Lamiaceae: An Insight on Their Anti-Allergic Potential and Its Mechanisms of Action

The prevalence of allergic diseases such as asthma, allergic rhinitis, food allergy and atopic dermatitis has increased dramatically in recent decades. Conventional therapies for allergy can induce undesirable effects and hence patients tend to seek alternative therapies like natural compounds. Considering the fact above, there is an urgency to discover potential medicinal plants as future candidates in the development of novel anti-allergic therapeutic agents. The Lamiaceae family, or mint family, is a diverse plant family which encompasses more than 7,000 species and with a cosmopolitan distribution. A number of species from this family has been widely employed as ethnomedicine against allergic inflammatory skin diseases and allergic asthma in traditional practices. Phytochemical analysis of the Lamiaceae family has reported the presence of flavonoids, flavones, flavanones, flavonoid glycosides, monoterpenes, diterpenes, triterpenoids, essential oil and fatty acids. Numerous investigations have highlighted the anti-allergic activities of Lamiaceae species with their active principles and crude extracts. Henceforth, this review has the ultimate aim of compiling the up-to-date (2018) findings of published scientific information about the anti-allergic activities of Lamiaceae species. In addition, the botanical features, medicinal uses, chemical constituents and toxicological studies of Lamiaceae species were also documented. The method employed for data collection in this review was mainly the exploration of the PubMed, Ovid and Scopus databases. Additional research studies were obtained from the reference lists of retrieved articles. This comprehensive summarization serves as a useful resource for a better understanding of Lamiaceae species. The anti-allergic mechanisms related to Lamiaceae species are also reviewed extensively which aids in future exploration of the anti-allergic potential of Lamiaceae species.

Introduction

Allergy is one of the manifestations of an abnormal regulation of the immune system. It can present as a mild to severe disorder, such as allergic rhinitis, food allergies, asthma, conjunctivitis, angioedema, urticaria, eczema, insect allergies and life-threatening anaphylaxis (Galli et al., 2008). Nowadays, allergy has become a global health concern. The cases of allergic disorders are increasingly rising and have reached an alarming rate. This statement is supported by some of the statistical figures provided by Pawankar (2014). According to Pawankar (2014), there are roughly 300 million individuals experiencing asthma and approximately 200 to 250 million individuals experiencing food allergies around the world. Additionally, 1/10 of the population experienced medication hypersensitivities and around 400 million people suffered from allergic rhinitis. Allergy can be very irritating to an extent that can greatly affect the quality of life, lead to an economic burden and can even jeopardize one’s life (Pawankar, 2014). Seeing the staggering pattern of morbidity and mortality caused by allergic disorders, this health issue must not be neglected and must be taken seriously with the active involvement of patients and healthcare professionals.

Currently, there are many treatment options for allergic disorders. Some of the widely used therapeutics are anti-histamine drugs, corticosteroids, leukotriene inhibitors and mast cell stabilizers to treat and control allergic conditions (Cota et al., 2012). All these medications are found to be efficactive in alleviating allergic symptoms. However, the drugs do not actually cure the allergy conditions. Instead, long term consumption of such drugs has been associated with undesirable side effects and sometimes may worsen the conditions (Han et al., 2017). Some examples of common side effects encountered by anti-histamine agents users are dry mouth, drowsiness, gastrointestinal disturbances, headache, agitation, confusion, etc. (Simon and Simons, 2008). As for corticosteroids, they work effectively in relieving allergic disorders, like allergic asthma, eczema, allergic rhinitis, etc. However, they often brings about undesirable side effects to patients in a long-term therapy. For instance, patients who are using inhaled corticosteroids for asthma control are likely to encounter undesirable effects like oral candidiasis (Fukushima et al., 2003) and adrenal suppression (Robert Webb, 1981). Patients with eczema who usually use topical steroidal treatment can develop Cushing’s syndrome (Tiwari et al., 2013) and skin thinning (Atherton, 2003) as well as easy bruising (Coondoo et al., 2014). Due to the limitations of modern medicines, there is an increasing interest in using complementary and alternative medicine, particularly herbal medicine for allergy conditions management (Engler et al., 2009).

Undeniably, medicinal plants have been widely utilized as healing modalities for both preventive and curative purposes. They play an extremely crucial role in human health. In recent years, there has been a growing trend in the world population with as many as 80% of people globally relying on the use of herbal medicinal products and supplements for their primary healthcare needs (Schuster, 2001; Ekor, 2013). This increasing demand and interest in the use of herbal medicinal products has encouraged new drug discoveries and developments (Ekor, 2013). In fact, many active ingredients of new drugs are derived from medicinal plants proven to be remarkably important in aiding drug discovery and development (Katiyar et al., 2012). Hence, studies need to be actively conducted on plants in order to identify possible candidates as safer and effective anti-allergic agents in future.

The Lamiaceae family is one of the biggest plant families among flowering plants, consisting of 236 genera with a coverage of more than 7,000 species (Khoury et al., 2016). It is also an important herbal family which comprises a wide array of plants with biological and medical applications (Uritu et al., 2018). Lamiaceae species often have four-angled or quadrangular stems with the presence of glandular hairs (Harley et al., 2004). Their roots are usually made of branched tap root. Their flowers are typically hypogynous and bilaterally symmetric with five united petals and sepals (Kokkini et al., 2003; Ramasubramania Raja, 2012; Carović-Stanko et al., 2016). The leaves are simple and arranged oppositely, each pair at a right angle to the previous one or whorled (Harley et al., 2004). Fruits are made of four dry one-seeded nutlets (Kokkini et al., 2003). Seeds are non-endospermic (Ramasubramania Raja, 2012). The environment adaptation of Lamiaceae is highly varied. The species predominantly distribute in the summer rainfall areas but also occur in winter rainfall areas. The species usually can be found in habitats which are dry, rocky, woodland or grassland, along forest margins and in fynbos (Will and Claßen-Bockhoff, 2014). The diversity of Lamiaceae species is mainly concentrated in Mediterranean regions and a small portion of them inhabit Australia, Southwest Asia and South America (Kokkini et al., 2003).

Khoury et al. (2016) reported that the high content of volatile compounds has contributed to many medicinal properties in Lamiaceae species. Historically, Lamiaceae plants have been reported to be effective in alleviating a range of conditions like exhaustion, weakness, depression, memory enhancement, circulation improvement, strengthening of fragile blood vessels, skin allergies and asthma (Wang et al., 2004; Naghibi et al., 2010; Ramasubramania Raja, 2012). In the Eastern Himalayan region of India, several Lamiaceae species have been utilized traditionally to treat certain conditions. For instance, the leaves of Clerodendrum serratum have been used as a traditional remedy for eye disorders. Moreover, the leaves of Elsholzia blanda is used to relieve itching conditions. The seed of Perilla frutescens is also claimed to be effective against fever and headache (Kala, 2005). Meanwhile, in China, the Chinese tea brewed using the leaves of Salvia officinalis is used as a traditional remedy to treat tonsillitis and hypertension (Li et al., 2013). Another Lamiaceae species, Scutellaria baicalensis has been extensively used as traditional Chinese medicine (TCM) for thousands of years. It is known as Huang Qin in Chinese. The decoction prepared from dried roots is used as a traditional remedy for diarrhea, dysentery, hypertension, hemorrhaging, insomnia, inflammation and respiratory infections (Zhao et al., 2016). In Mediterranean regions, like Lebanon, Mentha spicata is formulated into infusions to ease digestive disorders, arthritis, gastritis. The infusion is also used as an antiemetic and antimicrobial agent (Khoury et al., 2016). The medicinal uses of commonly used Lamiaceae species are summarized in Table 1.

TABLE 1

Table 1 Medicinal uses of commonly used Lamiaceae species.

This review is particularly focused on the summarization of the anti-allergic activities of the Lamiaceae family linked to the phytochemistry and ethnopharmacology reported in research studies. In addition to anti-allergic activities, toxicological investigations of Lamiaceae species are also highlighted in this review.

Anti-Allergic Activity

The abundance of species within the Lamiaceae family has led to a variety of medicinal uses, making the family pharmacologically important. The diversity is believed to be due to the wide variety of biologically active constituents in this plant family. Each species comprises a mixture of phytochemicals which attributes to the bioactivity of the plant (Carović-Stanko et al., 2016). Phytochemical investigations of the Lamiaceae family have demonstrated the presence of various bioactive compounds such as flavonoids (da Silva et al., 2015; Mamadalieva et al., 2017; Aghakhani and Kharazian, 2018), alkaloids (Malik et al., 2003; Asghari et al., 2017), phenolics (Berdowska et al., 2013; Zielińska and Matkowski, 2014; Skendi et al., 2017), lignans (Hong et al., 2009; Brandão et al., 2017), terpenoids (Ye et al., 2018), saponins (Ramasubramania Raja, 2012; Shah et al., 2014), etc. All these chemical constituents contribute to multidirectional pharmacological activities. Some of the remarkable bioactivities reported within this plant family are anti-allergic (Malik et al., 2003; Makino et al., 2003; Kim et al., 2009), anti-inflammatory (Borges et al., 2018), antimicrobial (Khoury et al., 2016; Cocan et al., 2018), free radical scavenging (Khaled-Khodja et al., 2014; Politeo et al., 2018), antinociceptive (Hwang et al., 2018; Uritu et al., 2018), anti-cancer activities (Nguyen et al., 2018; Sajjadi et al., 2018), etc. Many pharmacological activities of the Lamiaceae family have been widely studied and investigated. However, this study is mainly focused on the potential biologically active candidates with promising anti-allergic activity from Lamiaceae species in order to provide a direction in the discovery of potential novel, safe and efficacious natural anti-allergic agents in future. In the past, numerous in vitro, in vivo and ex vivo studies have been conducted and evaluated on the plant parts of Lamiaceae species to investigate the anti-allergic potential of Lamiaceae plants. Figure 1 and Table 2 show a summarization of the remarkable anti-allergic activities of the Lamiaceae family. The mechanisms of anti-allergic activities of Lamiaceae species are extensively discussed in this review.

