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Secondary metabolites from cetrarioid lichens: chemotaxonomy, biological activities and pharmaceutical potential.

ABSTRACT

Background: Lichens, as a symbiotic association of photobionts and mycobionts, display an unmatched environmental adaptability and a great chemical diversity. As an important morphological group, cetrarioid lichens are one of the most studied lichen taxa for their phylogeny, secondary chemistry, bioactivities and uses in folk medicines, especially the lichen Cetraria islandica. However, insufficient structure elucidation and discrepancy in bioactivity results could be found in a few studies.

Purpose: This review aimed to present a more detailed and updated overview of the knowledge of secondary metabolites from cetrarioid lichens in a critical manner, highlighting their potentials for pharmaceuticals as well as other applications. Here we also highlight the uses of molecular phylogenetics, metabolomics and ChemGPS-NP model for future bioprospecting, taxonomy and drug screening to accelerate applications of those lichen substances.

Chapters: The paper starts with a short introduction in to the studies of lichen secondary metabolites, the biological classification of cetrarioid lichens and the aim. In light of ethnic uses of cetrarioid lichens for therapeutic purposes, molecular phylogeny is proposed as a tool for future bioprospecting of cetrarioid lichens, followed by a brief discussion of the taxonomic value of lichen substances. Then a delicate description of the bioactivities, patents, updated chemical structures and lichen sources is presented, where lichen substances are grouped by their chemical structures and discussed about their bioactivity in comparison with reference compounds. To accelerate the discovery of bioactivities and potential drug targets of lichen substances, the application of the ChemGPS NP model is highlighted. Finally the safety concerns of lichen substances (i.e. toxicity and immunogenicity) and future-prospects in the field are exhibited. Conclusion: While the ethnic uses of cetrarioid lichens and the pharmaceutical potential of their secondary metabolites have been recognized, the knowledge of a large number of lichen substances with interesting structures is still limited to various in vitro assays with insufficient biological annotations, and this area still deserves more research in bioactivity, drug targets and screening. Attention should be paid on the accurate interpretation of their bioactivity for further applications avoiding over-interpretations from various in vitro bioassays.

Keywords:

Cetrarioid lichens

Chemotaxonomy

Ethnopharmacology

Lichen substances

Pharmaceutical potential

Phytogeny

Introduction

Lichens are in fact an ecosystem comprising of a photobiont that can either be a green alga (Chlorophyta) or a cyanobacterium and a mycobiont that in most cases belongs to the Ascomycetes. The nomenclature of a certain lichen taxon stems from its mycobiont partner and they are taxonomically classified within the fungi where majority of lichen-forming fungi belong to Lecanoromycetes (Tehler and Wedin 2008). With a special symbiotic lifestyle, a vast genetic diversity and interactions with various environmental factors, they produce lichen-unique profiles of primary and secondary metabolites (i.e. lichen substances) with interesting physiochemical properties, such as lipophilicity and UV filtration (Nguyen et al. 2013), and marked biological activities determined by a series of in vitro and in vivo assays (Boustie et al. 2011). In particular, antioxidant, antimicrobial, anti-inflammatory and anti-proliferative activities of certain lichen substances are well studied (Fernandez-Moriano et al. 2016; Haraldsdottir et al. 2004; Ingolfsdottir et al, 1997; Ingolfsdottir 2002). Several reviews have recently been published describing the pharmaceutical potential of lichen substances (Gomez-Serranillos et al. 2014; Muller 2001; Shrestha and Clair 2013; Shrestha et al. 2015; Shukla et al. 2010; Zambare and Christopher 2012), their ecological and biotechnological roles (Oksanen 2006), their biosynthetic pathways (Stocker-Worgotter 2008) as well as the methodologies employed in the symbiotic mechanisms of both lichen partners (Eisenreich et al. 2011). Recent interest in lichen substances also tends to expand towards the bioactive compounds produced by lichen-associated bacteria, especially Actinobacteria and Cyanobacteria (Parrot et al. 2015; Suzuki et al. 2016). In particular, the reviewing of lichen substances was pioneered by the prominent monographs, "Chemical and botanical guide to lichen products" by Culberson (1969) and "Identification of lichen substances" by Huneck and Yoshimura (1996) illustrating contemporary analytics and depicting about 700 lichen substances; as well as "Catalogue of standardized chromatographic data and biosynthetic relationships for lichen substances" by Elix (2014) which describes 854 compounds. Furthermore Stocker-Worgotter et al. (2013) has indicated that hitherto the identified lichen substances have outnumbered 1000.

