Molecular Mechanism Underlying Anti-Inflammatory and Anti-Allergic Activities of Phytochemicals: An Update

The resort worldwide to edible medicinal plants for medical care has increased significantly during the last few years. Currently, there is a renewed interest in the search for new phytochemicals that could be developed as useful anti-inflammatory and anti-allergic agents to reduce the risk of many diseases. The activation of nuclear transcription factor-kappa B (NF-κB) has now been linked to a variety of inflammatory diseases, while data from numerous studies underline the importance of phytochemicals in inhibiting the pathway that activates this transcription factor. Moreover, the incidence of type I allergic disorders has been increasing worldwide, particularly, the hypersensitivity to food. Thus, a good number of plant products with anti-inflammatory and anti-allergic activity have been documented, but very few of these compounds have reached clinical use and there is scant scientific evidence that could explain their mode of action. Therefore, this paper intends to review the most salient recent reports on the anti-inflammatory and anti-allergic properties of phytochemicals and the molecular mechanisms underlying these properties.


Introduction
Plants have been the basis of many traditional medicine systems throughout the World for thousands of years and still remain as the main new source of structurally important chemical substances that lead to the development of innovative drugs [1,2]. The use of medicinal plants for the treatment of many diseases is associated with folk medicine from different parts of the World [3,4]. Nowadays, the search for new anti-inflammatory and anti-allergic agents from the huge array of medicinal plant resources is intensifying [5]. In fact, a variety of bioactive components have been shown to modulate inflammatory responses [6]. The inflammatory response is a critical protective reaction to irritation, injury, or infection, characterised by redness, heat, swelling, loss of function and pain [7]. Redness and heat result from an increase in blood flow, swelling is associated with increased vascular permeability, and pain is the consequence of activation and sensitisation of primary afferent nerve fibres [8].
The understanding of the cellular and molecular mechanisms involved in the inflammatory process has increased considerably in recent decades and this has permitted the discovery of many promising targets for the development of new drugs to treat chronic inflammatory diseases [8]. A great number of inflammatory mediators including kinins, platelet-activating factor (PAF), prostaglandins, leukotrienes, amines, purines, cytokines, chemokines and adhesion molecules, has been found to act on specific targets, leading to the local release of other mediators from leukocytes and the further attraction of leukocytes, such as neutrophils, to the site of inflammation [6].
The constant advent of new findings from immunohistochemical, biochemical, molecular and functional animal models, together with clinical trials, has greatly increased the interest in the study of the mechanisms that underlie the inflammatory process [8]. Recently, roles have been identified for several inflammatory cells and for a large number of inflammatory mediators in important pathologies not previously known to be linked to inflammation, such as Alzheimer's disease and cardiovascular disorders including atherosclerosis, as well as cancer, reviewed in Akiyama et al. [9] and Libby et al. [10].
Natural products have long been, over the years, contributed to the development of modern therapeutic drugs [11]. Evidence exists that drugs derived from natural products can modulate various inflammatory mediators (arachidonic acid metabolites, peptides, cytokines, excitatory amino acids, etc.), the production and/or action of second messengers (cGMP, cAMP, protein kinases, and calcium), the expression of transcription factors such as AP-1, NF-κB, and proto-oncogenes (c-jun, c-fos, and c-myc), and the expression of key pro-inflammatory molecules such as inducible NO synthase (iNOS), cyclooxygenase (COX-2), cytokines (IL-1β, TNF-α), neuropeptides and proteases [6][7][8].
In parallel, the allergic process has an important inflammatory component in which mast cell activation and degranulation are the first phenomena observed. During this process, mast cells release several inflammatory mediators including histamine (5-HT), platelet aggregating factor (PAF), leukotrienes, and a variety of cytokines [12,13]. Hypersensitivity type I, an allergic reaction, is an IgE mediated immune response, resulting in histamine secretion from mast cells and blood basophils. The early phase reaction of allergy occurs within minutes after allergen exposure, whereas the late phase reaction occurs hours later and involves in cytokines secretion such as TNF-α and IL-4 [14].
The discovery of drugs that can be used for the treatment of inflammatory and allergic diseases is important in human health. Drug discovery from plants involves a multidisciplinary approach combining botanical, ethnobotanical, phytochemical and biological techniques [2]. Several natural product drugs of plant origin are in clinical use and some are undergoing Phase II and Phase III clinical trials [2][3][4][5]. This review highlights the current patents about the potential benefits and effectiveness of phytochemicals that have shown experimental or clinical anti-inflammatory or anti-allergic activities, the possible mechanism of action and their therapeutic value.