FIGURE 1

Figure 1 Chemical structures of phytochemicals isolated from Lamiaceae species with anti-allergic activity.

TABLE 2

Table 2 Mechanism of action of extracts and isolates of Lamiaceae species with anti-allergic activity.

Inhibition of Allergen-Specific IgE

Immunoglobulin E (IgE) is of central importance in the regulation of immune responses against parasitic infestations and most importantly, it is also recognized as a main mediator for immediate-type allergies or type I hypersensitivity reactions, such as allergic asthma, rhinitis, atopic diseases, anaphylaxis, etc. (Al-Mughales, 2016). It is a potent mast cell activator able to trigger mast cell degranulation and downstream responses with a minute amount (Actor, 2014). It exists in trace amounts in plasma but the amount can be substantially elevated in allergic reactions (Gould and Beavil, 1998; van der Burg et al., 2014). It possesses an additional constant region, CH₄, which particularly restricts it to bind to high affinity IgE receptors on mast cells and basophils (Flaherty, 2012). Upon the first encounter with the antigen, the plasma cells start to produce IgE molecules. The secreted IgE molecules bond to the high affinity IgE receptors (FcεRI) on the mast cells and basophils surfaces via their Fc portion, forming IgE-FcɛRI complexes. In this form, the half-life of IgE can be prolonged to two to three weeks or sometimes can even be retained on the cell surface for months (Actor, 2014; van der Burg et al., 2014). Upon the re-exposure to the same antigen, the antigen will cross-link with the IgE-FcεRI complexes which then lead to mast cell degranulation (Actor, 2014). Inhibition of IgE production and IgE-mast cell cross-linking are particularly essential to prevent the progression to mast cell degranulation.

There are several studies demonstrating that Lamiaceae species have a suppressive effect on IgE levels and IgE-mast cell cross-linking. These findings could be useful to recognize potential treatment options for allergic disorders. From the study of Sharma et al. (2018), results revealed that the essential oil of Mentha arvensis significantly decreased (P < 0.001) the serum IgE level in OVA-sensitized mice at a concentration of 200 µl/kg. The study successfully identified three compounds in the essential oil, which are menthol, menthone and 1,8-cineole, with particularly large percentage contents of menthol. However, the compound which contributed to the anti-allergic activity was not known (Sharma et al., 2018). Therefore, this provides a clue for further findings on the possible anti-allergic compound in future. In the work of Lee et al. (2006), it was proposed that the aqueous extract of Mosla dianthera exhibited anti-allergic effects through an in vivo model. When the mice were sensitized with compound 48/80 and anti-DNP IgE, intraperitoneal pretreatment of 1–1,000 mg/kg of aqueous extract resulted in a dose-related reduction in passive cutaneous anaphylaxis (PCA) reaction (Lee et al., 2006). Similar activities were displayed by the aqueous extract of species Perilla frutescens (Shin et al., 2000), Phlomis umbrosa (Shin et al., 2008), Salvia plebeia (Shin and Kim, 2002), Schizonepeta tenuifolia (Shin et al., 1999) and Teucrium japonicum aqueous extract (Kim et al., 2009). Sridevi et al. (2009) highlighted that the ethanolic extract of Ocimum sanctum at 400 mg/kg effectively reduced mortality (41%) due to anaphylactic shock-induced bronchospasm in tested subjects with a significant drop (P < 0.001) in serum IgE level to 25.80 ± 4.85 ng/ml (P < 0.001), as compared to sensitized control (125.06 ± 9.66 ng/ml). These findings confirm that the anti-allergic potential of O. sanctum is worthwhile to be further explored.

Over the past two decades, many studies have been conducted on P. frutescens species to explore and determine their anti-allergic potential. For example, Makino et al. (2001) isolated rosmarinic acid (1) and apigenin 7-O-[β-glucuronosyl (2→1) β-glucuronide] (2) from P. frutescens, which demonstrated anti-allergic activity with potent suppression of PCA reaction in antigen-challenged mice with inhibition of 41% (P < 0.01) and 32% (P < 0.05) respectively. Meanwhile, Ueda et al. (2002) isolated rosmarinic acid (1), caffeic acid and luteolin (3) from the leaves of P. frutescens and tested them for respective anti-allergic effects with oxazolone-induced ear edema test. Interestingly, only luteolin (3) showed an inhibitory effect on oxazolone-induced ear edema at 1 mg, whereas the other compounds did not show any inhibitory activity (Ueda et al., 2002). However, in a continuation of the work by Makino et al. (2003), the results suggested that the anti-allergic titer of rosmarinic acid (1) was 8 folds higher than the conventional anti-allergic drug tranilast, where 19 mg/kg of rosmarinic acid (1) was sufficient to achieve an equivalent PCA reaction suppression as 150 mg/kg of tranilast. Such a potent anti-allergic effect from rosmarinic acid (1) is certainly exciting and worthy to be further studied in the development of anti-allergic agents. In light of the study by Chen et al. (2015), an OVA-induced murine model of allergic asthma was employed. Results demonstrated a promising reduction in serum IgE level in the OVA-sensitized mice with 320 µg of ethanolic extract of P. frutescens leaves and hence amelioration of asthmatic symptoms (Chen et al., 2015). A similar reduction outcome was obtained in the study using Der f (Dermatophagoides farinae) mite-induced atopic dermatitis murine model with oral administration of P. frutescens leaves extract (Komatsu et al., 2016). In the latest work by Kamei et al. (2017), a new active principle, 8-hydroxy-5,7-dimethoxyflavanone (PDMF) (4) was isolated from the leaves of P. frutescens and demonstrated to have a potent suppressive effect on PCA reaction in anti-DNP IgE-stimulated-BALB/c mice. In addition, sneezing frequency, the allergic rhinitis nasal response, was also reduced with 1.5 mg of PDMF (4) after the BALB/c mice were challenged with Japanese cedar pollen grains (Kamei et al., 2017). Considering all these evidences together, P. frutescens possesses a great potential to be developed as an effective anti-allergic agent as shown in allergic asthma, atopic dermatitis and allergic rhinitis models.

According to Mizushina et al. (2014), the isolated compound carnosic acid (5), from the Rosmarinus officinalis leaves, possesses the ability to suppress PCA reaction at a dose of 100 mg/kg in sensitized mice with percentage inhibition of 67.1%. Interestingly, the inhibition caused by carnosic acid (5) was greater than that of tranilast, a frequently used anti-allergic drug. In fact, tranilast at 100 mg/kg only inhibited PCA reaction by 23.9% as compared to 67.1% suppression by carnosic acid (5), which was approximately 2.8 folds stronger than tranilast (Mizushina et al., 2014). Hence, it can be assumed that carnosic acid (5) has a strong potential to be used as anti-allergic compound. In another account, Schizonepeta tenuifolia demonstrated a 46.26% reduction in serum IgE level with a treatment of 1% of S. tenuifolia extract with phosphate buffered saline/olive oil (P/O) in proportion of (9:1) mixture in DNCB-induced BALB/c mice (Choi et al., 2013).

Salvia miltiorrhiza is a perennial herb which is well known to have tanshinones as principal bioactives. This plant is widely employed as traditional remedy, particularly in TCM (Li et al., 2015). Over the past decade, researchers have conducted studies to investigate its anti-allergic effect. Yang et al. (2008) proposed that a dose-dependent reduction of PCA reaction occurred at 25–100 mg/kg of ethanol extract of S. miltiorrhiza leaves (P < 0.001). When the IgE-stimulated rats were fed with 50 mg/kg of extract, the PCA reaction appeared to decrease by approximately 36.4% (Yang et al., 2008). A study conducted by Trinh et al. (2010a) highlighted the potency of the PCA reaction inhibition exhibited by the active principles of S. miltiorrhiza in the following manner: tanshinone I (6) (59%) > 15,16-dihydrotanshinone I (7) (49%) > tanshinone IIA (8) (35%) > cryptotanshinone (9) (32%). Another species from the same genus, S. plebeia, was reported to suppress Der f-induced elevated serum IgE level in BALB/c mice of atopic dermatitis model at a concentration of 100 mg/kg of ethanolic extract (Choi et al., 2014). Therefore, this finding suggests that S. plebeia could be a good candidate for atopic dermatitis treatment in future.