Cetrarioid lichens, one of the most studied groups of lichens in the Parmeliaceae (lichen-forming Ascomycetes) family, are designated by their morphology with "foliose/subfruticose thalli with marginal apothecia and pycnidia", and chemically they contain lichenan, which is a linear [beta]-(1 [right arrow] 3, 1 [right arrow] 4) homoglycan (Nelsen et al. 2011). Considerable progress has been made in revealing the phylogeny (i.e. evolutionary relationships) of lichenized fungi in cetrarioid lichens using various genetic marker sequences of mycobiont nuclear ribosomal genes, such as group I intron, internal transcribed spacer (ITS), small subunit (SSU) and large subunit (LSU), and even polyketide synthase (PKS) genes (Nelsen et al. 2011; Opanowicz et al. 2006; Thell et al. 2009). Phylogenetic resolution of cetrarioid lichens has further increased and new phylogeny was recently proposed (Nelsen et al. 2011). According to a most recent article on the phylogeny of cetrarioid lichens, this group contains 25 genera and 149 species (Randlane et al. 2013), implying a great diversity of genetic resources and secondary metabolites.

The past two decades have witnessed a mounting number of scientific papers on discovery, biosynthesis and bioactivity of lichen substances, which reflects an increasing research interest in this area. However, accompanying the interest, insufficient structural elucidation (e.g. the absolute configuration is not indicated) and discrepant bioactivity results (e.g. antimicrobial activities of physodic acid as discussed in later section) in some studies may impede the accurate interpretation of bioactivities of lichen substances. In order to improve our understanding and to promote the application of lichen substances, it is urgent to have a critical attitude towards the research findings and a detailed library about the properties of lichen compounds and their bioactivities should be established. Thus, this review aims to present a more detailed and updated overview of the knowledge of secondary metabolites from cetrarioid lichens in a critical manner, highlighting their potentials for pharmaceuticals as well as other applications. Meanwhile, promising tools for bioprospecting, taxonomy and hit screening using molecular phylogenetics, metabolomics and ChemGPS are also proposed.

Ethnic uses of cetrarioid lichens and molecular phylogenetics for future bioprospecting

Crawford (2015) gave a very elaborate record of the ethnic uses of cetrarioid lichens, including Cetraria islandica, Cetrelia pseudolivetorum, Flavocetraria cucullata, Flavocetraria nivalis, Masonhalea richardsonii, Nephromopsis pallescens, Vulpicida canadensis, Vulpicida juniperinus and Vulpicida pinastri. They were mainly prepared as decoction or herbal tea with a variety of medicinal uses, such as treatment of coughs and inflammation, while Vulpicida species has also been used as a poison ingredient for wolves. Particularly, the medicinal lichen Cetraria islandica, also known as Iceland Moss, has been included in European Pharmacopoeias from 1600s and traditionally used to treat lung diseases and inflammation of oral and pharyngeal mucosa (Saroya 2011). In Iceland it is also used in folk medicines to treat cold symptoms and other minor ailments as dried and pulverized lichen (sometimes in capsules), as herbal tea or as a traditionally prepared milk soup (lichen boiled in milk) (Johannsdottir 2012). Iceland moss is also sold as polysacchariderich mixtures to treat cold and stomach ailments and used as a food ingredient in e.g. bread and soup (Kristinsson 1968).

