Use of Natural Components for Treatment of Inflammatory Skin Diseases

The incidence of inflammatory skin diseases is increasing, so the search for relevant therapeutics is of major concern. Plants are rich in phytochemicals which can alleviate many symptoms. In this review we concentrate on compounds found in the seeds of widely cultivated plants, regularly used for oil production. The oils from these plants are often used to alleviate the symptoms of inflammatory diseases through synergetic action of unsaturated fatty acids and other phytochemicals most commonly derived from the terpenoid pathway. The knowledge of the chemical composition of oil seeds and the understanding of the mechanisms of action of single components should allow for a more tailored approach to treatment for many diseases. In many cases these seeds could serve as an efficient material for the isolation of pure phytochemicals. Here we present the content of phytochemicals, assumed to be responsible for healing properties of plant oils, in widely cultivated oil seed plants and review the proposed mechanism of action for fatty acids, selected mono- , sesqui-, di- and triterpenes, carotenoids, tocopherol and polyphenols.

As the skin is the largest (representing one sixth of the total body weight) and first-contact organ of the human body, its balance and proper functionality are crucial for our health. The skin participates in sensitivity and offers protection against microorganisms, chemicals and ultraviolet radiation. In addition, it is constantly exposed to environmental factors of UV light, pathogens, chemical threats and temperature changes. All of this coupled with the genetic background can cause severe diseases including cancer and inflammation. Skin diseases associated with chronic inflammation are becoming more and more common nowadays, especially due to air pollution, the high hygiene level and above all the increasing amount of chemicals directly interfering with our bodies from our diet and cosmetics.

A study published last year in JAMA Dermatology reports on the prevalence of skin diseases around the world and their likelihood of creating disability during the life to define the following 10 most challenging conditions (arranged in order of decreasing 'disability-adjusted life years'): dermatitis, acne, hives, psoriasis, viral skin diseases, fungal skin diseases, scabies, melanoma, pyoderma, cellulitis, non-melanoma skin cancer, decubitus ulcer, and alopecia areata.. Even though those diseases contributed to 1.79% of the global burden of disease measured in disability-adjusted life years they substantially affect the quality of life of patients.

The main skin disorders associated with an inflammatory imbalance are allergic contact dermatitis, atopic dermatitis and psoriasis, which besides the loss in skin functionality have a high social and psychological impact. The inflammation-related skin disorders are multifactor diseases, but they all manifest with lymphocyte, monocyte and macrophage recruitment after activation of the skin defense system (with keratinocytes and dendrocytes as the main players) by external or internal stimuli, and ongoing propagation of the inflammatory state in the skin. The complicated networks of inflammatory skin disorders’ interactions have been widely investigated and already well-reviewed.

The development of inflammatory skin disease is most commonly associated with T lymphocyte recruitment and the production of a wide range of proinflammatory agents, mainly protein factors such as interferons and interleukins (for example interferon gamma, interleukin 17, and interleukin 22 ) often acting not only as the inflammation propagators but also as growth factors. The mentioned molecules act in synergy with tumor necrosis factor α (TNF-α), also produced by the lymphocytes, causing first of all a significant increase of dermal keratinocytes’ inflammatory response, resulting in production of many other cytokines and chemokines. The proteins secreted by the recruited lymphocytes also change the extracellular matrix composition and cause alterations in the skin cells’ growth and differentiation process. The keratinocytes are very susceptible to IFN-γ action and they are also able to produce many cytokines and chemokines in response both to primary and secondary inflammation-related stimuli; therefore they are thought to play a central role in the development and chronicity of inflammatory skin diseases. The increase of cytokine and chemokine production leads to propagation of the inflammatory state, changes in the expression of cell cycle regulating genes and additionally, as already mentioned, some of the produced proteins can act on keratinocytes as growth factors. These processes cause increased keratinocyte proliferation, while their maturation is impaired, resulting in thickening of the epidermis, additional blood vessel formation and as a consequence impairments of skin and scarfskin layers’ arrangement and functionality.

In the case of deregulation of the inflammatory state in the skin IFN-γ is released by the recruited T lymphocytes and after binding to the specific receptor on the keratinocyte cell surface, activates the Janus kinase 2 and signal transducer and activator of transcription 1 (JAK2/STAT1) signaling pathway leading to STAT1 transcription factor activation in epidermal keratinocytes. STAT1 regulates the expression of cytokines, adhesion molecules, cell cycle regulators and other transcription factors, responsible for the development of the disease. This signaling pathway is very important in psoriasis, where the JAK2/STAT1 negative regulators (suppressor of cytokine/chemokine signaling 1 and 3 – SOCS1 and SOCS3) were shown to impair the IFN-γ-induced expression of intracellular adhesion molecule 1 (ICAM1), the chemokine (C-X-C motif) ligand 9 (CXCL9) and 10 and C-C motif chemokine ligand 2 (CCL2). TNF-α, modulating the nuclear factor κB (NF-κB)-related pathway, also plays an important role in the development of skin inflammatory disease, in this case by influencing the expression of the cell differentiation process and cell death regulating genes. SOCS1 is also shown to be related to this pathway, influencing the activity of protein kinase B. Another signaling molecule that is important in skin inflammatory diseases is transforming growth factor β (TGF-β), required for T helper 17 (Th17) lymphocyte differentiation, but also regulating skin cells’ growth and development. The vascular endothelial growth factor (VEGF), another growth factor produced by the epidermal keratinocytes after immunological activation, is involved in additional blood vessel formation and infiltration of the lymphocytes in the lesion region of the skin.

