A Review of the Composition of the Essential Oils and Biological Activities of Angelica Species

A number of Angelica species have been used in traditional systems of medicine to treat many ailments. Especially, essential oils (EOs) from the Angelica species have been used for the treatment of various health problems, including malaria, gynecological diseases, fever, anemia, and arthritis. EOs are complex mixtures of low molecular weight compounds, especially terpenoids and their oxygenated compounds. These components deliver specific fragrance and biological properties to essential oils. In this review, we summarized the chemical composition and biological activities of EOs from different species of Angelica. For this purpose, a literature search was carried out to obtain information about the EOs of Angelica species and their bioactivities from electronic databases such as PubMed, Science Direct, Wiley, Springer, ACS, Google, and other journal publications. There has been a lot of variation in the EO composition among different Angelica species. EOs from Angelica species were reported for different kinds of biological activities, such as antioxidant, anti-inflammatory, antimicrobial, immunotoxic, and insecticidal activities. The present review is an attempt to consolidate the available data for different Angelica species on the basis of major constituents in the EOs and their biological activities.


Introduction
In traditional systems of medicine, a number of plants have been widely used for the treatment of various disorders since ancient times. Plants are a versatile source of bioactive metabolites, including polysaccharides, phenolics, alkaloids, essential oils (EOs), steroids, lignins, resins, tannins, etc. [1]. Among them, EOs obtained from plants have various applications, especially in the health, agriculture, food, and cosmetic industries. So far, more than 3000 EOs have been isolated from about 2000 plant species, out of which 300 have been commercially used for various purposes [2]. Previous scientific studies clearly revealed that EOs possess various pharmacological properties such as antioxidant, antimicrobial, antiviral, antimutagenic, anticancer, anti-inflammatory, and immunomodulatory activities [3].
EOs are mainly stored in the oil ducts, resin ducts, glands, or trichomes of the plants [2]. They are a complex mixture of low molecular weight volatile compounds, mainly monoterpenes and sesquiterpenes, and their oxygenated derivatives. Each type of EO contains about 20-100 different components from a variety of chemical classes [4]. In general, the bioactivities of a particular EO are decided by its major components [3]. However, the presence of minor components also plays an essential role in the bioactivities of EOs. They can be obtained from different organs of various medicinal and aromatic plant materials using classical and advanced techniques. Hydrodistillation and steam distillation

The Chemical Composition of Essential Oils of Angelica Species
The main aim of this review is to offer an overview on the chemical composition of EOs from different species of Angelica growing in various countries. Table 1 shows the plant name, plant parts, extraction methods, yield, and the major components of EOs in relation to different species of Angelica. The published reports revealed that the EOs of the genus Angelica isolated by steam distillation or the hydrodistillation method mainly consist of monoterpene hydrocarbons. Figure 1 depicts the chemical structure of some of the major components of EOs from Angelica species.
Chen et al. [30] compared the volatile compositions of A. acutiloba roots, stems, and leaves using steam distillation and headspace solid-phase microextraction (HS-SPME). In all three parts, a total of 61 and 33 compounds were detected by SD and HS-SPME, respectively. In the steam distillation, 3n-butyl phthalide, γ-terpinene, p-cymene, and cis-β-ocimene were the main compounds. On the other hand, γ-terpinene and p-cymene were the main compounds in HS-SPME. Further, the authors reported that monoterpene components were found to be higher in the HS-SPME sampling method when compared with steam distillation.

Antimicrobial
A. koreana EO and its main components, sabinene and m-cresol, showed antifungal activity against different species of Aspergillus and Trichophyton with minimal inhibitory concentrations (MICs) of 125-1000 µg/mL. In addition, EO exhibited synergistic activity when combined with itraconazole [36]. The EO of A. glauca showed appreciable antimicrobial activity against selected strains of bacteria (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pasteurella multocida) and fungi (Candida albicans, Microsporum canis, Aspergillus flavus, and Fusarium solani). Among the bacterial strains tested, Escherichia coli and Staphylococcus aureus were the most sensitive bacteria with minimum inhibitory concentration (MIC) values of 141.3 and 159.3 µg/mL, respectively. In regards to fungal strains, Microsporum canis was the most sensitive organism with a MIC value of 178.1 µg/mL [24].
Cavaleiro et al. [55] evaluated the antifungal activity of the EO of Angelica major and its major components, α-pinene and cis-β-ocimene, against clinically important yeasts and molds. A. major EO exhibited a broad spectrum of antifungal activity, including all tested fungi (animal and human pathogenic species or spoilage fungi): Candida spp., C. neoformans, Aspergillus spp., and dermatophytes. α-Pinene was more active against all of the tested fungi than cis-β-ocimene. A. sinensis and A. dahurica EOs exhibited significant antibacterial activity against three mastitis-causing pathogens: Staphylococcus aureus, Staphylococcus chromogenes, and Streptococcus uberis [47]. Tabanca et al. [20] reported that A. pubescentis root EO exhibited weak antifungal activity against Colletotrichum acutatum, Colletotrichum fragariae, and Colletotrichum gloeosporioides. In the case of A. dahurica root EO, there was no antifungal activity observed against tested fungal strains.

Insecticidal
EOs from the root of A. dahurica and A. pubescentis were studied as pest management prospectives. When compared with A. pubescentis EO, A. dahurica EO showed better biting deterrent and insecticidal activity against Aedes aegypti and Stephanitis pyrioides. In mosquito bioassays, components of A. dahurica EO, 1-dodecanol and 1-tridecanol, showed antibiting deterrent activity against Aedes aegypti [20]. Chung et al. [44] investigated the immunotoxicity effect of EOs from the leaves of A. anomala, A. cartilagino-marginata var. distans, A. czernevia, A. dahurica, A. decursiva, Angelica fallax, A. gigas, and A. japonica. Among them, the EO of A. dahurica showed a significant toxic effect against early fourth-stage larvae of Aedes aegypti, with a LC 50 value of 43.12 ppm. In another study, out of 33 plant species tested, A. sinensis EO showed the best repellent activity against Aedes aegypti, with a median complete protection time of 7.0 h [35].