With an applied perspective, there has been a debate whether the ethnic knowledge of traditional herbal medicines could provide hints for drug discovery. To address this question, recently researchers use molecular phylogeny representing the relationship of plant species and connect that to their ethnic uses, and finally it is found that traditionally medicinal plants tend to cluster in selected groups of plant species, which could be a good direction for future bioprospecting (Saslis-Lagoudakis et al. 2012; Zhu et al. 2011). Therefore, a question could be raised if the molecular phylogeny of lichens could be a powerful tool in predicting the production of bioactive compounds by taking the advantage of the well-established lichen phylogeny using multiple gene locus, such as nr ITS and nr LSU or PKS. Since lichens produce special molecular scaffolds with known bioactivities, such as depsides, depsidones and some special polysaccharides, it can be hypothesized that similar bioactive compounds may cluster in certain group of lichens.

Chemotaxonomy of cetrarioid lichens by secondary and primary metabolites

"A character in itself has no taxonomic value a priori, but may have importance when correlated with other independent characters. This, however, can only be evaluated a posteriori. Chemical characters do not fundamentally differ from other character sets, their nature, however, leads to an unreflected use when applied schematically."

Above is the conclusion made by Lumbsch (1998) by reviewing the historical opinions on chemical variants and lichen chemotaxonomy. It is hard to define how much value should be given to chemical character of lichens for taxonomic purposes, and actually the value varies from taxa to taxa. At least, chemical character has no independent taxonomic value.

Prior to the advent of modern DNA sequencing techniques, comparative lichen phytochemistry, which is mainly based on lichen secondary metabolites, undeniably is the most useful character accompanying morphology in the species delimitation of lichens (Culberson and Culberson 1970). To this end, a series of standard spot testing and thin layer chromatography (TLC) methods has been used and developed for decades (Culberson and Amman 1979). Even in contemporary lichen taxonomic monographs, one can always find chemical data generated from conventional spot testing and TLC of a certain lichen taxon, as exemplified in the fourth Volume of the Nordic Lichen Flora (Thell and Moberg 2011). From those data, it seems that a certain group of lichen taxa, which were defined by their morphology, tends to have a stable pool of secondary metabolites, which is a good indication of their classification. For instance, in cetrarioid lichens, yellow thallus predominantly containing usnic acids can be an indication of Flavocetraria species.

The knowledge of lichen secondary metabolites and their profiles in lichens is rapidly expanded using both classical and novel high performance liquid chromatography methods (Feige et al. 1993; Huneck et al. 1994). As a consequence, it is not uncommon for lichen chemotaxonomist to encounter chemical variants posing taxonomic problems at both species and subspecies levels, which may exist in multiple patterns, such as acid deficiency and chemosyndrome (Egan 1986). One example is the study of Cetraria islandica complex: by a careful examination of over 3000 specimens, Kristinsson (1969) found that this group contained both fumarprotocetraric acid-producing and -deficient variants revealed by p-phenylenediamine spot testing, and that such chemotypes had no correlations with morphology and geography. Furthermore, the lichen Cetraria ericetorum is also classified as an acid-deficient taxon with similar morphology to C. islandica but minor differences in lobe shape and pseudocyphellae position (Egan 1986), and thus chemotaxonomy using spot testing here is apparently insufficient to circumscribe those two lichens. That example also raises interesting questions about the biosynthesis of fumarprotocetraric acid and lichen species concept (Rogers 1989): what is the reason or mechanism for the differential gene expression in those chemical variants? How much variation in chemistry, morphology and gene sequence can we accept and recognise a species? A good hint to the answer was given by DePriest (1993), who proposed that the lichen acid-deficient chemotype may result from "suppression of intron slicing from genes that encode enzymes in the chemical pathways". However, no studies have been conducted in proving that hypothesis for the case of C. islandica group.