The endocannabinoid system is also often mentioned as an important signaling pathway involved in the inflammation dysregulations of the skin. Cannabinoid receptors (CB), especially CB2 – highly expressed in immune cells and peripheral tissues – can also be involved in the possible activity of the hydrophobic components against the development of inflammatory skin diseases. CB2 activation leads to the inhibition of adenylate cyclase and lowers the level of intracellular cyclic adenosine monophosphate (cAMP). The cAMP level has a great impact on expression of various inflammation-related genes and is associated with inflammatory skin diseases, especially psoriasis and atopic dermatitis. The endocannabinoid receptor ligands have been shown to influence the proliferation of keratinocytes and the process of their differentiation, offering great opportunities in psoriasis and allergic contact dermatitis treatments . All these as the main players and many other signaling molecules, pathways, transcription factors and their regulators represent the complicated interplay between epidermal keratinocytes and the immune cells infiltrating the skin, deregulation of which leads to the disease.

Numerous different treatments for skin diseases are available, which may allow for some short-term improvement and long-term control, but for many of them there is still no cure. Even if the treatments are available, some of them can cause severe side effects. An example of a disease without a cure is the aforementioned psoriasis, a chronic inflammatory skin disease characterized by thickened, and silvery-scaled patches. The treatment, including topical applications, systemic therapies and phototherapy, allow for some control of the disease. These treatments, while effective, are still associated with significant adverse effects. Thus, there is a constant search for better therapeutics, especially for inflammation-related diseases. Nowadays the discovery of new drugs is facing serious challenges due to the reduction in the number of new drug approvals coupled with the exorbitant rising costs. Many plants are used traditionally to treat various diseases and even now are important sources of novel pharmacologically active compounds, with many drugs being derived directly or indirectly from plants. This is not surprising, as plants contain a very broad range of various phytochemicals, some of which are very difficult or even impossible to synthesize chemically. Plants materials are also used for isolation of various chemicals as a basis for chemical modifications to obtain new structures.

The diet has been suggested to be involved in the etiology and pathogenesis of psoriasis. Fasting, low-energy and vegetarian diets have been shown to improve psoriasis symptoms, as well as diets rich in polyunsaturated fatty acids. These diets modify the polyunsaturated fatty acid metabolism and influence the eicosanoid profile, so that inflammatory processes are suppressed. When it comes to evaluation of the importance of phytochemicals in various diseases, the situation is complicated, as quite often the whole plant extract or the crude oils are used. On the other hand, there is a possibility that this is the exact reason why these various diet regimes work at all, as synergy of action of plant components needs to be considered. Another example is the use of sesame oil in one study, where it was shown to inhibit many cytokines and signaling pathway elements connected to NF-κB and STAT1 in the TNF-α and IFN-γ induced keratinocyte cell line. This could be attributed to sterol, unsaturated fatty acid and some other phytochemicals present in minor quantities.

In this review we decided to concentrate on oilseed plants as they are widely cultivated, easily available and at the same time rich in combinations of phytochemicals. As indicated above, in many cases it is impossible to point out the relevance of any given chemical, but when possible we tried to combine the data from clinical trials with laboratory experiments to underline the possible mechanisms of action of these components.

Oilseed plants are cultivated mainly for the food and feed industry and for production of biofuels. According to European Commission data from 2017, the worldwide production of oilseed plants reached an average 522.3 million metric tons (MMT), of which over 300 MMT are soybeans. Apart from soybeans, rapeseed (69.5 MMT), cotton (42.1 MMT), peanut, (41.2 MMT), sunflower (40.7 MMT) and palm kernel (16.1 MMT) are also grown. In the European Union itself, mainly rapeseed (22.3 MMT), sunflower (9 MMT), soy (2.3 MMT) and flax (0.1 MMT) are cultivated (data from EU Crops Market Observatory - Oilseeds and protein crops. Available from: https://ec.europa.eu/agriculture/market-observatory/crops/oilseeds-protein-crops/statistics_en.). The oil most frequently used for nutritional purposes, after palm oil, is soybean oil. In many countries (especially in Europe), the use of rapeseed oil in cooking is very popular. Another important oil consumed by humans is sunflower oil.

