Gaultheria: Phytochemical and Pharmacological Characteristics

The genus Gaultheria, comprised of approximately 134 species, is mostly used in ethnic drugs to cure rheumatism and relieve pain. Phytochemical investigations of the genus Gaultheria have revealed the presence of methyl salicylate derivatives, C6-C3 constituents, organic acids, terpenoids, steroids, and other compounds. Methyl salicylate glycoside is considered as a characteristic ingredient in this genus, whose anti-rheumatic effects may have a new mechanism of action. In this review, comprehensive information on the phytochemistry, volatile components and the pharmacology of the genus Gaultheria is provided to explore its potential and advance research.


Introduction
The genus Gaultheria (Ericaceae) is widely distributed around the Pacific Ocean, westwards to western slopes of the Himalayas and the southern areas of India [1]. Most Gaultheria species growing in Southwest China are regarded as traditional herbal medicines. Parts of plants in this genus are used by nine minority nationalities for the treatment of wind-damp, as well as relieving pain. Additionally, G. procumbens is used as a folk remedy in America and Canada, and G. fragrantissima is employed in

OPEN ACCESS
India [2]. Modern research has demonstrated that these plants exhibit anti-inflammatory, anti-oxidative, antibacterial and analgesic activities. To the best of our knowledge, about 109 compounds were reported from this genus, including methyl salicylate derivatives, C 6 -C 3 constituents, terpenoids, and steroids. In particular methyl salicylate (1) and three methyl salicylate glycosides, methyl salicylate 2-O-β-D-glucopyranoside (2), gaultherin (3) and methyl benzoate-2-O-β-D-xylopyranosyl (1)(2)[O-β-Dxylopyranosyl(1-6)]-O-β-D-glucopyranoside (5), from the aerial parts of G. yunnanensis, display notable analgesic and anti-inflammatory activities, which has impelled a number of studies on the phytochemistry and biology of this genus [3]. Meanwhile, it's worth mentioning that methyl salicylate glycoside when used in animal experiments to explore its pharmacological effects could overcome the side-effects caused by aspirin in the clinic [3][4][5]. Herein, we summarize the phytochemical and biological studies on the genus Gaultheria. What's more, all the compounds reported in the essential oils of Gaultheria are listed below, and the corresponding plants are included as well.

Methyl Salicylate Derivatives
Methyl salicylate (1) and its glycoside derivatives 2-6, namely the methyl salicylate derivatives obtained from Gautheria species, possess remarkable analgesic and anti-inflammatory activities [3,[6][7][8]38,39]. Methyl salicylate (1) is the chief component in the ethanol extract of the aerial part of G. yunnanensis. It also represents a large percentage in the volatile oils of Gaultheria plants [3,6,7]. Methyl salicylate has a wide range of applications in flavors, organic synthesis intermediates and solvents [3,38]. Medically, it has an important role in the anti-inflammatory and analgesic effects for dental medicine [38,39] [3]. Nowadays many researchers consider the methyl salicylate glycosides as characteristic marker components in this genus, and as non-steroidal anti-inflammation drug (NSAID) leads, devoting themselves to finding other examples of those types of components in the genus, and trying to elucidate their mechanism of action for fighting rheumatism.

Lignans
Compounds 25-34 are cyclolignans, in which the aromatic carbon atom at the C(6) position of one phenylpropanoid unit is directly linked with the aliphatic carbon at the C(7′) position in the other C 6 -C 3 unit. These sorts of compounds were also regarded in the past as active components against rheumatism in this genus [15][16][17][18][19]. The ten abovementioned compounds were all found in G. yunnanensis [6,[15][16][17][18][19].  (26) is the highest in the roots of G. fragrantissima and the lowest in the roots of G. leucocarpa var. yunnanensis. The former is 25 times the latter. The sequence of the total content of those three lignans in roots is G. fragrantissima > G. leucocarpa var. yunnanensis > G. leucocarpa var. cumingiana > G. tetramera > G. griffithiana [16].
Compounds 66-77 are benzoic acid derivatives, with several hydroxyl-, methoxyl-and formoxylgroups connected to different positions of the benzoic acid. Methyl gentisate (77) from the aerial part of G. yunnanensis, is usually used as a skin-lightener and antioxidant. It appears to be more efficient than the free acid as well as other well-known hypopigmentation agents [6,42].

Volatile Chemical Constituents
The plants of the genus Gaultheria were first studied for their aromatic character. The essential oils of this genus were usually obtained by hydrodistillation, and their structures elucidated by gas chromatography-mass spectrometry (GC-MS) or solid-phase micro-extraction gas chromatographymass spectrometry (SPME-GC-MS) [43,[46][47][48][49][50][51][52][53][54]. Ninety seven chemical constituents were recently reported from the essential oils of four Gaultheria plants: G. yunnanensis, G. leucocarpa Bl var. crenulata, G. fragrantissima and G. procumbens (see Table 2). These essential oils are composed primarily of methyl salicylate (five compounds), alkanes (19 compounds), monoterpenes (22 compounds), sesquiterpenes (14 compounds) and aromatic derivatives (nine compounds). Methyl salicylates are major components found at fairly high concentrations (70-99%) in contrast with other components present in only trace amounts. Through odor-evaluation and blending, it was determined that essential oils of G. yunnanensis a sweet and long staying, and thus more suitable to make gum essence and tooth-paste fragrances. They have been the subject of extensive studies due to their economic importance. The constituents showed good prospects for application in the fragrance industry [47].