Lichen chemotaxonomy using secondary metabolites should also take the advantage of rapid developments of analytics using liquid chromatography-mass spectrometry (LC-MS) and advanced chemometrics, which could generate more informative data and are particularly potential in resolving closely related plant species and subspecies where certain DNA data are not taxonomically informative (Messina et al. 2014).

Interestingly, the use of polysaccharides seems to be another alternative for chemotaxonomy and phylogeny. Olafsdottir and Ingolfsdottir (2001) proposed the taxonomic potential of lichen polysaccharides, but in a later study the use of homoglycans (i.e. [beta]-glucan) in delimiting species from genera Parmotrema and Rimelia was not shown to be successful when data from [sup.1]H- and [sup.13]C-NMR, methylation analysis and Smith degradations were compared (Carbonero et al. 2005). In contrast to the use of homoglycans, the use of 1H-NMR spectra of heteroglycans seems to be very promising (Leal et al. 2010), and the authors developed a concept of "polysaccharide phylogenetic tree".

Fatty acid composition has also been used for chemotaxonomical purpose. A study based on the fatty acid composition of lichenized fungi presents the role of lipids in lichen taxonomy (Sassaki et al. 2001), which also leads to the discovery of two unusual fatty acids in the lichen Cetraria islandica: namely, octananedioic acid and nonanedioic acid. A dendogram based on fatty acid profiles of different lichen taxa was also established to show the clustering of lichen species, which were "most consistent with their taxonomic position" as claimed by the authors. However, that study did not investigate the fatty acid compositions of closely-related lichen taxa so the taxonomic value of lipid profiles for the delimitation of related species remains to be seen.

The application of lichen secondary metabolites in chemotaxonomy has been extensively practiced and proven to be quite useful. Nonetheless, the taxonomic value of lichen primary metabolites has been assumed but largely less tested, and the analytical procedure for those compounds, such as glycans and fatty acids, often requires more labor and time than the analysis of secondary metabolites (Paulsen et al. 2002; Sassaki et al. 2001). All in all, whatever chemical profiles are used for a careful taxonomic examination, they should be combined with other phenotypic and genotypic data as a "polyphasic approach" (Frisvad et al. 2008) for species delimitation.

Secondary metabolites in cetrarioid lichens and their bioactivities

Mycobiont-generated secondary metabolites are located on the hyphal surface of mycobiont cell walls, accounting for about 0.1-10% of total dry weight of lichen thalli. The lichen secondary metabolites: depsidones, depsides, dibenzoquinones and dibenzofurans were early considered to be exclusive to lichens (Galun and Shomer-Ilan 1988). More recently non-lichenized fungi were found to be able to produce depsidones, such as botryorhodines A-D in endophytic fungus Botryosphaeria rhodina (Abdou et al. 2010), the depsidone folipastatin in Aspergillus unguis (Hamano et al. 1992), and depside, such as depside guisinol in Emericella unguis (Nielsen et al. 1999). Angiosperms under elicitor treatment can also produce dibenzofuran, such as eriobofuran in Sorbus aucuparia (Huttner et al. 2010). They share the structural feature of two substituted phenolic rings (i.e. orcinol or [beta]-orcinol derivatives) joined by an ester linkage (i.e. depside, similar to olivetoric acid), or by an ester and an ether linkages (i.e. depsidone, similar to fumarprotocetraric acid), or a [sigma]-bond and an ether linkage (i.e. dibenzofuran, similar to usnic acid), or a [sigma]-bond between two aromatic rings (i.e. dibenzoquinone, similar to napthtoquinone). The distribution of these compounds that have been identified in cetrarioid lichens is listed in Table 1. The absolute configuration of compounds is not stated in Table 1, since it has not been determined in many cases because the data are mostly obtained from routine TLC or HPLC methods exclusively for taxonomic uses. Further details about secondary metabolites of cetrarioid lichens follow the order based on their structural characters: aliphatic acids (Fig. 1), quinones (Fig. 2), depsides (Fig. 3), depsidones (Fig. 4), carotenoids (Fig. 5), terpenoids and steroids (Fig. 6 and Fig. 7), dibenzofurans (Fig. 8), pulvinic acid derivatives (Fig. 9) and xanthones (Fig. 10).