Major Classes of Phytochemicals
Plants are rich in a wide variety of secondary metabolites, the great majority of which do not appear to participate directly in growth and development [15]. Based on their biosynthetic origins, phytochemicals can be classified as carotenoids, phenolics, alkaloids, nitrogen-containing compounds, and organosulfur compounds. Interestingly, an important classification has been depicted by Liu [16] gathering nearly most of dietary phytochemical classes and the structures of their main chemically relevant components ( Figure 1). Phytochemicals, although noted for the complexity of their chemical structures and biosynthetic pathways, they have been widely perceived as biologically insignificant and have historically received little attention from most plant biologists. Organic chemists, however, have long been interested in these novel phytochemicals and have investigated their chemical properties extensively since the 1850s [15]. At present numerous studies have established that the phytochemical content of plants contributes to their protective effects against acute, chronic, and degenerative diseases [17-19].

Inflammation
Wide ranges of phytoconstituents were responsible for anti-inflammatory activity including phenolics, alkaloids, and terpenoids [19]. However, efforts have focused on a class of compounds to elucidate the mechanisms of action of herbs, characterize and establish their potential utility as therapeutic agents in the treatment of inflammatory diseases.
Several mechanisms of action have been proposed to explain the anti-inflammatory actions of phytoconstituents, it consist broadly in: (1) Antioxidative and radical scavenging activities; (2) Modulation of cellular activities of inflammation-related cells (mast cells, macrophages, lymphocytes, and neutrophils); (3) Modulation of proinflammatory enzyme activities such as phospholipase A 2 (PLA 2 ), cyclooxygenase (COX), and lipoxygenase (LOX) and the nitric oxide (NO) producing enzyme, nitric oxide synthase (NOS); (4) Modulation of the production of other proinflammatory molecules; (5) Modulation of proinflammatory gene expression.
The Tables 1 and 2

Herbal formulation/Compound Indication Clinical efficiency References
Curcumin Antirheumatic -Exerted an antirheumatic activity comparable to that of phenylbutazone [184] Active constituents of honeysuckle (Lonicera japonica)      [196] Berry extract containing stable anthocyanin Treating inflammation, oxidative damage, or cancer -Inhibition of proliferation of HT-29 human colorectal cancer cells -Ihibition of IL-12 release from murine dendritic cells [197] Free-B-Ring flavonoids from Scutellaria baicalensis Treatment of COX-2 mediated diseases and conditions -Inhibition of COX-1 of THP-1 cells and COX-2 of HOSC cells [198] The inflammatory process can be initiated by various inflammatory stimuli including viruses, chemicals, and reactive oxygen/nitrogen species, which subsequently increases the synthesis and secretion of proinflammatory cytokines. Moreover, the unchecked activation of NF-κB/AP-1 and the production of TNF-α signaling have provided compelling evidence about the critical role for these factors in coupling inflammation and many chronic diseases. Phytochemicals have been shown to modulate various points in these inflammatory processes [6]. These modulations serve as controlling points where the amplification of the inflammatory processes can be disconnected and thereby reduce subsequent diseases risk.

Allergy
The allergic process has an important inflammatory component. Hypersensitivity reactions can be divided into four types: Type I: Called immediate or anaphylactic hypersensitivity mediated by IgE. Mast cells and basophils play a central role in immediate allergic inflammation through releasing chemical mediators such as histamine and cysteinyl leukotrienes, cytokines and chemokines. The reaction may involve skin (eczema), eyes (conjunctivitis), nasopharynx (rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis).
Type II: Known as antibody-mdiated cytotoxicity mediated by antibodies of the IgM or IgG classes and complement. Antibodies directed against cell surface antigens causes cell damage such as hemolytic disease of the newborn (Rh disease) and myasthenia gravis (MG).
Type III: Known as immune complex hypersensitivity mediated by IgG or IgM classes. The reaction may be general (serum sickness) or may involve individual organs including skin (systemic lupus erythematosus), joints (rheumatoid arthritis) or other organs.
Type IV: Known as cell mediated or delayed type hypersensitivities. These reactions are mediated by CD4+T cells, and involved in the pathogenesis of many autoimmune diseases (multiple sclerosis). Another form of delayed hypersensitivity is contact dermatitis (poison ivy).

