaluated. A 107]. clear improvement of skin histology was achieved. The The anti-inflammatory activity of I. verum was topical application of I. naturalis ointment may be a demonstrated in two studies in which plant extract sup- safe and effective therapy for the treatment of psoriasis. pressed chemokines, cytokines, and adhesion mole- Its action is mediated, at least in part, by modulating cules in TNF-α/IFN-γ-stimulated HaCaT cells and the differentiation and proliferation of keratinocytes atopic dermatitis-like skin lesions [108, 109]. In an- and by inhibiting the infiltration of T lymphocytes and, other study, the inhibitory effects of I. verum extract consequently, the inflammatory reactions observed in and two constituents, namely p-anisaldehyde (10) and lesions. trans-anethole (11) (Fig. 3), on IFN-γ-induced ICAM-1 Successively, I. naturalis treatment showed an in- expression and their regulatory mechanisms were increased involucrin expression and a decreased prolifer- vestigated in the HaCaT cell line [110]. Specifically, I. ating cell nuclear antigen (PCNA) in psoriatic lesions verum significantly inhibited IFN-γRα expression and [114]. Moreover, I. naturalis extract (10-500 µg/ml) consequent phosphorylation of Jak2, which is pre- was applied to keratinocytes and cell viability was de- dominantly autophosphorylated in IFN-γ-treated termined. After the treatment, cultured keratinocytes HaCaT cells, and STAT1. I. verum decreased ICAM-1 decreased. An increase of the G0/G1 arrest was ob- mRNA and protein. served in a dose-dependent manner. In treated kerati- Studies have shown that suppressor of cytokine sig- nocytes, a decrease in PCNA-stained nuclei and an in- nalling (SOCS) proteins are key physiological regula- crease in cytosolic involucrin were evident. These re- tors of inflammation. Among SOCS proteins, SOCS1 sults demonstrated the anti-psoriatic effects of I. natu- inhibits IFN-γ signaling through the Jak/STAT path- ralis related, at least in part, to the modulation of way [111]. Sung et al., [110] demonstrated that I. keratinocytes differentiation and proliferation. verum increased the expression of SOCS1, which at- The ability of I. naturalis extract to increase the ex- tenuated the phosphorylation of Jak2, with a conse- pression of claudin-1 and tight junction (TJ) function quent inhibition of the phosphorylation of STAT1 and was investigated in human keratinocytes and psoriatic reduction of the expression of inflammatory genes. lesions [115]. I. naturalis was able to up-regulate both Moreover, I. verum inhibited the IFN- -induced adher- γ mRNA and protein expression of claudin-1 and func- ence of Jurtkat T cells to HaCaT cells by inhibition of tion of TJ in a concentration-dependent manner. I. the expression of ICAM-1. The I. verum tested com- naturalis increased also the activity of protein kinase C pound p-anisaldehyde (10) demonstrated to inhibit (PKC). ICAM-1 expression and adherence of T cells. This activity is comparable to that demonstrated by trans- I. naturalis and indirubin (12), the major I. naturalis anethole (11). active constituent, were investigated in primary and immortalized keratinocytes for their potential to de- 5.10. Indigo Naturalis crease the expression of CDC25B that demonstrated to Indigo naturalis is a Chinese herb, also known as have an important role in the hyper-proliferation of “Qing dai”, prepared from the leaves of Baphica- keratinocytes [116,117]. cavthus cusia, Isatis indigotica, Indigofera tinctoria, Both I. naturalis and indirubin (12), tested at differ- and Polygonum tinctorium. I. naturalis has been tradi- ent concentrations, down-regulated the expression of tionally used to treat various inflammatory disease and CDC25B at both the mRNA and protein levels. The dermatosis [14]. Topical application of I. naturalis to growth-dependent expression of CDC25B was demonstrated by the increased expression in serum-stimulated 1260 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al. and immortalized keratinocytes. I. naturalis and its lated with M. aquifolium extract and the other one with main constituent 12 also inhibited the activation of calcipotriol and fluticasone propionate. EGF receptor