Aliphatic acids

Protolichesterinic acid is an aliphatic [gamma]-lactone with a methylene group on the [alpha]-carbon, consisting of two enantiomers: (+)-protolichesterinic acid 1 could be found in Cetraria islandica (Huneck and Yoshimura 1996) and Flavocetraria cucullata (Nguyen et al. 2014), while (-)-protolichesterinic acid 2 is only reported in Cetraria ericetorum (Huneck and Yoshimura 1996). Species belonging to other genera, such as Allocetraria, also contain protolichesterinic acid, but unfortunately the specific rotation has not yet been measured (Divakar et al. 2003). According to the work by Turk et al. (2003), protolichesterinic acid (absolute configuration not tested) may not be an effective antimicrobial agent against ubiquitous bacterial (e.g. Bacillus, cereus, B. subtilis, Staphylococcus. aureus, Escherichia coli, Proteus, vulgaris, Pseudomonas, aeruginosa, P. syringae, Streptococcus faecalis, Aeromonas hydrophila, Yersinia enterocolitica, Listeria monocytogenes and Klebsiella pneumoniae) and fungal pathogens (e.g. Fusarium oxysporum, F. culmorum, F. moniliforme, F. solani, Penicillum sp., Cladosporium sp., Rhizopus sp., and Aspergillus sp.) using bacterial cultures and fungal agar plates, due to the exceedingly high minimum inhibitory concentration (MIC) above 3.6 mg/ml (11.10 mM). Weak antimycobacterial activity of (+)-protolichesterinic acid (MIC = 334 [micro]M) was found against the non-pathogenic species Mycobacterium aurum similar to pathogenic M. tuberculosis (Ingolfsdottir et al. 1998). The ethnic use of the lichen Cetraria islandica in the treatment of gastric and duodenal ulcer has stimulated researchers to study the role of (-i-)-protolichesterinic acid in the inhibition of Helicobacter pylori (Ingolfsdottir et al. 1997), and the MIC value is still high (MIC = 32 [micro]g/ml or 98.6 [micro]M). However, (+)-protolichesterinic acid revealed good potential as an antitrypanosomal agent against Trypanosoma brucei with a MIC value of 12.5 [micro]M, where its relatively high hydrophobicity favors its permeability to pathogen cells from molecular docking studies (Igoli et al. 2014). Interference with DNA metabolism has been adopted as a strategy in chemotherapy, and (+)-protolichesterinic acid is an in vitro potent inhibitor towards human immunodeficiency virus-1 reverse transcriptase ([IC.sub.50] = 24 [micro]M) (Pengsuparp et al. 1995) as well as human DNA ligase I ([IC.sub.50] = 20 [micro]M) (Tan et al. 1996). Anti-proliferative activity of (+)-protolichesterinic acids has been conducted using numerous human malignant cell-lines, and it has displayed a specifically strong activity against ZR-75-1 (breast carcinomas, [ED.sub.50] = 3.4 [micro]M), RPMI 8226 (human multiple myeloma, [IC.sub.50] = 5.55 [micro]M), Capan-1 (pancreas carcinoma, [EC.sub.50] = 33.2 [micro]M), HCT-116 (colon carcinoma, [IC.sub.50] = 34.3 [micro]M), SK-BR-3 (breast carcinomas, [IC.sub.50] = 10.8 [micro]M) and T-47D (breast carcinomas, [IC.sub.50] = 11.7 [micro]M) cell lines (Bessadottir et al. 2014; Bessadottir et al. 2015; Brisdelli et al. 2013; Haraldsdottir et al. 2004; Ogmundsdottir et al. 1998), and there is no antiproliferative activity of (+)-protolichesterinic acid against human keratinocyte cell line (HaCaT cells) at the concentrations as high as 5 [micro]M (Kumar and Muller 1999b). Cell apoptosis induced by protolichesterinic acid has been found in LNCaP and DU-145 prostate cancer cell lines (Russo et al. 2012) as well as RPMI 8226 and U266 human multiple myeloma cells (Bessadottir et al. 2015). To elucidate its anti-proliferative and pro-apoptotic effects, Russo et al. (2012) speculated the possible involvement of protolichesterinic acid (enantiomer not indicated) in the inhibition of Hsp 70 protein expression and a redox-sensitive mechanism in cell apoptosis. Nonetheless, in vitro antioxidant activity assays did not show any pronounced antioxidant activity of (+)-protolichesterinic acid using modelled membrane lipid peroxidation, diphenylpicrylhydrazyl (DPPH) radical scavenging and deoxyribose degradation assays (Kumar and Muller 1999a), and the authors indicate that (+)-protolichesterinic acid tends to have a specific enzyme interaction, rather than a non-specific redox mechanism. In addition, affecting the lipid metabolism of cancer cells (e.g. inhibiting 5- and/or 12-lipoxygenases) and inducing endoplasmic reticulum stress could be another mechanism (Bessadottir et al. 2010; Bessadottir et al. 2014; Bucar et al. 2004; Ingolfsdottir et al. 1994; Ogmundsdottir et al. 1998). One recent study by Bessadottir et al. (2015) has proven that inhibiting lipoxygenase activity cannot explain the observed anti-proliferative and pro-apoptotic effects of (+)-protolichesterinic acid, but it has entered into the cancer cells, which could lead to other intracellular effects.