Behavioral
Repeated administration of nicotine can produce behavioral sensitization, and this is a good model for studying drug addiction. Zhao et al. [43] reported that the inhalation of A. gigas EO significantly ameliorated nicotine-induced behavioral sensitization by decreasing dopamine release in the nucleus accumbens and locomotor activity in repeated nicotine-induced rats. Pathak et al. [41] found that the EO of the A. archangelica root exhibited antiseizure activity against electrically and chemically-induced seizures in mice. Chen et al. [50] investigated the anxiolytic activity of Angelica EO in a mice model. The results revealed that the EO of Angelica exhibited considerable anxiolytic-like effects at the concentration of 30.0 mg/kg (orally), as measured in the elevated plus-maze, the light/dark, and the stress-induced hyperthermia tests. In addition, Angelica EO significantly improved the behavioral performances in the social interaction test of anxiety and the hole-board test of exploration and locomotor activity in rats [51]. Sharma et al. [45] reported that the EO of A. glauca exhibited broncho-relaxant activity against histamine and ovalbumin-induced bronchoconstriction in guinea pigs by decreasing absolute blood eosinophil count, serum levels of immunoglobulin E, and the number of eosinophils and neutrophils in bronchoalveolar lavage fluid. Sowndhararajan et al. [14] investigated the effect of inhalation of EO of A. gigas root on electroencephalographic activity in humans. The results revealed that absolute low beta significantly increased at left temporal and left parietal region during the inhalation of the EO of A. gigas root, and these changes may contribute to the enhancement of language learning abilities in humans.

Anti-Inflammatory
Zhang et al. [32] used the metabonomics based on GC-MS to study the possible anti-inflammatory mechanisms of EO of A. sinensis in rats with acute inflammation. In the carrageenan-injected rats, treatment with the EO of A. sinensis significantly restored the levels of prostaglandin E2, histamine, and 5-hydroxytryptamine in the inflammatory fluid, similar to the normal group. GC-MS analysis identified 14 metabolite biomarkers detected in the inflammatory fluid. Zhong et al. [48] evaluated the anti-inflammatory effect of EOs obtained from processed products of A. sinensis. For this purpose, EOs from stir-fried A. sinensis, fried A. sinensis with alcohol, cooked A. sinensis with soil, and fried A. sinensis with sesame oil were applied to intervene the carrageenan-induced acute inflammation of the model rats. The results showed that the EOs of A. sinensis significantly inhibited the release of prostaglandin E2, histamine, 5-hydroxytryptamine, and tumor necrosis factor-α. Furthermore, A. sinensis exhibited an anti-inflammatory effect against the lipopolysaccharide (LPS)-induced inflammation rat model by regulating the Krebs cycle, enhancing the glucose content, and restoring the fatty acid metabolism [33].
Li et al. [49] investigated the effects of A. sinensis EO on the LPS-induced acute inflammation rat model. A. sinensis EO exhibited anti-inflammatory and liver protection effects by inhibiting the secretion of the pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6), the inflammatory mediators (histamine, 5-hydroxytryptamine, prostaglandin E2, and nitric oxide), the inflammation-related enzymes (inducible nitric oxide synthase and cyclooxygenase 2), as well as promoting the production of the anti-inflammatory cytokines interleukin-10. Wang et al. [19] reported that the EO of A. dahurica (at 100 mg/kg) showed anti-inflammatory activity against xylene-induced ear swelling and carrageenan-induced paw edema in a mice model. In addition, the EO significantly alleviated Freund's complete adjuvant-induced arthritis in rats by improving hind paw swelling and reducing the serum levels of nitric oxide, tumor necrosis factor-α, prostaglandin E2, and serum nitric oxide synthase activity.

Skin Permeation Enhancer
It is well known that EOs can reversibly overcome the stratum corneum barrier to improve the skin permeation of drugs. Chen et al. [53] studied the penetration enhancement effect of five EOs (clove, Angelica, Chuanxiong, Cyperus, and cinnamon) on the transdermal drug delivery of ibuprofen using dysmenorrheal model mice. Among five EOs tested, Chuanxiong and Angelica oils effectively enhanced the transdermal drug delivery of ibuprofen. In another study, turpentine, Angelica, Chuanxiong, Cyperus, cinnamon, and clove oils (at 3% w/v) were evaluated for the potential to enhance the skin penetration of ibuprofen in rats. When compared with azone, the tested EOs had significantly higher penetration enhancement effect and lower skin irritation potential. The results revealed that EOs can enhance the skin permeation of ibuprofen mainly by disturbing the stratum corneum lipids [54].

Conclusions
EOs have been isolated from different plant parts of Angelica species. The most abundant components in the EOs were α-pinene, β-pinene, α-phellandrene, β-phellandrene, δ-3-carene, sabinene, γ-terpinene, limonene, p-cymene, ligustilide, butylidene phthalide, α-cadinol, and β-eudesmol. Based on the previous reports, the EOs from different Angelica species exhibit appreciable antioxidant, antimicrobial, insecticidal and anti-inflammatory activities. In addition, EOs significantly enhance behavioral performances and promote the skin permeation of drugs. Among the different Angelica species, A. archangelica, A. sinensis, and A. dahurica were the most studied plant species in relation to the biological activities of EOs. This review will offer a scientific basis for future studies in relation to biological activities of EO-bearing plants.