For more than 2,000 years, Chinese people have recognized the dried root of Scutellaria baicalensis as a very valuable medicinal herb and many people have regarded it as the golden herb due to its diverse medicinal uses. It is traditionally known as Huang-Qin and it is now listed officially in the Chinese Pharmacopoeia (Zhao et al., 2016). It is widely employed in TCM as treatment for cardiovascular diseases and bleeding disorders, such as hematemesis, hematuria and metrorrhagia (Yoon et al., 2009; Chen et al., 2013). In recent years, it has started to emerge as potentially possessing anti-allergic properties as many studies were actively carried out to investigate its anti-allergic effect. Lim et al. (2003) highlighted that S. baicalensis root contains active constituents that are particularly useful against allergic diseases. Four flavonoids were isolated from the root of S. baicalensis, wogonin (WG) (10), ganhuangenin (GHG) (11), wogonoside (WGS) (12) and 3,5,7,2’,6’-pentahydroxyl flavanone (PHF) (13). WG (10), GHG (11) and WGS (12) were found to potently suppress the production of IgE from the concanavalin A (ConA)-stimulated spleen lymphocytes obtained from Sprague–Dawley rats, at 10 and 100 µM, except PHF (13), even when tested with the highest dose (Lim et al., 2003). This outcome could be due to the structural differences with methoxy substitution and their respective positions on the polyphenolic ring (Lim, 2002). Meanwhile, Li et al. (2014) evaluated the efficacy of three different extracts (ethanol, acetone and ethyl acetate extract) of S. baicalensis against allergic reactions. Result revealed that ethanol extract showed the most promising outcome among the three extracts. It demonstrated the highest inhibitory activity against mice ear PCA reaction with percentage inhibition of 55.17% at a dose of 1.42 g/kg.With the same dose, the total serum IgE level was recorded at the lowest level (3.23 ± 1.05 IU/ml) as compared to treatment with the other two extracts and was comparable to the positive control, 0.1 g/kg of sodium cromoglycate (3.19 ± 1.14 IU/ml) (Li et al., 2014). In the latest work of Zhou et al. (2016), another active constituent, oroxylin A (14), isolated from S. baicalensis, was reported to cause a potent suppression (P < 0.01) in serum IgE levels in OVA-sensitized mice (Zhou et al., 2016). Other than oral administration, the efficacy of topical application on anti-allergic effect was also evaluated. In the study of Kim et al. (2013), the aqueous extract of S. baicalensis was topically applied onto DNFB-induced ear swelling and result suggested that the cutaneous reaction significantly reduced (P < 0.05) by 31% with 5% of extract (Kim et al., 2013). In a continuation of the study from the same researchers a few years later, in addition to cutaneous reactions, the serum IgE level in DNCB-induced contact dermatitis was also proven to be suppressed by topical treatment of S. baicalensis aqueous extract (Kim et al., 2016). Considering these results, S. baicalensis showed to be effective against IgE production and thus to have preventive effects towards allergy. Hence, it is suitable to be further developed as natural anti-allergic agent.

Furthermore, Zhou et al. (2014) demonstrated that 2-isopropyl-5-methylphenol (thymol) (15) from Thymus vulgaris portrayed a dose-dependent reduction trend in the production of IgE with the pretreatment of 4 mg/kg, 8 and 16 mg/kg of thymol (15) in OVA-challenged mice. Among the three concentrations used, 16 mg/kg of thymol (15) showed a comparable inhibition (P < 0.01) of OVA-specific IgE with positive control, dexamethasone (Zhou et al., 2014). Likewise, Vitex rotundifolia also showed similar inhibitory activity with 43% suppression in serum IgE level with the treatment of V. rotundifolia’s phytoconstituent, 1H,8H-pyrano [3,4-c] pyran-l,8-dione (PPY) (16) (Lee et al., 2009).

Inhibition of Mast Cells and Basophils Degranulation

A few species of Lamiaceae have successfully displayed compelling mast cell stabilizing activity. For instance, Vadnere et al. (2007) evaluated the mast cell stabilizing activity of Clerodendron phlomidis using in vivo murine system. The mast cell stabilization was achieved by using leaf aqueous extract of C. phlomidis in tested mice. Results revealed that 100 mg/kg of extract was able to confer protection as high as 73.25% from mast cell degranulation which was almost comparable to the standard drug, disodium cromoglycate, that exhibited a protection of 83.75% (Vadnere et al., 2007). Furthermore, O. sanctum leaves were also studied for their mast cell stabilization activity in the research of Choudhary (2010). The leaves were prepared into ethanolic extract and flavonoidal fraction isolated from ethanolic extract. The albino rats were fed orally with 100 and 200 mg/kg of leaf ethanolic extract after sensitization. The results demonstrated that 62.44 ± 3.80% and 67.24 ± 2.94% of mast cell stabilization activity was respectively recorded at 100 and 200 mg/kg of ethanolic extract. Meanwhile, significant inhibition of mast cell degranulation was also seen with 75 and 150 mg/kg of isolated flavonoidal fraction, which marked with 54.62 ± 1.76% and 60.48 ± 2.72% respectively (Choudhary, 2010). In addition to that, Patel and Deshpande (2011) employed an in vitro assay to evaluate the inhibitory activity of mast cell degranulation of Vitex negundo. The rat mesenteric mast cells were stimulated with compound 48/80 to induce mast cell degranulation. At the end of experiment, the numbers of intact and disrupted mast cells were counted and compared. Result suggested that the number of intact mast cells was more than that of disrupted mast cells after the pretreatment with 500 µg/ml of aqueous sub-fraction of V. negundo. The mast cell protection was significant, which marked with a percentage of 80.99 ± 0.7231% (P < 0.001) (Patel and Deshpande, 2011).

In a study conducted by Murata et al. (2010), it was found that Lycopus lucidus contains bioactive compounds that contribute to anti-allergic activity through inhibition of hyaluronidase enzyme (Murata et al., 2010). Hyaluronidase is an enzyme that cleaves hyaluronic acid in an extracellular matrix of connective tissue and is well known for being involved in allergic reactions by causing increased capillary permeability (Sakamoto et al., 1980). Inhibition of this enzyme is known to have suppressive effect on mast cell degranulation, which is a hallmark manifestation of allergy (Asada et al., 1997). Therefore, inhibition of hyaluronidase enzyme can thus become one of the targets to prevent the occurrence of allergy. Murata et al. (2010) isolated 22 compounds from dried aerial parts of L. lucidus. Amongst the 22 compounds isolated, only six of them were identified to possess hyaluronidase inhibitory activity. Isolated rosmarinic acid (1) was previously identified as a good hyaluronidase inhibitor. It was set as the positive control in this study and marked with hyaluronidase inhibition with IC₅₀ value of 309 µM. By comparison, the other five constituents were considered as strong hyaluronidase inhibitors with smaller values of IC₅₀ as compared to the positive control. The potencies of inhibition of the six phytoconstituents were arranged in a descending manner: clinopodic acid C (17) (IC₅₀ value: 80.1 µM) > clinopodic acid E (18) (IC₅₀: 82.8 µM) > lycopic acid A (19) (IC₅₀: 134 µM) > lycopic acid B (20) (IC₅₀: 141 µM) and scizotenuin A (21) (IC₅₀: 241 µM) > rosmarinic acid (1) (IC₅₀: 309 µM) (Murata et al., 2010). This has provided scientific evidence to support future research on L. lucidus for its anti-allergic potential. Similarly, in the work of Ippoushi et al. (2000), it was found that the leaf methanolic extract of Melissa officinalis, which is also commonly known as lemon balm, possessed the highest hyaluronidase inhibition among 46 plants tested, achieving as low as only 1.0 ± 0.3% of enzyme activity (Ippoushi et al., 2000). The potency of lemon balm in suppressing hyaluronidase is worthy to be further explored, so that it can become an anti-allergic therapeutic in future. Taken together, these outcomes suggest that these species can be used as potential novel anti-allergic therapeutic agents through mast cell degranulation inhibition.

Inhibition of Allergic Mediators and Secretory Granules

Following mast cell degranulation, various chemical mediators are released from the mast cells or basophils. One of the most prominent mediators release from mast cells is histamine. Histamine was discovered as a potent vasoactive agent in 1911 by Dale and Laidlaw and recognized as a major contributor to allergic diseases (White, 1990; Xie and He, 2005). Histamine participates in both early and late phase allergic reactions. In the early phase of allergic reactions, the histamine released from degranulated mast cells and basophils triggers an array of acute allergic symptoms which can be seen within minutes. Some of the examples of allergic symptoms are increased vascular permeability causing redness, swelling, itchiness and pain, bronchoconstriction, anaphylaxis, etc. (Jutel et al., 2009). The onset of immediate allergic reactions is followed by the late phase responses (LAR) which contribute to more sustained inflammation. During the LARs, histamine acts as the chemoattractant to effector cells, notably T_H2 lymphocytes, eosinophils, and basophils for recruitment to the inflammatory site and hence is implicated in the pathogenesis of late phase chronic allergic inflammatory reactions (He et al., 1997; Galli et al., 2008).