The major part of consumed oils consists of fatty acids, with additional components being mostly terpenoids. For the regulation of inflammation the composition of fatty acids seem to be of greatest importance. It is believed that the ratio of omega-6 (n-6) and omega-3 (n-3) fatty acids is crucial for the human body in the regulation of the immune response. Omega-6 and omega-3 are the two major families of polyunsaturated fatty acids (PUFAs). Plants synthesize linoleic acid (18:2, n-6) and α-linolenic acid (18:3, n-3), and consequently these two fatty acids are found in many seeds, nuts, seed oils and products produced from seed oils. Neither of these can be synthesized in animals, and therefore they need to be obtained from the diet. After consumption they can be converted into other fatty acids such as eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid.

EPA and DHA derived from omega-3 fatty acids show anti-inflammatory activity and are capable of partially inhibiting many aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte-endothelial adhesive interactions. Prostaglandins and leukotrienes derived from arachidonic acid produced from omega-6 are believed to promote inflammation. Mechanisms underlying the anti-inflammatory actions of EPA and DHA include altered cell membrane phospholipid fatty acid composition, inhibition of activation of the pro-inflammatory transcription factor NF-κB and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor (PPAR) γ. Animal experiments demonstrate some benefits from EPA and DHA treatments in a range of models of inflammatory conditions. However, it is important to note that both of these groups are essential for human health, and the importance of omega 6 is overlooked due to the high content of these fatty acids in the Western diet and quite common deficiency in omega 3 consumption.

Also monounsaturated oleic acid (e.g. oleic acid found in olive and rapeseed oil) is believed to help fight inflammation with the involvement of AMP-activated protein kinase. It has been proven that monounsaturated fatty acids can attenuate IL-1β-mediated insulin resistance and adipose dysfunction despite obesity.

It has been suggested that the ratio of oleic acid (OA) to linoleic acid (LA) in natural oils determines their effects on the skin. When a panel of 14 natural oils were compared for their ability to prevent experimentally induced irritant contact dermatitis in humans, positive effects (based on clinical scoring of irritation, trans-epidermal water loss and chromometry) were associated with low OA and high LA content. A significant difference was observed for people with atopic history – with a defective skin barrier. The imbalance of polyunsaturated fats may result in increased inflammation. The deficiency in γ-linolenic acid (GLA) in the skin is proposed to be one of the mechanisms contributing to atopic dermatitis development. Evening primrose oil and borage oil are considered the richest natural sources of GLA and have been extensively studied as natural substances that potentially support the treatment of atopic dermatitis.

The results obtained from a total of 27 studies (1596 participants, 19 studies on evening primrose oil and 8 tests assessed borage oil) showed no significant improvement in global eczema compared to the placebo group (evaluated on an analogue scale from 0 to 100 by physicians and participants). The authors claim that orally administered borage oil and evening primrose oil lack an effect on eczema, since the improvement was similar to respective placebos used in trials. Visible beneficial effects of the direct action of GLA on the skin were observed in a clinical experiment consisting of using undershirts coated with borage oil on children with atopic dermatitis. After 2 weeks of treatment improvements in erythema and pruritus were observed. Additionally, the trans-epidermal water loss from the back was decreased. It seems, therefore, that the key point for GLA is the route of administration.

Most recently] it was shown that borage oil restores the skin's acidic pH. Borage oil provided in the diet rebuilds skin pH by regulating skin lactate level and free fatty acid (FFA) metabolism (especially acidic FFA) by up-regulation of lactate dehydrogenase, secreted phospholipase A2, filaggrin and peptidylarginine deiminase-3 activity, both at the protein and mRNA levels.

It was reported that saturated fatty acids (present e.g. in palm oil) were able to directly stimulate inflammatory gene expression by way of Toll-like receptor 4 (TLR4) signaling in vitro. The relative potency of various saturated fatty acids changes inversely in proportion to the chain length, lauric acid (12:0) showing the greatest activity, whereas myristic acid (14:0) and stearic acid (18:0) exhibit little proinflammatory activity. In contrast, pre-treatment of cells for 3 h with a variety of PUFAs or oleic acid (octadecanoic acid; 18:1, n–9) significantly reduced the subsequent proinflammatory effect of lauric acid treatment. The ability of PUFAs to block inflammatory responses induced by bacterial lipopolysaccharide (LPS) or lauric acid was dependent on TLR4. Dietary hempseed oil (also rich in PUFAs) caused significant changes in plasma fatty acid profiles and improved the clinical symptoms of atopic dermatitis. Patients reported statistically significant decreases in skin dryness, itchiness and the use of dermal medications after hempseed oil dietary intake.

Fatty acids, especially unsaturated, can also be the regulatory element of a very special system of receptors, as they can be the substrates for endocannabinoids synthesis in human body. Incorporated into biological membranes in the form of phospholipids fatty acids are converted by N-acyl-phosphatidylethanolamine-selective phospholipase D into amides, that can bind to cannabinoid receptors and regulate the infammation-related processes as well as many other cellular pathways. These processes are thought to play important roles in the inflammatory skin diseases like psoriasis or atopic dermatitis, where topical aplication of oils comprised of unsaturated fatty acids were shown to relief the symptoms of inflammation.