that is highly expressed in psoriatic le- Out of 32 participants, 30 patients successfully sions. completed the experience, 27 patients achieved an improvement of the disease, with passage of state from 5.11. Mahonia aquifolium (Pursh) Nutt. severe to moderate and only three patients did not see Mahonia aquifolium is a specie of flowering plant in any improvement [124]. In a subsequent study, 33 par- the family Berberidaceae, native to western North ticipants with skin lesions on both arms were assigned America. This plant is traditionally used for the treat- to two groups. In the first group, M. aquifolium cream ment of inflammatory diseases of the skin, such as pso- was applied on one arm and placebo on the other one. riasis. The use of M. aquifolium for medical purposes In the second group, a cream of calcipotriol and tazaro- dates back to the Indian tribes, who used to treat dys- tene was applied on one side, and placebo on the other pepsia. Its extract has analgesic, anti-inflammatory, side. After four weeks of treatment, an improvement in antioxidant and hepatoprotective properties. These redness and irritation was observed [125]. properties are mainly due to the presence of alkaloids A randomized double-blind trial, which involved as berberine, palmatine, jartrorrhizine, berbamine and the use of a cream containing an extract of M. aquifo- oxycanthine [118]. lium (consisting mainly in psoberine), was conducted Berberine (13) is an isoquinoline alkaloid with a in the US and Canada. Two hundred subjects partici- great variety of effects including anti-inflammatory pated either using the homeopathic product containing properties. Cyclooxygenase-2 (COX-2) plays a key a M. aquifolium extract (cream Reliéva) or placebo role in the synthesis of prostaglandins, thus causing the twice a day for 12 weeks of treatment. The PASI was onset of inflammation. Berberine (13) reduced the lev- evaluated at the beginning and end of the treatment. els of prostaglandin E2 in a dose-dependent manner by The Quality of Life Index (QLI) was evaluated at 0, 4, inhibition of COX-2 expression [119]. 8, and 12 weeks. The oral ingestion of berberine (13) for four weeks Improvements in both PASI and QLI in the M. aqui- reduced the presence of TNF-α, interferon gamma folium-treated group were observed. Infrequent side (IFN-γ) and interleukin-1 alpha (IL-1α) [120]. It also effects such as rash when applying the cream and seems to have an inhibitory effect against the release of clothing stain were detected [126]. nitric oxide (NO), an important mediator of inflammation [121]. The products of the lipoxygenase metabo- 5.12. Memecylon malabaricum (C. B. Clarke) Cogn. lism play an important role in the pathogenesis of pso- Memecylon malabaricum (Melastomataceae) is a riasis. Some benzylisoquinoline alkaloids isolated from shrub or small tree with blue flowers. M. malabaricum M. aquifolium were tested for their potential lipoxy- is traditionally used for the treatment of skin diseases genase inhibitory activity. Among these, berberine (13) including psoriasis [127]. The hydroalcoholic extract, and oxicantine were the most active. Moreover, both aqueous extract of M. malabaricum leaves and their alkaloids are able to inhibit lipid peroxidation. These fractions were investigated for their potential antipsori- data suggest that inhibition of the peroxide tone could atic properties. play an important role in the inhibition of lipoxygenase. This mechanism could explain the efficacy of Decoction was fractionated with water saturated n- M. aquifolium extract in the treatment of psoriasis butanol to give an n-butanol and a water fraction. Hy- [122]. droalcoholic extract was fractionated with chloroform and water saturated n-butanol to give chloroform, n- Wiesenauer et al. [123] examined M. aquifolium butanol and water fractions. Samples were studied in bark extract for the treatment of psoriasis. Eighty-two vitro by using HaCaT cells, for their lipoxygenase and patients were told to apply two types of ointment thymidine phosphorylase inhibitory activity, and in (verum/placebo) one to the left side of their body the vivo by mouse-tail test [128]. M. malabaricum hydro- other to the