In addition, β-hexosaminidase is another popular biomarker used to evaluate mast cell degranulation in many the allergy studies (Kuehn et al., 2010). Similar to histamine, it is produced and stored as secretory granules within mast cells and basophils. However, unlike histamine, it does not have any significant involvement or contribution to allergic reactions. Instead, β-hexosaminidase was reported to have the ability to confer host defense against bacterial infection (Fukuishi et al., 2014). Nevertheless, it is widely employed as a mast cell degranulation marker because it is released together with histamine during the degranulation process (Cota et al., 2012; Huang et al., 2016). As compared to histamine, the release of β-hexosaminidase is slower and persists for a longer time. This makes β-hexosaminidase a better indicator for mast cell degranulation detection than histamine (Huang et al., 2016). Apart from histamine and β-hexosaminidase, mast cells also contain other mediators like eicosanoids, such as prostaglandin D₂ and leukotrienes C₄, chemotactic factors and immunoregulatory cytokines (Xiang et al., 2001; Parikh et al., 2003). During degranulation, these substances are also released from mast cells and basophils through exocytosis. Therefore, they are also used as biomarkers of mast cell degranulation in the allergy studies.

Anti-allergic activity of plants can be evaluated through the potency of the plant in suppressing the mediators, secretory granules or any functional changes induced by the mediators as aforementioned. In a study by Vadnere et al. (2007), a significant inhibition (P < 0.05) in histamine-induced tracheal contraction was seen at concentrations of 4 and 10 mg/ml of leaf aqueous extract of Clerodendron phlomidis on isolated goat tracheal chain. At the same time, intraperitoneally administered leaf aqueous extract of C. phlomidis at concentrations of 100 mg/kg showed a potent reduction (P < 0.05) in histamine-induced vascular leakage in sensitized murine model (Vadnere et al., 2007). Lee et al. (2011) explored the possibility of C. trichotomum on anti-asthmatic potential employing in vivo guinea pig model. A phenylpropanoid glycoside, acteoside (22) was isolated from the ethyl acetate fraction from C. trichotomum leaves. At dose 25 mg/kg, specific airway resistance (sRaw) was significantly (P < 0.05) inhibited in immediate phase response (IAR) and LAR in ovalbumin-challenged guinea pigs by 32.14% and 55.88% respectively. The result seemed promising as it was superior to positive controls, 5 mg/kg dexamethasone (55.88%) and 10 mg/kg disodium cromoglycate (52.94%) in LAR. Meanwhile, concentration of 50 mg/kg of acteoside (22) was significantly (P < 0.05) against the histamine release and phospholipase A₂ (PLA₂) activity in BALF in which the histamine content was marked with 26.40 ± 1.96% and PLA₂ activity recorded with only 28.08 ± 2.05% (Lee et al., 2011b).

Park et al. (2010) investigated the anti-allergic potential of Clinopodium gracile using both in vivo and in vitro studies. In the in vivo study, the mice were treated with compound 48/80 to induce systemic anaphylaxis after the pretreatment with intraperitoneal administration of aqueous extract of C. gracile with concentrations ranging from 1–100 mg/kg. The mortality of mice due to anaphylactic shock was assessed. Results revealed that the systemic anaphylactic death event was reduced concentration-dependently, in which the doses of 50 mg/kg and above were identified as the effective doses that prevented the mice from fatal anaphylactic shock. The reduction of systemic anaphylaxis corresponded to the reduced serum histamine. On the other hand, aqueous extract of C. gracile was also shown to significantly (P < 0.05) suppress the release of histamine in in vitro RPMC and HMC-1 cells assays. The suppressive effect occurred in a dose-dependent manner with the concentrations ranging from 1–100 µg/ml. As aforementioned, calcium influx is pivotal in the releasing of secretory granules and mediators from mast cell degranulation. Therefore, a reduction of intracellular calcium level can result in the inhibition of chemical mediators such as histamine and β-hexosaminidase release (Oka et al., 2005). In the same study, intracellular calcium level was also evaluated in HMC-1 cell line. Results showed that pretreatment with aqueous extract of C. gracile caused a suppression in intracellular calcium level induced by PMACI. Hence, this finding is supported by the theory which suggests the involvement of intracellular calcium in the inhibition of histamine release from mast cells. In addition, mast cell-mediated hypersensitivity also occurs with the involvement of NF-κB and inflammatory cytokines. NF-κB activation is essential to regulate downstream pro-inflammatory cytokine expression, such as TNF-α and IL-6 which play a critical role in initiating and sustaining the allergic inflammatory responses (Blackwell and Christman, 1997). Therefore, the attenuation of NF-κB activation causes a reduction in downstream inflammatory cytokines gene expression and hence produces suppressive effects in allergic inflammation. NF-κB-dependent transcriptional activity was evaluated through luciferase activity assay. Results revealed that treatment with aqueous extract significantly (P < 0.05) inhibited the activation of NF-κB and its downstream cytokine expression (TNF-α and IL-6) at doses of 1 and 10 µg/ml. These findings provide evidence that C. gracile is has the potential to be developed as an anti-allergic agent in the future, given its potential in reducing allergic inflammation (Park et al., 2010). Similarly, aqueous extracts of Dracocephalum argunense (Kim and Shin, 2006; Kim et al., 2006), Elsholtzia ciliata (Kim et al., 2011), Isodon japonicus (Kim et al., 2004; Shin et al., 2004), Lycopus lucidus (Shin et al., 2005), Mentha arvensis (Shin, 2003), Mosla chinensis (Kim et al., 2012), M. dianthera (Lee et al., 2006), Perilla frutescens (Shin et al., 2000), Phlomis umbrosa (Shin et al., 2008), Pogostemon cablin (Yoon et al., 2016), Prunella vulgaris (Shin et al., 2001), Salvia plebeia (Shin and Kim, 2002), Schizonepeta tenuifolia (Shin et al., 1999), Stachys riederi (Shin, 2004), Teucrium japonicum (Kim et al., 2009) and Vitex rotundifolia (Shin et al., 2000) also exhibited similar outcomes as portrayed in the experiment conducted using C. gracile.

In another account, Inoue et al. (2001) prepared four different extracts and separated fractions (50% ethanolic extract, water eluate, 50% ethanolic eluate and ethanolic eluate) from M. piperita leaves to investigate their anti-allergic potential on allergic rhinitis. It was found that 50% ethanolic eluate exhibited the most potent inhibition to histamine release, with an IC₅₀ value of 2.55 µg/ml and exerted its antagonizing effect on nasal responses at doses of 300 and 1,000 mg/kg in antigen-challenged rats (Inoue et al., 2001). In the continuation of their previous work, Inoue et al. (2002) focused on the 50% ethanolic eluate to isolate the active compounds responsible for the anti-allergic effect. Following the isolation of the compounds, a total of eight chemical constituents were considered. However, among the eight compounds, luteolin-7-O-rutinoside (31) was found to be the most effective in suppressing histamine release from compound 48/80-induced RPMC with IC₅₀ value of 21.9 µM. The nasal responses were reduced at doses of 100 and 300 mg/kg of luteolin-7-O-rutinoside (31) (Inoue et al., 2002). Recently, Sato and Tamura (2015) evaluated anti-allergic activity of M. piperita leaves using β-hexosaminidase assay. Five major flavonoids components, 5,6,4’-trihydroxy-7,8-dimethoxyflavone (32), 5,6,4’-trihydroxy-7,8,3’-trimethoxyflavone (33), 5,6-dihydroxy-7,3’,4’-trimethoxyflavone (34), 5,6-dihydroxy-7,8,3’,4’-tetramethoxyflavone (35) and 5,6-dihydroxy-7,8,4’-trimethoxyflavone (36) isolated from leaves dichloromethane extract were all shown to possess potent anti-allergic activity. However, 5,6,4’-trihydroxy-7,8,3’-trimethoxyflavone (33) and 5,6-dihydroxy-7,8,3’,4’-tetramethoxyflavone (35) proved to have the strongest inhibitory activity on β-hexosaminidase release from RBL-2H3 cells, which were recorded with IC₅₀ values of 2.4 and 3.0 µM respectively. Their safety profiles also seemed promising as they had relatively lower cytotoxicity than another typical natural anti-allergic substance, luteolin (3) (Sato and Tamura, 2015). Therefore, this might indicate that 5,6,4’-trihydroxy-7,8,3’-trimethoxyflavone (33) and 5,6-dihydroxy-7,8,3’,4’-tetramethoxyflavone (35) can be potentially developed into safe and effective anti-allergic agents. Another species from the same genus, M. spicata, was shown to have similar activity with its flavones, 5,6,4’-trihydroxy-7,8,3’-trimethoxyflavone (33) and 5,6-dihydroxy-7,8,3’,4’-tetramethoxyflavone (35) and aliphatic glycoside, (3R)-1-octan-3-yl β-D-glucopyranoside (37). The potency of inhibitory activities was arranged in a descending manner: 5,6,4’-trihydroxy-7,8,3’-trimethoxyflavone (33) with IC₅₀ of 6.4 µM > 5,6-dihydroxy-7,8,3’,4’-tetramethoxyflavone (35) with IC₅₀ of 56 µM > (3R)-1-octan-3-yl β-D-glucopyranoside (37) with IC₅₀ of 560 µM. Although (3R)-1-octan-3-yl β-D-glucopyranoside (37) showed the weakest activity, it was however a great discovery as this was the first time an anti-histaminic activity from an aliphatic glycoside was recorded (Yamamura et al., 1998).