Biological Activities
Many studies have verified that the extracts and compounds derived from Gaultheria plants exhibit a wide spectrum of pharmacological activities in vitro and in vivo, covering anti-inflammatory, analgesic, anti-oxidative and antibacterial properties.

Anti-Inflammatory Activities
It was found that the H 2 O, EtOAc and n-butanol extracts of G. leucocarpa had remarkable anti-inflammatory activity by significantly reducing the level of joint swelling in a rat adjuvantinduced arthritis model [40].
Gaultherin (3), having a similar chemical structure to aspirin, inhibited the abdominal contractions in the acetic acid-induced writhing test in mice at a dosage of 200 mg/kg. Compared to aspirin, it did not show gastric ulcerogenic effects, which is the main clinical side-effect of aspirin. The possible reason is that gaultherin released salicylate in the intestine slowly, not in stomach and it left the cyclooxygenase-1 unaffected. It was the source of cytoprotective prostaglandin in gastric epithelium [55]. Methyl salicylate 2-O-β-D-lactoside (4) inhibits the IKK/NF-κB signal pathway to protect from LPS-induced inflammation [8]. MSTG-A (5) and MSTG-B (6) from G. yunnanensis display antiinflammatory effects through inhibiting the production of pro-inflammatory cytokines, NO and ROS. The two methyl salicylate glycosides dose-dependently inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, respectively. They also can remarkably suppress the accumulation of NO, with an inhibitory rate of 56.20% and 51.72% at 3.0 μg/mL concentration, respectively [56].

Analgesic Activities
Zhang et al. reported that EtOAc and n-butanol fractions of G. yunnanensis roots (100 mg/kg and 200 mg/kg) have remarkable anti-inflammatory effects through significantly inhibiting murine peritoneal capillary permeability [57].

Anti-Oxidative Activities
Li et al analyzed the antioxidant capacity of different polar parts and furthermore, gradient elution samples obtained through macroporous resin column chromatography from an EtOH extract of G. leucocarpa were also tested. The ethyl acetate part and the 100% MeOH-elution part showed more striking ABTS and DPPH radical scavenging effects. The major constituent of the 100% MeOH is quercetin-3-O-β-D-glucuronide (13), which is suggested to be responsible for the efficacy [58]. In 2011, it was demonstrated that the fruit extracts of G. fragrantissima and G. tiliaefolia possessed anti-oxidative activities [59]. The EtOAc extract of G. shallon displayed a high anti-oxidative activity in scavenging DPPH with an IC 50 value of 14.76 ± 0.85 μg/mL, compared to ascorbic acid (IC 50 = 18.53 ± 1.58 µg/mL), as reference compound [60].

Antibacterial Activities
The 95% EtOH extract, the EtOAc, and n-butanol fractions of the stems or roots of G. leucocarpa significantly inhibited Staphylococcus aureus. Additionally, the EtOAc and n-butanol parts of G. leucocarpa stem revealed certain inhibitory effects towards Escherichia coli and Pseudomonas aeruginosa [61]. The essential oil from the leaves of G. yunnanens presented similar antibacterial effects as methyl salicylate. It has antibacterial activity against E. coli and S. aureus, but the essential oil is superior to methyl salicylate, and the lowest antimicrobial concentration is 0.3125% and 5%, respectively [38].

Conclusions
This article summarized a total of 109 compounds and abundant volatile components that have been reported from the genus Gaultheria, with 63 references cited. The genus Gaultheria is widely distributed all over the World, and many species have been used as traditional herbal medicines [62,63]. So far, phytochemical research on the genus has revealed the extensive presence of methyl salicylate derivatives, C 6 -C 3 constituents, terpenoids, and other compound types, together with prolific essential oils. The pharmacological activities of pure compounds and crude extract from this genus were mainly focused on anti-inflammatory and analgesic properties. For their significantly anti-inflammatory activities, methyl salicylate glycoside is a research hotspot in the abovementioned plants. So far, some experiments point out the anti-rheumatic effects of methyl salicylate derivatives may be due to a new mechanism of action. As a whole, the phytochemical and biological investigations were mainly concentrated on the G. yunnanensis, with little or no attention being paid to other species. This species has several fractions with demonstrated anti-inflammatory and analgesic abilities. In view of this background, plenty of further studies are necessary in order to examine the other plants of the Gaultheria genus, together with the some fractions and different constituents of the G. yunnanensis to identify the medicine effects. The authors hope this review will provide valuable data for the exploration and advanced research on Gaultheria species.