As shown in Table 1, lichesterinic acid has a quite broad distribution among cetrarioid lichens. Semi-synthesized (+)- and (-)-lichesterinic acid are active inhibitors towards 5-lipoxygenase from porcine leucocytes (Ingolfsdottir et al. 1994). (+)-Lichesterinic acid 3 isolated from Cetraria islandica has a significant inhibitory activity on the growth of Trypanosoma brucei with an MIC value of 6.30 [micro]M compared to suramin (MIC = 10 [micro]M) as a positive reference (Igoli et al. 2014). Interestingly, there is a patent (Table 2) using the combination of (+)-lichesterinic and (+)-protolichesterinic acids to stimulate pigmentation of human skin and appendages (Boustie et al. 2012), while another patent describes the sole use of (+)-lichesterinic acid to inhibit the pigmentation (Boustie et al. 2015).

The lichen Cetraria islandica contains (+)-methyl protolichesterinate 4 as recorded by Huneck and Yoshimura (1996). The compound is inactive in inhibiting the activity of 5-lipoxygenase from porcine leucocytes (Ingolfsdottir et al. 1994). Furthermore, allo-protolichesterinic acid 5 and lichesterylic acid 6 can be found in Cetraria ericetorum and Cetraria islandica, respectively (Huneck and Yoshimura 1996), and no studies about their bioactivity have been reported. (+)-Roccellaric acid 7 was first found as a minor compound in Cetraria islandica using a "fluorous tag-catch and release strategy", as it normally co-elutes with protolichesterinic acid in TLC (Horhant et al. 2007). As lichens are a rich source of paraconic acids (i.e. y-butyrolactones carboxylated at carbon-3), it is of interest to explore the chemotaxonomic distribution of paraconic acid mixtures in cetrarioid lichens.

Quinones

Endocrocin 10 is an anthraquinone with an orange color, which has been found in the genus Nephromopsis: N. endocrocea (Huneck and Yoshimura 1996) and N. omata (Basionym: Cetraria omata) (Yosioka et al. 1972). Isolated endocrocin from Rumex nepalensis has been reported to be a moderate anti-inflammatory agent (0.5 mg/ear) in a mouse ear edema assay, and its inhibitory effects on the cyclooxygenases COX-2 and COX-1 are supposed to be involved in the anti-inflammatory activity (Gautam et al. 2010). Due to its natural orange color, it has been used as a natural pigment (Gill and Steglich 1987) and considered as a potent food grade colorant (Caro et al. 2012), but more evidence on its safety is needed.