In 2007, Cariddi et al. investigated the anti-allergic activity of Minthostachys verticillata. The experiment was conducted using basophils from allergic patients pretreated with essential oil extracted from the stems and leaves of M. verticillata and followed by β-hexosaminidase assay. Results suggested that the essential oil showed a promising suppressive effect on β-hexosaminidase release with percentage inhibition ranging from 32.15% to 39.72%, which was comparable to dexamethasone (39.75%) and theophylline (41.63%) (Cariddi et al., 2007). A few years later, Cariddi et al. (2011) carried out an in-depth study on the components of the essential oil extracted from M. verticillata to identify the constituent responsible for anti-allergic effect. Limonene (38), pulegone (39) and menthone (40) were found to be present in the essential oil. Results suggested that limonene (38) appeared to be the most effective compound in the inhibition of β-hexosaminidase release from human basophils as compared to the other two compounds, pulegone (39) and menthone (40). It was shown that 20 µg/ml of limonene (38) was able to achieve inhibitory effect while the other two compounds both required a higher concentration of 40 µg/ml to reach the desired inhibition. The inhibitory effect could be achieved at a lower concentration (10 µg/ml) when the compounds were used in combination (Cariddi et al., 2011). This can be explained with the synergistic effect of the three compounds.

Jeon et al. (2014) highlighted that luteolin (3) isolated from the leaves of P. frutescens potently (P < 0.05 to P < 0.001) suppressed histamine release from compound 48/80-stimulated RPMC at 5, 10 and 20 µM in a dose-related manner. The expression and production of TNF-α and IL-1β were significantly (P < 0.05 to P < 0.001) reduced in PMACI-stimulated HMC-1 cells, with inhibition rates of 31.9%–76.8% and 27.3%–81.2% respectively, at the range of 5–20 µM of luteolin (3) (Jeon et al., 2014). Likewise, Ueda et al. (2002) also reported a similar activity on the TNF-α production with a dose range of 1–1,000 µg of luteolin (3) in sensitized mice. A the same time, in vivo studies conducted on ICR mice demonstrated that compound 48/80- or serotonin-induced scratching behavior and vascular permeability were dose-dependently decreased at concentrations of 5, 10 and 20 mg/kg of luteolin (3) (Ueda et al., 2002). According to a study conducted by Heo et al. (2011) on the anti-atopic effect of P. frutescens, the aqueous fraction demonstrated a promising outcome whereby the DNFB-sensitized mice experienced a 35% reduction in ear swelling symptoms with the administration of 100 µg/ml. In light of the study carried out by Zhu et al. (2014), rosmarinic acid methyl ester (41) was found to be able to produce a stronger β-hexosaminidase release inhibition than that of rosmarinic acid (1) extract prepared from P. frutescens leaves using supramolecular technique, in which the IC₅₀ values were marked with 9.9 ± 0.8 and 52.9 ± 6.7 µg/ml respectively. Furthermore, Kamei et al. (2017) suggested that PDMF (4) significantly (P < 0.05) inhibited histamine release from RBL-2H3 cells with an IC₅₀ value of 68.5 µM which was much more potent than other polyphenols. Hence, this finding deduced that PDMF (4) is a newly emerged potent anti-allergic component.

In light of a study by Ryu et al. (2000), 2α,3α-dihydroxyurs-12-en-28-oic acid (42) isolated from the methanolic extract of Prunella vulgaris possessed a significant (P < 0.01) inhibitory activity on β-hexosaminidase release from RBL-2H3 cells with IC₅₀ of 57 µM. Another histamine release assay conducted recently by Choia et al. (2016) intended to provide more evidence on the anti-allergic effect of P. vulgaris. The results suggested that three triterpenoids isolated from the spike of P. vulgaris exhibited significant inhibitory effects on histamine release from HMC-1 cells. The active principles represented by β-amyrin (43), 2α,3α,23-trihydroxyursa-12,20(30)-dien-28-oic acid (44) and euscaphic acid (45) demonstrated a percentage inhibition of 46.7%, 57.9% and 54.2% respectively. It is noteworthy that 2α,3α,23-trihydroxyursa-12,20(30)-dien-28-oic acid (44) was isolated for the first time and possessed promising activity against histamine release (Choia et al., 2016). Putting all the evidence together, P. vulgaris is experimentally proven to have high potential to be developed into efficacious anti-allergic agent. On the other hand, Mizushina et al. (2014) highlighted that carnosic acid (5) from Rosmarinus officinalis leaves significantly inhibited the release of β-hexosaminidase from RBL-2H3 cells at 10 µM.

Likewise, Choi and Kim (2004) and Ryu et al. (1999) reported that 15,16-dihydrotanshinone-I (7) and cryptotanshinone (9) isolated from the root of S. miltiorrhiza showed to have IC₅₀ values of 16 ± 2.4 and 36 ± 3.7 µM on β-hexosaminidase release. Additionally, the ethanolic extract of S. miltiorrhiza also inhibited other chemical mediators, such as leukotriene C₄ with a IC₅₀ value of 2.6 µg/ml, COX-1 and COX-2-dependent prostaglandin D₄ with IC₅₀ values of 3.96 and 21.54 µg/ml respectively (Yang et al., 2008). With the aid of findings from Yang et al. (2008), Li et al. (2015) successfully identified 15,16-dihydrotanshinone-I (7) as the compound responsible for the inhibition of intracellular calcium level, hence suppressing the downstream release of leukotriene C₄ and prostaglandin D₄ from activated bone marrow-derived mast cells (BMMC). The inhibition percentage achieved was as high as 90% with a dose of 20 µM of 15,16-dihydrotanshinone-I (7) (Li et al., 2015).

In addition, the four active constituents isolated from Scutellaria baicalensis root, wogonin (WG) (10), ganhuangenin (GHG) (11), wogonoside (WGS) (12), 3,5,7,2’,6’-pentahydroxyflavanone (PHF) (13), all showed a significant suppression of histamine (P < 0.01) and leukotriene B₄ (P < 0.01) release from A23817-induced rat peritoneal exudate cells (PEC) at a concentration of 100 µM (Lim, 2003). Moreover, Kim et al. (2010) reported that baicalin (46) isolated from the roots of S. baicalensis possessed a significant (P < 0.001) inhibitory activity of histamine and leukotriene release from OVA-sensitized guinea pig lung mast cells at 10, 30 and 60 µg. The histamine inhibition rates recorded with 47.1%, 59.4% and 61.5% while leukotriene production remarkably suppressed by 37.9%, 47.3% and 50.4% with the pretreatment of the three different doses of baicalin (46). Interestingly, studies showed that the standardized extract of baicalin (46) at high dose produced a greater inhibition on both histamine and leukotriene production as compared to pure baicalin (46). Results revealed that 70.4% of histamine suppression and 78% of leukotriene inhibition (P < 0.001) were found at high dose (60 µg) of standardized extract. However, the percentage inhibitions produced by low and medium dose standardized extract treatments were smaller than that of pure baicalin (46) (Kim et al., 2010). In a very interesting study conducted by (Trinh et al., 2010b), baicalin (46) isolated from rhizome of S. baicalensis was metabolized into baicalein (47) and oroxylin A (14) followed by oral administration. All three compounds possessed inhibitory activity against histamine-induced scratching behavior and vascular permeability in in vivo ICR mice model at doses of 20 and 50 mg/kg. However, the metabolite, oroxylin A (14) showed the most potent inhibition instead of its parent compound, baicalin (46). In the study of Li et al. (2014), it was suggested that ethanol extract potently inhibited (P < 0.01) 4-AP-induced allergic skin pruritus, histamine-induced mice paw swelling and cutaneous anaphylactic-ear swelling at 1.42 g/kg. For instance, ear swelling inhibition produced by 1.42 g/kg of ethanol extract (47.10%) was superior to that of the positive control, 0.1 g/kg of cromolyn sodium (32.43%) (Li et al., 2014). In a food allergy study, 25 mg/kg of ethanol extract of S. baicalensis conferred 60% protection to food allergy anaphylactic death in OVA-sensitized mice (Shin et al., 2014b). Henceforth, these promising experimental outcomes make the anti-allergic potential of S. baicalensis worthwhile to be further explored.

Regulation of T Cell Responses

It has been long recognized that allergic sensitization is led by lymphocytes (Zhang et al., 2014). There are various types of T lymphocytes, such as CD4⁺, CD8⁺, and natural killer T cells, in which each population produces response to allergens with different capacities. Among the different types of T lymphocytes, CD4⁺ T cells are predominantly implicated in the pathogenesis of allergy. With the expression of major histocompatibility complex (MHC) class II molecules and allergen specific T-cell receptors (TCR), CD4⁺ T cells are able to recognize peptide antigen presented by antigen-presenting cells (APCs). Antigen recognition is then led to the activation of downstream immune responses, such as allergic inflammatory cascade (Kallinich et al., 2007; Woodfolk, 2007).

