Elsholtzia: phytochemistry and biological activities

Plants of the genus Elsholtzia (Lamiaceae) have a long history of medicinal use in folk. The phytochemical investigations revealed the presence of flavonoids, phenylpropanoids, terpenoids, and other compounds. Abundant volatile components are also identified. Pure compounds, volatile constituents and crude extracts from the genus exhibited a wide spectrum of in vitro and in vivo pharmacological activities. The aims of this review hopefully provide comprehensive information on the distribution, phytochemistry, volatile components, and pharmacological research of Elsholtzia for exploring the potential and advance researches.

Previous phytochemical investigations showed that flavonoids are major ingredients in Elsholtzia. They are characterized by the presence of the substitutional groups and modes, as well as their glycosides. Phenylpropanoids, terpenoids, phytosterols, and cyanogenic glycosides are also main chemical constituents in this genus. In this section, we summarize and classify all reported constituents from Elsholtzia. Compounds 1-144 and the corresponding plant sources are list in Additional file 2: Table S2 and the structures 1-132 are showed in Additional file 3: Figure S1.

C6-C3 constituents
Up to now, there are 68 C6-C3-C6 compounds isolated and reported from Elsholtzia, including flavonoids and their glycosides. Its number and content are the most in all secondary metabolites derived from the genus.
Compounds 69-73 are linear furanocoumarins, in which 70-73 were found in E. densa as new furanocoumarins [11,14,23]. 69-72 exhibit a prenyl group or prenyl derivative in the C-5 position and a methoxy group in the C-8 position.

Volatile chemical constituents
The plants Elsholtzia are aromatic herbs in general, as they possess plentiful volatile oils. The oils have been developed and utilized as medicines, food and the source of honey manufacture [1]. Many phytochemistry and pharmacology scientists are interested in the volatile constituents and its biological activities. The latest paper reported that the volatile constituents exert strong inhibition against central nervous system and take on considerate analgesic effect [41]. It also shows antibacterial effects [42][43][44].

Pharmacological activities
Pharmacological investigations on the extracts and pure compounds from Elsholtzia cover the activities of antiviral, antibacterial, anti-inflammatory, anti-oxidant, and myocardial ischemia protection, as well as other activities. Researchers are increasingly concerning on the pharmacological activities of the genus.
Essential oil from E. densa showed a significant inhibitory properties against Asia influenza virus A and Orphan virus in vitro. And it can postpone the symptom appearance by 72-96 h after being infected by virus in vivo. Also, it showed inhibition against H3N2 subtype of influenza A virus, and exhibited remarkable therapeutic effect on mouse pulmonic induced by influenza virus when the mouse was administered with the essential oil (100 mg/kg) [41].
The ethanol extracts of E. blanda and E. rugulosa exhibited remarkable inhibitory activity against methicillinresistant S. aureus, with its MIC values of 1.32 and 1.43 mg/mL, respectively [83].
Essential oils from E. splendens are inhibitory against S. aureus, P. acnes and S. epidermidis. Its MIC against P. acnes was 0.31 μL/mL. As we known, P. acnes and S. epidermidis are involved in the formation acne, thus the inhibition against the two bacteria supports the considerable potential of the E. splendens essential oil for the treatment of acne [42]. It was also reported that volatile components from E. ciliata and E. rugulosa inhibit common bacteria, such as S. aureus, P. aeruginosa, B. enteritidis, B. subtilis, Proteus vularis, Shigella dysenteriae, and E. coli [43,44].

Anti-inflammatory
The 75% ethanol extract of the aerial part of E. splendens can significantly inhibit acute inflammation (mouse ear edema by croton oil-inducing) and subchronic inflammation (ear edema by phorbol ester inducing). E. splendens significantly inhibited PGE2 production by pre-induced cyclooxygenase-2 of lipopolysaccharide-treated RAW 264.7 cells. It was thus believed that inhibition against cyclooxygenase-2 is probably one of the function mechanisms [84].
On chemical view, luteolin (16), a widely contained flavone with many hydroxyl substitutions, is a bioactive constituent in Elsholtzia plants for anti-inflammatory activity. It can inhibit the production of NO and generation of other inflammatory cytokine, such as TNF-α, IL-1β, IL-6, NF-κB, etc. [41]. Therefore, rich production of hydroxylated flavone and/or its derivatives is one of reasons to some extend to explain the anti-inflammatory action for Elsholtzia plants.