Cuculoquinone 11 was isolated from the red thallus tips of Flavocetraria cucullata by Krivoshchekova et al. (1982), who have also elucidated the structure as 7,7'-bis(1,4,5,8-tetrahydroxy-3-ethylnaphtha-2,6-quinone). However, a recent re-investigation of the proposed structure using IR spectroscopy led to 3,3'-bis(6-ethyl-2,5,7,8-tetrahydroxy-l,4-naphthoquinone) (Pokhilo et al. 2011). The only reported study on the bioactivity of cuculloquinone (Stepanenko et al. 2002) showed that it had a stronger radical scavenging activity than butylated hydroxytoluene (BHT) using the DPPH assay.

Allocetraria endochrysea and A. stracheyi are among the cetrarioid lichens containing hybocarpone 12 (Randlane et al. 2001). This compound was first isolated from the lichen Lecanora hybocarpa, and it showed potent cytotoxicity against murine P815 mastocytoma cell line with [IC.sub.50] of 0.27 [micro]M (Ernst-Russell et al. 1999). A good antibacterial activity of hybocarpone has also been described against methicillin- and multidrug-resistant Staphylococcus aureus, and hybocarpone was the most active among tested lichen substances with a MIC value of 8.13-16.3 [micro]M (4-8 [micro]g/ml) (Kokubun et al. 2007).

3-Ethyl-2,7-dihydroxynaphthazarin 13 and islandoquinone 14a-d are naphthoquinones, co-isolated from a variant of Cetraria islandica, namely Cetraria islandica var. polaris which typically lacks lichesterinic acid (Stepanenko et al. 1997). No reports can be found on the bioactivities of 3-ethyl-2,7-dihydroxynaphthazarin and islandoquinone, but unsubstituted naphthazarin has moderate radical scavenging activity towards DPPH radicals, excellent inhibitory effect on 5-lipoxygenase ([IC.sub.50] = 3 [micro]M) and potent anti-proliferative activity towards human keratinocyte cell line (HaCaT cells) among selected lichen compounds with an [IC.sub.50] = 0.7 [micro]M (Muller et al, 1997). The molecular structure of islandoquinone was just revised recently about the connection of the two naphthazarin moieties and absolute configuration (Borisova et al. 2014).

Depsides

Hiascic acid 15 is a tri-depside found in Cetrariella delisei (Huneck and Yoshimura 1996). Hiascic acid is suggested to be toxic to fungi, and to have the potential to be used in pesticides (Dayan and Romagni 2001), but no scientific publication was found to support that claim presented in the article.

The antimicrobial activity of olivetoric acid 16 (MIC [greater than or equal to] 1.3 mM) against various bacterial and fungal pathogens is rather weak compared with both (+)- and (-)-usnic acids, but stronger than its depsidone analogue physodic acid (Tay et al. 2004; Turk et al. 2006; Yilmaz et al. 2004). Significant in vitro anti-angiogenic activity of olivetoric acid against rat adipose tissue endothelial cells (RATECs) was found at a high dose of 200 [micro]M, which was verified by the anti-proliferation of RATECs, the inhibition of RATEC tube formation as well as the depolymerization of actin stress fibers (Koparal et al. 2010).

In vitro bioactivity studies of gyrophoric acid 17 resulted in a high anti-proliferative activity towards cultured human keratinocyte cell line (HaCaT cells) with an [IC.sub.50] value of 1.7 [micro]M through cytostatic effects (Kumar and Muller 1999b). However, it showed very low cytotoxic effect ([IC.sub.50] > 200 [micro]M after incubation for 72 h) towards some other selected human cancer cell lines, such as HeLa, MCF-7, SK-BR-3, HT-29, HCT-116 and Jurkat (Backorova et al. 2011). Weak antimicrobial activity of gyrophoric acid is discovered against selected bacteria and fungi (Candan et al. 2006). The bioactivity of gyrophoric acid may be related to its DNA-interacting property, and it is the only inhibitor towards DNA topoisomerase I activity among tested lichen compounds (Plsikova et al. 2014).