Naive CD4⁺ T cells can be differentiated towards T_H1, T_H2, T_H17 and Treg phenotypes (Zhang et al., 2014). T_H2 subsets are particularly renowned as the major contributors to the immunopathology of allergy. Late-phase allergic responses are provoked by the persistent existence of allergens, leading to T-cell activation (Palomares et al., 2010). Activated T_H2 lymphocytes play a critical role in the production of T_H2 cytokines (IL-4, IL-5, IL-9 and IL-13) (Deo et al., 2010; Ozdemir et al., 2010). IL-4 and IL-13 are crucial to the development of T_H2 cells and induction of IgE isotype switching from B cells, which are the major risk factor for the development of allergic asthma (Steinke and Borish, 2001; Woodfolk, 2007). IL-5 mainly mediates eosinophil recruitment and increases eosinophil survival while IL-9 stimulates mast cells and basophils (Woodfolk, 2007; Ozdemir et al., 2010). In contrast, T_H1 cells differentiation occurs in response to microbial activation of APC under the influence of IL-12 (Deo et al., 2010). These cells orchestrate the production of IL-2, IFN-γ and TNF-β (Romagnani, 2004). T_H1 cytokines tend to produce pro-inflammatory responses which are important in killing phagocytosed microbes and perpetuating autoimmune responses (Berger, 2000). Recent evidence demonstrate that minimal microbial exposure in early life causes the T_H1/T_H2 balance in the immune system to skew towards the pre-allergic T_H2 response (Berger, 2000; Deo et al., 2010).

Recently, Treg cells emerged as the key component in the sensitization stage of allergy (Zhang et al., 2014). The transcriptional factor, FOXP₃ serves as a lineage specification factor of Treg cells which is required for the differentiation of Treg cells (Rudensky, 2011; Noval Rivas and Chatila, 2016). FOXP_3, which is dominantly expressed by Tregs, inhibits T_H2 cells activation, thus reducing the production of T_H2 cytokines, which is essential during the effector phase of allergic reactions (Albano et al., 2013). Treg cells also suppress allergic inflammation through direct action on mast cells, basophils and eosinophils (Palomares et al., 2010; Noval Rivas and Chatila, 2016). It has been shown that constitutive FOXP⁺ Treg controls the symptomatic phase of mast cell activation and IgE-dependent anaphylaxis in mice (Kanjarawi et al., 2013). Apart from that, T_H17 cells and their corresponding cytokine, IL-17, are also highlighted for their involvement in the progression of T_H2-mediated allergic disorders (Oboki et al., 2008). A balance between T_H17 and Tregs is essential for immune homeostasis. Excessive or exaggerated T_H17 function and elevated T_H17 cells together with a defect in Treg function or reduction in Treg population lead to the development of allergic disorders, like allergic asthma and rhinitis. Restoring the balance between T_H17 and Treg can promote the resolution of allergic disorders, such as allergic inflammation seen in allergic asthma (Albano et al., 2013).

Natural compounds with the ability to regulate T cell responses have a great potential in the development of novel anti-allergic therapeutic agents. In this review, there are several plants described to have compelling effects on the down-regulation of T_H2 cytokines, re-establishment of T_H1/T_H2 balance, T_H17 inhibition and promotion of Treg cells functions. For example, 100 mg/kg of ethanolic extract of Mentha haplocalyx was reported to exhibit significant (P < 0.05) inhibition on the expression and production T_H2 cytokines (IL-4 and IL-5) in BALF (Lee et al., 2011a). Besides, Costa et al. (2012) evaluated the effectiveness of Ocimum gratissimum in alleviating allergic asthma. Results revealed that Blomia tropicalis mite-immunized and challenged mice receiving 100 mg/kg of O. gratissimum methanolic extract had a significant reduction (P < 0.05) in IL-4 level in BALF in relation to those of the untreated group (Costa et al., 2012). In addition, Trinh et al. (2010a) stated that tanshinone I (6), 15,16-dihydrotanshinone I (7), tanshinone IIA (8) isolated from Salvia miltiorrhiza possessed inhibitory activity on IL-4 and TNF-α expression in IgE-antigen complex-stimulated RBL-2H3 cells at a dose of 50 µM. The ability of S. miltiorrhiza in inhibiting IgE-switching cytokine, IL-4 and pro-inflammatory cytokine, TNF-α is thought to be a spring for allergic reactions improvement (Trinh et al., 2010a). Another species from the same genus, S. plebeia, was reported to reduce symptoms of atopic dermatitis through regulation of T cells responses (Choi et al., 2014). At a concentration of 100 mg/kg of ethanol extract of S. plebeia, the expression of T_H1, T_H2 and T_H17 cytokines was significantly reduced (P < 0.05) in Der-f-induced atopic dermatitis-like skin lesions (Choi et al., 2014). On the other hand, Schizonepeta tenuifolia demonstrated a significant reduction (P < 0.05) of IFN-γ, IL-4 and IL-13 in IgE-induced allergic model of RBL-2H3 cells with 100 µg/ml of aqueous extract. In the same study, S. tenuifolia aqueous extract showed no cytotoxicity even at a higher concentration up to 1,000 µg/ml (Lin et al., 2018). However, a more thorough and detailed toxicological investigation is required to develop a more evidence-based safety profile.

In another account, Perilla frutescens also suppressed T_H2 responses which then contributed to anti-allergic effect (Sanbongi et al., 2004). Results demonstrated that the expression and production of T_H2 cytokines (IL-4 and IL-5) were potently inhibited by daily oral administration of 1.5 mg of rosmarinic acid (1) from P. frutescens (P < 0.05) in in vivo house mite-challenged murine model (Sanbongi et al., 2004). Meanwhile, Chen et al. (2015) reported that IL-5 and IL-13 were diminished in OVA-induced allergic asthma murine model with ethanolic extract of P. frutescens leaves. Interestingly, aqueous fraction of P. frutescens leaves showed its effectiveness in alleviating atopic dermatitis through balancing of T_H1 and T_H2 cells (Heo et al., 2011). The effect was achieved by suppressing the release of IL-31, which is a T_H2 cytokine that promotes allergic symptoms like pruritus and allergic skin disorders (Heo et al., 2011; Meng et al., 2018). At the same time, the T-bet protein expression was augmented with 100 µg/ml of P. frutescens aqueous fraction (Heo et al., 2011). T-bet protein expression is essential for T_H1 cell differentiation (Chatila et al., 2008). Therefore, the combination of suppressed IL-31 and augmented T-bet protein expression resulted in T_H1/T_H2 balance and hence alleviation of allergic symptoms. Besides, Komatsu et al. (2016) suggested that the CD4⁺/CD8⁺ ratio in splenic T lymphocytes obtained from Der f-induced atopic dermatitis NC/Nga mice was decreased from 1.82 ± 0.32% to 1.50 ± 0.07% after receiving treatment of Perilla leaves extract. This suppression is believed to be associated with the T_H1 and T_H2 balance (Komatsu et al., 2016). Additionally, Liu et al. (2013) employed an in vitro assay to investigate the effect of P. frutescens extract on Der p 2-challenged human bronchial epithelial cells BEAS-2B cells. Result displayed that the pro-allergic cytokines (IL-4, IL-5, IL-13) and GM-CSF productions were all dose-dependently reduced (P < 0.05) in Der p 2-stimulated BEAS-2B cells with treatment of 5–50 µg/ml of methanolic extract of P. frutescens leaves (Liu et al., 2013).

In a recent work by Bae et al., 2016, Scutellaria baicalensis showed to be effective in ameliorating ovalbumin-induced food allergy murine model through the regulation of Treg cells with its natural flavonoid compound, baicalein (47). Results revealed that baicalein (47) was able to increase Treg cells population through induction of CD4⁺ FOXP₃⁺ T cell differentiation without causing any cytotoxicity at concentrations smaller than 10 µmol/L (Bae et al., 2016). In light of a study by Jung et al. (2017), linoleic acid (50) in hexane fraction from ethanol extract of S. baicalensis roots was reported to cause a significant suppression (P < 0.05) in the production of pro-allergic cytokines (IL-4, IL-5, IL-10 and IL-13) and enhancement of secretion of T_H1 cytokines (IFN-γ (P < 0.05) and IL-12 (P < 0.01)). The fact that a fatty acid from a plant can contribute anti-allergic effect through restoration of T_H1/T_H2 balance is a new discovery (Jung et al., 2017). A similar outcome was noted in a food allergy murine model conducted by Shin et al. (2014b) with S. baicalensis ethanol extract. Interestingly, the ethanol extract also down-regulated the IL-17 level produced by T_H17 and hence produced effective prevention to food allergy (Shin et al., 2014b). Within the same year, the same group of researcher successfully discovered that the active compounds isolated from S. baicalensis, represented by wogonin (WG) (10), baicalin (46) and baicalein (47), all inhibited the T_H2 cytokines (IL-4, IL-5, IL-10 and IL-13) and IFN-γ at dose of 50 µmol/L in an ex vivo study. However, only WG (10) was able to produce inhibition without affecting cell viability as compared to the other two active compounds (Shin et al., 2014a). This finding suggests that WG (10) could be a safer anti-allergic compound at a higher dose, but its toxicity profile should be further investigated with more extensive toxicity testings. Kim et al. (2010) focused on the therapeutic potential of S. baicalensis on atopic dermatitis. In the experiment, the male NC/Nga mice were orally fed with aqueous extract of S. baicalensis after atopic dermatitis-like skin lesion was conventionally developed in the mice. The feeding process was continued for 6 weeks. After 6 weeks, blood was drawn from the mice and analyzed to measure the level of cytokine release. Interestingly, the results revealed that S. baicelensis aqueous extract only exhibited specific inhibition on IL-5 (P < 0.05) at a dose of 50 mg/kg. There was no significant change in the level of IL-4 and IL-10 between S. baicalensis treatment group and control group (Kim et al., 2010). However, in the study by Kim et al. (2016), it was proposed that topical application of aqueous extract of S. baicalensis onto the DNCB-induced contact dermatitis can significantly (P < 0.05) reduce the level of IL-4 and IFN-γ in BALB/c mice skin cells. Zhou et al. (2016) reported that oroxylin A (14) isolated from S. baicalensis was effective against allergic asthma with significant inhibition (P < 0.01) of IL-4, IL-5 and IL-13 production at doses of 15, 30 and 60 mg/kg of oroxylin A (14). In conclusion, S. baicalensis has good therapeutic potential in allergic diseases, such as atopic dermatitis, food allergy and allergic asthma through regulation of T cell responses.