right. After 4 weeks, patients as well as alcoholic extract and its water fraction caused maxi- physicians assessed the therapy's success on a three- mum orthokeratosis in the mouse tail test. Except for level ordinal rating scale. hydroalcoholic extract, all tested samples produced a In a randomized clinical trial, patients were sub- reduction in epidermal thickness. The chloroform frac- jected to two different treatments: one cream formu- tion of hydroalcoholic extract revealed the maximum Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1261 activity against HaCaT cells. M. malabaricum samples noresinol (15), and resveratrol (16), to inhibit the pro- demonstrated to inhibit LOX with a decreasing activity duction of NO through the inhibition of the expression of samples in the order water fraction of decoction > of iNOS mRNA [131-133]. decoction > water fraction of hydroalcoholic extract > butanol fraction of decoction > hydroalcoholic extract. 5.14. Viola tricolor L. High levels of the thymidine phosphorylase enzyme are Viola tricolor is a medicinal plant used in European found in psoriatic lesions. M. malabaricum decoction traditional medicine for the treatment of inflammatory was the only active extract in this test. Quercetin and skin disorders including psoriasis [32,134]. Its tradi- rutin were identified as main constituents of M. mala- tional use is described in the Pharmacopoeia of Europe baricum extracts and fractions. [135]. The analysis of literature revealed antioxidant, anti-inflammatory, and antimicrobial properties of V. 5.13. Picea mariana (Mill.) B.S.P. tricolor [136-140]. The anti-inflammatory and antino- Picea mariana (Pinaceae) is a North American spe- ciceptive activities of a gel containing the extract of V. cies traditionally used for its anti-inflammatory proper- tricolor flowers were recently investigated on thermal ties. Its resin is used to promote healing of wounds and burn induced by UVB irradiation [141]. Paw edema, to treat skin rashes purulent wounds, and burns [129]. neutrophilic cell infiltration, and static and dynamic Moreover, P. mariana improves several inflammatory mechanical allodynia were used as models. The gel skin disorders such as psoriasis. In a recent study, the was studied in order to evaluate its stability by analyz- ability of P. mariana bark extract to inhibit the TNF-α- ing viscosity, pH, and organoleptical aspects. Changes induced effects on psoriatic keratinocytes (PK) in com- in the mechanical allodynia models, paw edema, and parison with normal human keratinocytes (NHK) was myeloperoxidase activities were found after treatment investigated. P. mariana extract, which contains sev- with the gel containing V. tricolor. No significant eral classes of compounds such as simple phenols, changes were revealed in the stability study (studies phenolic acids, neolignans and lignans, flavonoids, and were carried out at temperature below 25 °C). proanthocyanidins, showed interesting anti-inflam- The main classes of constituents identified in V. tri- matory effects against lesional psoriatic keratinocytes color are catechins, cumarins, flavonoids, phenylcar- [130]. In particular, the extract down-regulated the NF- bonic acids, polysaccharides, and salicylic acid deriva- κB pathways associated with TNF-α stimulation, re- tives [138,139,142]. V. tricolor is also a rich source of duced the NO production and the expression of induc- small disulphide-rich peptides, called cyclotides. These ible nitric oxide synthase (iNOS), ICAM-1 expression, molecules, which usually consist of 28-37 amino acid IL-6 and VEGF production, IL-8 and fractalkine for- residues, possess many biological activities, including mation, and trappin-2/elafin generation. Previous antimicrobial, anti-HIV, uterotonic, and hemolytic works reported the ability of some main constituents of properties. Cyclotides are also described as promising P. mariana extract, such as p-coumaric acid (14), pi- immunosuppressive agents [143-145].

O O O H OCH3 NH O N+ N H3CO O H O 13 10 11 12

OCH3 OH O O OH H HO OH H HO HO O OH OCH3 14 15 16 Fig. (3). Chemical structure of compounds 10-16. 1262 Current Medicinal Chemistry, 2016, Vol. 23, No. 12 Bonesi et al.