Preventing contact dermatitis
Polyphenol (extract from the bark of Acacia mearnsii) Inhibited itching in atopic dermatitis by preventing the skin from drying [216] Polyphenols and anthocyanins derived from Vaccinium uliginosum L Improve atopic dermatitis disease in mice by reducing the Th2/Th1 ratio, IL-4 and IL-13 (as Th2 cytokines), IFN-γ, and IL-12 (as a Th1 cytokine) in spleens Decreased gene expression, such as IL-4, IL-5, CCR3, eotaxin-1, IL-12, IFN-γ, MCP-1, and IL-17, and suppressed Th 17 [217]   Prevention or therapy of pollen allergy, allergic rhinitis, atopic dermatitis, asthma or urticaria Animal trials: Inhibiting the production of total IgE antibodies in the blood of mice sensitized with cedar pollen Human trials: Therapeutic effects on patients suffering from cedar pollen allergy [221] Formulation(s) comprises of Tinospora cardifolia, Piper longum, Albizia lebbeck and Curcuma amada Treatment of allergy Decreased the histamine release (mast cell degranulation) in rats-Reduced lipid peroxidation and superoxide dismutase activity, and increased catalase activity in tissues (liver, kidney and heart) rats [222] The composition comprises at least one of the following ingredients: luteolin from Perilla leaf or seed, Cinnamon, Kiwi, Picao preto, Hesperidin, Acerola cherry, Guaco, Holy Basil, Kakadu, Solamum, Rosmarinic acid, Tinospora and Aframomum Inhibits and/or mitigates an allergic response Inhibition of the IgE secretion by U266 human myeloma cells-Reduction of the IgE receptor expression by RBL-2H3 cells-Inhibiting or preventing the release of mediators such as histamine, PGD 2 and LTC4 by RBL-2H3 cells [223] Flavonoid and/or a flavonoid derivative (Troxerutin or Veneruton ® ) Treating symptoms of common cold, allergic rhinitis and infections relating to the respiratory tract Showed success results on different patients suffering from common cold symptoms-Reduced the symptom score after treatment of patients suffering from allergic airway conditions [224] Kaempferol, apigenin Treatment of contact dermatis Inhibited iNOS induction produced in contact dermatitis [225] Dehydrocorydaline Treatment of hypersensivities reactions Inhibited the induction phase of picryl chloride-induced contact dermatitisin mice [226] Despite the promising use of plant products for medicinal purposes for the evidences discussed above, it is worth noting that many of the dietary phytochemicals or natural products are not without cytotoxic effect and can originate various allergic reactions. The well known allergenic phytoconstituents are sesquiterpene lactones and furanocoumarins. Many of plants containing sesquiterpene lactones cause allergic contact dermatitis and effective treatments are scarce. Other natural products such as flavonoids [227], alkaloids [228,229], and terpenoids [230,231] can also cause allergic reactions. Phenolics such as: anethol, atranorin, catechols, cinnamon, cinnamic derivatives, benzoic acid, curcumin, eugenol, isoeugenol, litreol, ginkgolic acid, resorcinols, oak moss resin, tertiaery-butylhydroquinone, urushiol, usnic acid. Alkaloids such as: atropine, pilocarpine, quinine, thebaine, codeine, and terpenoids such as: abietic acid, alantolactone, artesunate, asiaticoside, asiatic and madecassic acids, carvone, citral, β-cyclocostunolide, dehydroabietic acid, eucalyptol, farnesol, geraniol, limonene, α-pinene, phellandrene, linalool, menthol, myrrh, parthenolide, polygodial, sesquiterpenes, sesquiterpenes, thymol (reviewed in Rios et al. [232]). While flavonoids are only weakly antigenic and usually do not induce immune reactions after consumption or therapeutic application, antibodies against flavonoids have been found in human blood [227]. Adverse side effects of polyphenol intake on cardiovascular diseases have been also reported. A high consumption of polyphenol (2 g chlorogenic acid per day during 1 week) significantly increased homocysteinemia [233,234]. The consumption of tea has been associated with a higher bone mineral density [235]. A recent randomized crossover trial [236] revealed that moderate consumption of red wine reduced erythrocyte superoxide dismutase activity. Another randomized double-blind, placebo-controlled trial showed that the combination of vitamin C and grape-seed polyphenols increases blood pressure [237].

Conclusions
Phytochemicals show both anti-inflammatory and anti-allergic activities in vitro and in vivo. Several cellular action mechanisms are proposed to explain their mode of action. Any single mechanism could not explain all of their in vivo activities. They probably have multiple cellular mechanisms acting on multiple sites of cellular machinery. The continual efforts will provide new insight into the anti-inflammatory and anti-allergic activities of phytochemicals, and eventually lead to development of a new class of anti-inflammatory and anti-allergic agents. However, the concern and difficulties related to the investigation of herbal medicines have precluded the financial incentives that could be provided to pharmaceutical industries. As a function of such difficulties, few herbal drugs have been studied adequately and well-controlled double-blind clinical trials to prove their safety and efficacy have been lacking. The trend today, especially in an industrial setting, is to seek bioactive compounds from plants that will serve as lead compounds for synthetic or semisynthetic development, and knowledge of the main pharmacologically active plant compounds is an essential requirement to standardize procedures for obtaining herbal remedies in order to replace crude products with modern pharmacological formulations.