With the intention to explore the effectiveness of 2-isopropyl-5-methylphenol (thymol) (15) isolated from Thymus vulgaris in alleviating allergic asthma, Zhou et al. (2014) employed an in vivo allergic murine model of asthma. Results revealed that thymol (15) effectively reduced the symptoms of allergic asthma through dose-dependent inhibition of IL-4, IL-5 and IL-13 production at 4, 8 and 16 mg/kg in OVA-challenged mice. Particularly, a potent reduction (P < 0.01) of OVA-induced T_H2 cytokines was recorded at 16 mg/kg of thymol (15) (Zhou et al., 2014). Apart from thymol (15), carvacrol (51) from T. vulgaris was reported to effectively inhibit the production of IL-2, IFN-γ, IL-4 and IL-17 cytokines as well as T-bet expression in the ex vivo splenocytes cultures (Gholijani and Amirghofran, 2016). On the contrary, both thymol (15) and carvacrol (51) led to an increase in the level of IL-10 and TGF-β in mice splenocytes cultures (Gholijani and Amirghofran, 2016). Henceforth, the regulation of T cell responses that was shown by thymol (15) and carvacrol (51) suggests that these two compounds potentially benefit allergic disorders. Likewise, Lee et al. (2009) also highlighted that the active constituent of Vitex rotundifolia, 1H,8H-pyrano [3,4-c] pyran-l,8-dione (PPY) (16) potently suppressed the IL-5 production in BALF by 34%. Furthermore, hydro-ethanolic extract prepared from Zataria multiflora seeds was reported to restore T_H1/T_H2 balance by enhancing the ratio of IFN-γ/IL-4 in in vivo and in vitro assays (Boskabady et al., 2013). Another study conducted by Kianmehr et al. (2017) further supported the above finding. In addition to enhanced IFN-γ/IL-4 ratio, Z. multiflora hydro-ethanolic extract also caused potentiation of T_H1 and suppression effect on T_H2 and T_H17 cells, which led to therapeutic effect on allergic asthma in ovalbumin-sensitized BALB/c mice. Results showed that the number of Treg cells (P < 0.001), T_H1/T_H2 ratio (P < 0.001), IFN-γ/IL-4 ratio (P < 0.01), IFN-γ (P < 0.05) and FOXP₃ (P < 0.001) expression were increased significantly. Meanwhile, T_H2 and T_H17 cells (P < 0.01 to P < 0.001), IL-4, IL-17 and TGF-β (P < 0.05 to P < 0.001) expressions were significantly reduced in sensitized mice spleen cells (Kianmehr et al., 2017). In conclusion, Z. multiflora is able to produce anti-allergic therapeutic effects on type I hypersensitivities like allergic rhinitis, allergic asthma and urticarial by regulating T cell responses.

Suppression of Eosinophils Migration

Eosinophils are long-lived circulating granulocytes which play a central role in promoting allergic reactions. They arise and differentiate in bone marrow and are then widely distributed in the blood, lungs, thymus, uterus, adipose tissues, spleen, etc and lastly readily migrate to the allergic sites (Fulkerson and Rothenberg, 2013; Wen and Rothenberg, 2016). They migrate to the target sites with the influence of chemoattractant, eotaxin and particularly, IL-5 for eosinophil proliferation, survival and priming (Wen and Rothenberg, 2016). Unlike mast cells and basophils with extensive expression of high affinity IgE receptors, eosinophils have a minimal expression of FcεRI. Nevertheless, they express a great range of cell surface molecules, such as receptors for IgG and IgA, complement receptors, cytokine receptors, whose aggregation can trigger eosinophils activation and development (Rigoni et al., 2018). Often, the number of eosinophils is greatly elevated in circumstances associated with allergic disorders, such as allergic rhinitis, allergic asthma and atopic dermatitis (Stone et al., 2010). Henceforth, natural products with the ability to suppress eosinophil recruitment or infiltration to allergic sites can be the noteworthy pharmacological therapeutic options for allergic disorders.

Several Lamiaceae plant species have demonstrated their suppressive effects on the eosinophil recruitment. Vadnere et al. (2007) showed that intraperitoneally administration of 100 mg/kg leaf aqueous extract of Clerodendron phlomidis produced a potent antagonizing effect towards milk-induced eosinophilia by showing a marked reduction in blood eosinophil count in mice with the value of 13.8 ± 2.4 as compared to the control group (43.1 ± 1.25). This reduction is indicative of the effectiveness of C. phlomidis in conferring anti-allergic effect. Another species under the same genus, C. serratum, was evaluated by Bhangare et al. (2012) to study the anti-allergic effect of its aqueous extract prepared from root and stem using different concentrations. Results demonstrated that all extracts used possessed inhibitory activity on milk-induced leukocytosis. However, the most potent activity was shown by high dose (260 mg/kg) aqueous root extract as compared to low dose (130 mg/kg) or any doses of aqueous stem extracts. This extract accorded a more significant protection than the standard used, dexamethasone from milk-induced leukocytosis (Bhangare et al., 2012). This finding suggests that C. serratum might be a potential candidate for anti-allergic therapy. Moreover, Lee et al. (2011b) reported that acteoside (22) isolated from C. trichotomum at 25 mg/kg significantly (P < 0.05) reduced total leukocytes in BALF from 31.25 ± 6.12 × 10⁵ to 25.23 ± 4.72 × 10⁵. At 50 mg/kg, 29.70% of eosinophil infiltration suppression was achieved in guinea pigs model (Lee et al., 2011b). Similar outcome was seen with 200 µl/kg of Mentha arvensis essential oil (Sharma et al., 2018) and 100 mg/kg of ethanolic extract of M. haplocalyx in OVA-challenged mice (Lee et al., 2011a). In an attempt to investigate the effect of Ocimum gratissimum in alleviating respiratory allergy, Costa et al. (2012) carried out an experiment through in vivo model using male A/J mice. The mice were orally fed with 25, 50 or 100 mg/kg of methanolic leaves extract after subcutaneously injecting Blomia tropicalis antigen for respiratory allergy induction. Results revealed that O. gratissimum significantly suppressed the eosinophil counts (P < 0.05) in BALF as well as eosinophil peroxidase (P < 0.01) level at a dose of 100 mg/kg. The same concentration of methanolic extract O. gratissimum also attenuated mucus hypersecretion in airway, which is one of the features of allergic asthma (Costa et al., 2012). Henceforth, this suggests that O. gratissimum is effective against respiratory allergy disorders, like asthma.

Perilla frutescens is a Lamiaceae plant species which has a global distribution, but is especially concentrated in Asian countries, like China, Japan, Korea and Vietnam among others. In an effort to explore the isolate from P. frutescens with anti-allergic activity on respiratory allergy, Sanbongi et al. (2004) evaluated the isolate from the leaves of P. frutescens. Results from this study suggested that the isolated compound, rosmarinic acid (1), can bring about a significant reduction in eosinophil infiltration (P < 0.05), BALF eosinophil counts (P < 0.01) and eotaxin expression (P < 0.05) in the Der f-challenged C3H/He mice (Sanbongi et al., 2004). Parallel activity was seen in OVA-sensitized BALB/c mice with its ethanolic extract in the study of Chen et al. (2015). On top of that, in an anti-atopic study carried out by Heo et al. (2011), the immunohistochemistry test showed that the eosinophil count was remarkably reduced by 73.7% and the MMP-9 expression was also decreased significantly (P < 0.05) at a 100 µg/ml of P. frutescens aqueous fraction (Heo et al., 2011). Scutellaria baicalensis is another well-known Chinese herb which is widely used as an anti-allergic herb (Li et al., 2014). In light of the study of Zhou et al. (2016), it was proposed that oroxylin A (14) from S. baicalensis was effective to alleviate allergic asthma. Results demonstrated that oroxylin A (14) at doses of 15, 30 and 60 mg/kg were able to inhibit eosinophil infiltration in BALF and consequently led to reduced airway hyperresponsivess in OVA-challenged BALB/c mice (Zhou et al., 2016). In the same year, Kim et al. (2016) evaluated the efficacy of topical treatment of aqueous extract of S. baicalensis on contact dermatitis. Results revealed that topical application was effective in suppressing leukocytes infiltration and hence ameliorated contact dermatitis symptoms (Kim et al., 2016).