Since lymphocytes play an important role in the in- The most promising results were obtained with Aloe flammatory diseases, recently Hellinger et al. [146] vera, Boswellia serrata, Curcuma longa, Indigo natu- examined the effect of a V. tricolor aqueous extract on ralis, Mahonia aquifolium, and Viola tricolor and their the function and cell division of activated human lym- main constituents namely boswellic acids, curcumin, phocytes. The extract inhibited in a concentration- berberine, and indirubin. Their anti-inflammatory, anti- dependent manner the cell division of activated T- oxidant, anti-proliferative, immuno-modulatory, wound lymphocytes. Authors demonstrated that this effect is healing and/or anti-pruritic properties may partly ex- not cytotoxic. In fact, the extract induced overtime nei- plain the reported effects of these natural products. ther necrosis nor apoptosis. External stimuli start the These multiple effects make these plant extracts and/or secretion of the growth factor IL-2 that consecutively pure compounds potentially become suitable for the promotes interaction with its receptor that is upregu- treatment of psoriasis. Moreover, in addition to mono- lated on activated T-cells. V. tricolor inhibited the se- therapeutical applications of natural compounds, it is cretion of IL-2 and reduced the production of IFN-γ possible to prospect the use of combinations with well- and TNF-α, but not affected the expression of the IL-2 established immunosuppressive drugs because most of surface receptor and the level of degranulation activity. these substances are associated with side effects if The phytochemical screening confirmed the pres- given at an effective dosage. Then, the dose, and con- ence of cyclotides as active compounds. Cyclotides sequently the side effects, can be reduced below a cer- demonstrated to induce a reduction of the IL-2 cell sur- tain level. Futher studies on these possible combina- face marker expression and IL-2 cytokine expression tions are necessary to highlight the potentiality in the and secretion [147]. treatment of psoriasis.

CONCLUSION ABBREVIATIONS Psoriasis is a very multifaceted disease involving COX = Cyclooxygenase complex pathogenic interactions between the innate DLQI = Dermatology life quality index and adaptive immune system. Current treatment is EC = Half maximal effective concentration aimed at relieving symptoms such as itching, flaking, 50 dry mucous membranes and their sensitivity to acidic IC50 = 50% inhibitory concentration foods or relational problems due to exposure of body IL = Interleukin parts with conspicuous spots. Topical treatments with IMQ = Imiquimod glucocorticosteroids, vitamin D derivatives, or combinations of both are used to manage mild disease while iNOS = Inducible nitric oxide synthase calcineurin inhibitors are used to menage difficult ar- JAK = Janus kinase eas, such as the intertriginous areas or the face. Several adverse effects, practicability, and convenience often LOX = Lipoxygenase limit the use of these drugs. Patients with moderate-to- MAPK = Mitogen-activated protein kinases severe diseases are treated with a combination of pho- NF-κB = Nuclear factor kappa B totherapy and systemic therapy. NHK = Normal human keratinocytes Unfortunately, this therapy is usually used for short- term control of the disease and the long-term use of NO = Nitric oxide PUVA is limited by its carcinogenic potential. PASI = Psoriasis area severity index In the past decade, plants have demonstrated to play PCNA = Proliferating cell nuclear antigen a significant role in the discovery of new agents for the treatment of psoriasis. Many plants and different PhK = Phosphorylase kinase classes of phytochemicals, mainly flavonoids, have PK = Psoriatic keratinocytes been identified for their interesting antioxidant effects. PUVA = Psoralen plus ultraviolet light therapy Skin is a target of oxidative stress mainly due to ROS originating from the environment and skin metabolism PVDF = Polyvinylidene difluoride itself. Thus, the possibility to use natural antioxidant QLI = Quality of life index agents is of great interest. ROS = Reactive oxygen species SARs = Structure-activity relationships Anti-Psoriasis Agents from Natural Plant Sources Current Medicinal Chemistry, 2016, Vol. 23, No. 12 1263

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Received: January 26, 2016 Revised: March 17, 2016 Accepted: March 18, 2016

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