Phytochemical and Biological Properties of Ajuga decumbens (Labiatae): A Review

Ajuga decumbens Thunb is a member of Labiatae family and widespread in China, Korea and Japan. This plant possesses diverse pharmacological activities, such as anti-inflammatory, antitumor, antibacterial, antiviral, cytotoxic, as well as insecticidal activities. Several compounds have been isolated from A. decumbens, which display a wide spectrum of biological and pharmacological activities. Hence, it would be useful to review current literature for available pharmacological activities of the plant as well as its active ingredients.


INTRODUCTION
The genus Ajuga is widely spread throughout the temperate regions of Europe, Asia, Australia, North America, and Africa [1,2]; this group contains many medicinal plants such as A. decumbens Thunb., A. bracteosa Wall. ex Benth, A. forrestii Diels, A. nipponensis Makino, A. ciliata, etc. Studies have shown that Ajuga spp. are widely used for the treatment of hypertension, hyperglycemia, pneumonia, acute and chronic pharyngitis [3][4][5][6]. Additionally, Ajuga has been used in Iranian traditional medicine for the treatment of joint pain, gout, and jaundice [7]. All plants of A. decumbens have been utilized as a kind of folk medicine for a long time in China and Japan owing to their antibacterial, antiinflammatory, antitumor and antiviral activities [8][9][10][11]. Many compounds whose structures have been characterized were isolated from A. decumbens. Diterpenes and iridoid glycosides are the main bioactive compounds for the treatment of chronic pelvic inflammation and hysteromyoma [12,13]. It is urgent to understand the structure-activity relationships between the chemical constituents and biological activities of this plant with regard to its enormous social and economic implications. The primary objective of this review is to comprehensively report the various biological properties of A. decumbens as well as its main chemical constituents.

Iridoid glycosides
Iridoids are a class of secondary metabolites found in a wide variety of plants primarily served as a defense against herbivores or against infection by microorganisms [33]. The iridoids glycosides were firstly found by Takeda et al obtained six iridoids glycosides from the MeOH extract of A. decumbens, elucidated as Decumbeside A-D (39 -42), reptoside (43) and 8-Acetylharpagide (44) [34]. Similarly, Harpagide (45) was isolated from A. decumbens [25]. The structures and physical states of these compounds are described in Table 1

Ecdysteroids
Ecdysteroids are a group of chemically related polyhydroxylated steroids present in plants (phytoecdysteroids) and arthropods (zooecdysteroids).
The phytoecdysteroids stimulate protein synthesis in plants and activate cell mitosis, and possibly act as plant growth regulators [37]. In 1970, Ajugalactone (50) was isolated from A. decumbens [38]. Up to 1999, eight ecdysteroids (51 -58) were obtained from the flowering whole plant [39]. The structures of these compounds are described in Fig 1(

BIOLOGICAL PROPERTIES
Various extracts or purified compounds from A. decumbens exhibit diverse biological characteristics, which are anti-inflammatory, antitumor, antibacterial, antivirus, cytotoxic, as well as insecticidal activities. Herein, we describe the biological activities as well as its active extracts or compounds.

Anti-inflammatory activities
Several studies investigated that the whole plant of A. decumbens possessed the antiinflammatory effects described in the famous pharmacy book of China, Dictionary of Chinese Materia Medica [42][43]. The inhibitory activities on LPS -induced NO production of diterpenes were evaluated, compounds (22)(23)(24)(25)(26)28) showed inhibitory effects, indicating these substances were expected to be useful as effective potential anti-inflammatory agents [29,30]. Similarly, Ajugacumbin J (31) and ajugacumbin D (4) exhibited the inhibitory activities of LPS-induced NO production in RAW 264.7 macrophages with an IC 50 value of 46.2 and 35.9 mM, respectively [31]. The ethanol extracts of A. decumbens extracts (KE) improved the balance of bone resorption and bone formation, showing antiinflammatory effects. The results exhibited that KE were beneficial for sufferers of bone and joint disease [44]. Total flavonoids of A. decumbens (TFA) had a therapeutic effect on chronic serum sickness glomerulonephritis (CSS-GN) rats by increasing SOD activity, lowering MDA and inhibiting lipid peroxidation [45].
exhibited the strongest inhibitory effect on EBV activation [25]. In addition, compound 44 exhibited an anti-proliferative effect on mouse hepatic tumor using N-nitrosodiethylamine (DEN) as an initiator and phenobarbital (PB) as a promoter [46]. Takasaki et al also found that compounds 44 and 52 had potent antitumorpromoting activities on mouse skin in vivo twostage carcinogenesis procedure. Furthermore, compound 44 also exhibited potent chemopreventive activity in a mouse pulmonary tumor model [39]. Compounds 35 -37 exhibited moderate inhibitory activity on the proliferation of human breast cancer MCF-7 cells [32]. A. decumbens extracts showed anticancer and antimetastatic effects towards breast cancer through regulating the expression of MMPs and TIMPs [47]. Additionally, A. decumbens extracts exhibited an anti-proliferative effect on lung cancer A-549, liver cancer SMMC-7721 and Sarcoma S18 [48,49]. What is more, water extracts of A. decumbens significantly inhibited the proliferation of HepG2 cells in a dosedependent manner [50].

Antibacterial activities
A. decumbens extracts exhibited significantly antibacterial effect by inhibiting the growth of S. aureus, S. epidermidis, K. pneumonia, E. coli and P. aeruginosa [51]. Besides, through the analysis of antibacterial activity in vivo and in vitro, water extracts of A. decumbens also possessed antibacterial activities against Streptococci [52].

Antivirus activities
Ma et al found that the whole plant of A. decumbens showed potent antiviral activities against respiratory syncytial virus (RSV) with an IC 50 value of 131.6 μg/ml [53]. In addition, A. decumbens water extracts could inhibit infectious bronchitis virus (IBV) in vitro with the concentration of 750 -1500 mg/ml [54].

Cytotoxicity
Myrotheciumone A isolated from A. decumbens was found to exert cytotoxicity via induction of apoptosis in cancer cell lines [55].
The active extracts/compounds of A. decumbens and their mechanisms of action are provided in Table 2.