In addition, Zhou et al. (2014) reported that 2-isopropyl-5-methylphenol (thymol) (15) from Thymus vulgaris produced a dose-dependent reduction of eosinophils infiltration in BALF across concentrations of 4, 8 and 16 mg/kg. A remarkable inhibition (P < 0.01) was noted at a dose of 16 mg/kg which was comparable to 2 mg/kg of dexamethasone standard. Consequently, mucus hypersecretion and goblet cell hyperplasia in lung tissues as well as the airway hyperresponsiveness in OVA-sensitized mice in response to methacholine were drastically reduced (Zhou et al., 2014). In 2011, Patel and Deshpande identified the mast cell stabilization potential of Vitex negundo. In 2013, they conducted another experiment on V. negundo’s leaves to study their anti-asthmatic activity. They successfully isolated a flavonoid compound, 5-hydroxy-3,6,7,3’,4’-pentamethoxyflavone (52) from the leaves and found that this compound potently suppressed eosinophil count in BALF (9.50 ± 1.5044; P < 0.05) in egg albumin-sensitized guinea pigs. This result was remarkable as the inhibition portrayed was comparable to that of dexamethasone control (7.50 ± 0.5014; P < 0.05) at a dose of 200 mg/kg (Patel and Deshpande, 2013). This is indicative of the potential of V. negundo in the treatment of allergy diseases like asthma. Meanwhile, Lee et al. (2009) highlighted that 1H,8H-pyrano [3,4-c] pyran-l,8-dione (PPY) (16) isolated from V. rotundifolia fruits remarkably reduced eosinophil migration and eotaxin production by 48% and 70% respectively at 10 µg/ml in human type II-like epithelial lung cells (A549 cell media). In in vivo model, the eosinophil count in BALF was also shown to decrease significantly (P < 0.05) by 82% (Lee et al., 2009). In 2011, Koh et al. discovered another new compound, casticin (53), isolated from the fruits of V. rotundifolia which also showed to inhibit 63% of eosinophil infiltration at 10 µg/ml while eotaxin production decreased dose-dependently with 0.1–1 µg/ml of casticin (53) (Koh et al., 2011). In conclusion, the species mentioned above have the potential to fill the knowledge gap of anti-allergy with the inhibition of eosinophil functions.

Toxicology

Undeniably, in the past decades, the medicinal potential of Lamiaceae species has captured the attention and interest of many researchers to conduct extensive exploration on their pharmacological properties. Nonetheless, the toxicological aspects of the use of Lamiaceae species have not been studied in-depth. To date, there are several toxicological studies available on Lamiaceae species. For instance, Qi et al. (2009) carried out a toxicological investigation on wogonin (10), the active constituent of Scutellaria baicalensis, through acute toxicity testing and sub-chronic toxicity testing in murine models. In the acute toxicity testing, the mice were intravenously administered with 350, 315, 283.5, 255.5 and 229.64 mg/kg of wogonin (10) respectively. The mice were observed for their general behavior for an hour after the administration and intermittently observed for 24 h for signs of toxicity up to 14-day duration. In the first hour after treatment, the mice showed decreased locomotor activity, muscle relaxation, catatonia, loss of body-righting reflex and bradypnoea. However, these symptoms diminished within 2 h after treatment. The LD₅₀ value of wogonin (10) determined was 286.15 mg/kg. Meanwhile, in the sub-chronic toxicity study, doses of 30, 60 and 120 mg/kg of wogonin (10) were administered daily to the rats through intravenous route and the rats were put under observation for 90 days. Results revealed that a dose of 120 mg/kg of wogonin can cause heart injury with a long period of intravenous administration (10) (Qi et al., 2009).

In another account, the essential oil of Thymus vulgaris was evaluated on its toxicological profile (Fachini-Queiroz et al., 2012). Acute toxicity was assessed by administering single oral doses of 2,000, 3,000 and 4,000 mg/kg of T. vulgaris essential oil and monitoring for any signs of toxicity for seven consecutive days. There were no apparent behavioral side effects observed in the study and the median lethal dose, LD₅₀, of T. vulgaris essential oil determined was 4,000 mg/kg. The relatively high LD₅₀ value suggested that T. vulgaris essential oil is non-toxic and relatively safe for use (Fachini-Queiroz et al., 2012). Haq et al. (2012) evaluated Vitex negundo in an acute neurotoxicity study. Results suggested that no signs of neurotoxicity were seen with doses of 250, 500, 1,000 and 2,000 mg/kg in the tested mice. The LD₅₀ value determined was greater than 5,000 mg/kg, which indicates the extract of V. negundo has a good safety profile (Haq et al., 2012). In term of behavioral symptoms, symptoms started to show at a dose of 2,000 mg/kg, which presented with abdominal contraction, ataxia, reduced spontaneous activity and reduced alertness (Haq et al., 2012).

In China, people have been widely employing Salvia miltiorrhiza as a traditional herb for treating a range of cardiovascular disorders (Wang et al., 2012). Therefore, Wang et al. (2012) designed a toxicological study to assess the acute toxicity and sub-chronic toxicity of S. miltiorrhiza aqueous extract (Wang et al., 2012). In the acute toxicity investigation, the rats received two doses of 32 g/kg of aqueous extract of S. miltiorrhiza through intravenous administration. The sub-chronic toxicity was evaluated by assessment of hematological and biochemical parameters after administering 1.92, 5.76 and 19.20 g/kg of aqueous extract for 13 weeks. At acute doses, no deaths, weight gain or abnormal behavioral changes were observed. The LD₅₀ value was deduced to be greater than 64 g/kg. At the same time, sub-chronic toxicity demonstrated that there was a significant reduction (P < 0.05) in haemoglobin concentration in high dose male rats and a significant decrease (P < 0.05) in platelet count, plateletocrit in low dose female rats. The total bilirubin level was also elevated significantly (P < 0.05) in all doses received by rats. As for histopathological findings, focal inflammation was observed at the injection site and the severity increased dose-dependently. Other vital organs showed no abnormalities (Wang et al., 2012).

Despite the widespread interest for the use of Perilla frutescens, there were only few toxicological studies documenting the toxic potential of P. frutescens (Yu et al., 2017). In spite of the diverse medicinal uses of P. frutescens, it is actually a medicinal plant with toxic potential, given that certain plant parts contain high concentrations of toxic phytochemicals. According to Kerr et al. (1986), a high concentration of perilla ketone was accumulated in the flowers and seed parts of P. frutescens. Perilla ketone has been reported as a potent pulmonary toxin associated with atypical interstitial pneumonia (Wilson et al., 1977; Guerry-Force et al., 1988; Muller-Waldeck et al., 2010). Furthermore, the toxicological profile of Mentha arvensis leaves ethanolic extract was also assessed. The toxic potential of ethanolic leaves extract of M. arvensis was tested using brine shrimp cytotoxicity assay. The extracts were serially diluted to concentrations of 1,000, 250, 125, 100 and 75 µg/ml and each extract was added to the tubes containing Artemia salina. The number of survivors in each tube was counted after 24 h from the treatment to determine the lethal concentration of ethanolic extract of M. arvensis leaves. Result demonstrated that 100 µg/ml as the LD₅₀ dose caused a significant cytotoxic activity against the brine shrimp, Artemia salina (do Nascimento et al., 2009).

Conclusion and Future Perspectives

Undeniably, in recent years, there has been an increase in the global demand for natural products for healthcare supplementation. Lamiaceae species have been well known for their culinary values. Nonetheless, they are also a valuable plant family widely employed as medicinal herbs in traditional practices to treat a wide range of allergic inflammatory conditions, such as allergic skin diseases and allergic asthma. Therefore, this plant family may prove to be a diverse source of natural compounds for the development of novel therapeutic agents for allergic disorders. This review conveys deep insights into the botanical features, distribution, medicinal uses, phytochemistry, pharmacology and toxicological investigations conducted, with a particular focus on the anti-allergic activity of Lamiaceae species. A critical analysis of the relationship between phytoconstituents of Lamiaceae species and corresponding anti-allergic activity was done and documented. Currently available in vitro, in vivo and ex vivo studies have provided evidences to support the traditional uses of Lamiaceae species against allergic disorders. Moreover, after a comprehensive summarization, a total of 53 isolated constituents were identified as natural compounds that contribute to anti-allergic effects. In the present review, numerous compounds demonstrated promising anti-allergic activity, such as flavonoids, flavonoid glycosides, diterpenes and phenolics. Some of these constituents were shown to possess comparable anti-allergic activity to the positive control, including carnosic acid (polyphenol), rosmarinic acid, luteolin, oroxylin A, hispidulin and thymol (phenolic), marrubiin (diterpene) and acteoside (phenylpropanoid glycoside). Nevertheless, in the current review, it was found that many studies were conducted using plant extracts. Although the extracts were proven to exhibit anti-allergic effect, the active constituent responsible for the effect is yet to be identified. Therefore, further studies should be carried out on the plant extracts or fractions which exhibited promising experimental results in order to elucidate the exact active principles responsible for anti-allergic activity. With the availability of the information regarding phytochemicals, other studies such as the standardization of extracts and pharmacological studies as well as toxicological investigations of isolated bioactives can be conducted. Meanwhile, the natural compounds that have been successfully isolated should be further explored and scrutinized for their therapeutic potential to establish a more evidence-based clinical profile. Henceforth, the development of lead molecules for drug discovery can be quicken and accelerated.

Author Contributions

SLY obtained the literatures and wrote the manuscript, while NZAR and KH edited the manuscript.

Funding

This study was financially supported by Universiti Kebangsaan Malaysia (UKM) under grant number GUP- 2018-138.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We are grateful to Universiti Kebangsaan Malaysia (UKM) for allowing us to use all its facilities.

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