Anti-oxidant activity
The extracts of the aerial parts of E. rugulosa and E. bodineri displayed significant anti-oxidant activity in a radical-scavenged assay, which perhaps can elucidate why E. rugulosa has an anti-aging effect [85,86]. The flower of E. rugulosa is rich in flavonoids with its content up to 0.2352 mg/mL, and the flavonoids significantly scavenge the OHand O 2 ions, with its scavenging rate 30.8 and 40.5%, respectively [87]. The extract and extract-loaded nanoparticles of the flower of E. splendens showed a concentration-dependent manner in DPPH radical scavenging assay. E. splendens was also found to activate the antioxidant defense system against 7,12-dimethyl-benz(a)anthracene (DMBA)-induced oxidative stress and reduce several biomarkers of oxidative stress such as thio-barbituric acid reactive substance, protein carbonyls, serum 8-hydroxy-20-deoxyguanosine, and ovary CHO-K1 cells aging [88][89][90][91][92]. The maxium LPO inhibition ratio of the flavonoid extracts of E. blanda was 70.8% with the IC 50 0.23 mg/L. And the inhibition of LPO was induced by OH free radical [93]. The genus Elsholtzia owns rich polyphenols, thus having radical scavenging effects [94,95].

Myocardial ischemia protection
The total flavones from E. blanda (TFEB) could improve the recovery of myocardial function, and keep heart from ischemic damage due to coronary occlusion in Beagle dogs. The effect was achieved by the inhibition of serum creatine kinase-MB (CK-MB) and malondialdehyde (MDA), together with by the lowing of mean arterial pressure (MAP), coronary vascular resistance (CVR), etc. [96]. The TFEB not only could reduce infarct size during acute myocardial infarction (AMI) by inhibiting myocardial apoptosis through modulation of Bcl-2 family [97], but also might decrease the myocardial ischemia and 'Xiongbi Symtom' [98]. Luteolin 7-O-β-D-glucopyranoside (15) could protect cultured neonatal rat cardiomyocytes from oxidative damage obviously, and the beneficial effects may be related to its anti-oxidant properties and reduction of intracellular calcium overload [99].
A study indicated that E. splendens could obviously relieve symptoms of premenstrual syndrome. And the scores of depression and anxiety and the premenstrual instability decreased significantly [102]. The extracts of E. splendens had the potential of inducing structural aberration of chromosome. The ethanolic extracts of E. splendens have been found for reducing blood lipid by lowing low-density lipoprotein (LDL)-cholesterol [103,104]. And 'Ciwujia Xiangru Decoction' , one of Chinese Traditional Compound Medicines consisting of Acanthopanax senticosus and E. splendens, has been investigated the mentioned effect and used in clinic [105]. The extracts of E. splendens and E. stauntonii had fumigant toxicity, and may be potential fumigants for integrated pest management programs of stored-grain insect [106,107]. Additionally, E. bodinieri extracts exhibited certain effect on depressing blood-lipid by reducing the level of total cholesterol of rats [108].

Conclusion remarks
The review paper summarized a total of 144 compounds and abundant volatile components that were reported from the genus Elsholtzia, with 117 references cited. We noted that Elsholtzia has an extensive distribution, diverse biological and pharmacological activities of pure compounds, extracts and volatile components described. Previous phytochemical researches on the genus revealed the extensive presence of flavone, coumarin, terpenoid, and other compound types, together with prolific essential oils. The pharmacological activities of volatile constituents mainly were regarded on antioxidant, antiviral and antibacterial activities.
From the review, it can be seen that phytochemical investigations mainly focus on 10 Elsholtzia species, E. blanda, E. bodinieri, E. ciliata, E. cristata, E. densa, E. eriostachya, E. ianthina, E. rugulosa, E. splendens, and E. stauntonil. And the volatile constituents' analyses primarily concentrated on 20 species. However, related chemical and biological toward other Elsholtzia species, including E. kachinensis, E. capituligera, E. cephalantha, E. cyprianii, E. eriocalyx, E. flava, E. glabra, E. heterophylla, E. hunannensis, E. kachinensis, E. luteola, E. ochroleuca, E. oldhamii, E. penduliflora, E. pilosa, E. pygmaea, E. saxatilis, E. souliei, E. stachyodes, and E. winitiana, are still blank. So, plenty of further studies are necessary in order to illustrate the chemo-diversity and to make full use of the biological significance of the compounds and extracts of Elsholtzia, especially the antiviral and anti-inflammatory activities. The authors wish the review can provide a valuable data for explorations and advanced researches of Elsholtzia species.