Depsidones

The mutagenicity of physodalic acid 18 was early reported using the Ames Salmonella/microsome assay in the 1980s (Shibamoto and Wei 1984), and the authors found that the addition of cytochromes P450-containing S-9 mix significantly increased the revertant bacteria, meaning a higher mutagenicity was detected in the presence of S-9 mix. However, anti-mutagenicity of physodalic acid has later been revealed and shown to inhibit the mutation of bacteria induced by a heterocyclic amine, Trp-P-2 (Osawa et al. 1991). Significant anti-proliferative activity of physodalic acid to concanavalin A-treated rat thymocytes was found at the concentration of 1 [micro]g (p < 0.05) and 10 [micro]g (p < 0.001)/well of [10.sup.5] cells, and an increased level of intracellular reactive oxygen species (ROS) as well as decreased mitochondrial membrane potential (MMP) was considered to contribute to the induced cytotoxicity (Pavlovic et al. 2013). A weak anti-proliferative activity ([IC.sub.50] = 964 [micro]g/ml or 2.3 mM) of physodalic acid against HeLa cell line has been observed (Stojanovic et al. 2014).

Protocetraric acid 19 showed a weak antimycobacterial activity against Mycobacterium tuberculosis with an MIC value of 334 [micro]M (Honda et al. 2010). Nishanth et al. (2015), however, demonstrated a strong potential of protocetraric acid as a broad-spectrum antimicrobial agent, since it significantly inhibits the growth of medically important fungal and bacterial pathogens and the "absence of cytotoxicity to human normal cell lines". With disc diffusion assay, this substance showed better antibacterial activity against gram-negative bacteria Salmonella typhi (MIC = 1.34 [micro]M or 0.5 [micro]g/ml) and Klebsiella pneumoniae (MIC = 2.68 [micro]M or 1 [micro]g/ml), and gram-positive bacteria Mycobacterium smegmatis (MIC = 5.36 [micro]M or 2 [micro]g/ml) than a reference antibiotic ciprofloxacin (MIC= 10.72, 5.36 and 10.72 [micro]M or 4, 2 and 4 [micro]g/ml, respectively) among tested strains, with a better efficacy on gram-negative strains. A more pronounced antifungal activity was found against Trichophyton rubrum (MIC = 2.68 [micro]M or 1 [micro]g/ml) compared with the reference compound amphotericin B (MIC = 4.33 [micro]M or 4 [micro]g/ml). However, the research by Tay et al. (2004) did not show any promising activity of protocetraric acid against either gram-negative or -positive bacteria, and only weak antifungal activity against Candida glabrata (MIC = 52 [micro]g/ml or 0.14 mM) and Candida albicans (MIC = 52 [micro]g/ml or 0.14 mM). The contradictory results of these two studies might be explained by the different methods used to determine the antimicrobial activity, where Tay et al. (2004) used disk diffusion method for both bacteria ([10.sup.8] cell/ml) and fungi ([10.sup.8] spores/ml), and Nishanth et al. (2015) performed standard broth dilution method for bacteria (1 x [10.sup.5] CFU/ml) and fungi (0.4 x [10.sup.4] to 5 x [10.sup.4] CFU/ml). The diffusion properties and limited solubility of protocetraric acid could play a role. Protocetraric acid has shown cytotoxic activity to FemX (human melanoma, [IC.sub.50] = 58.68 [micro]g/ml or 156.8 [micro]M) and LS174 (human colon carcinoma, [IC.sub.50] = 60.18 [micro]g/ml or 160.8 [micro]M) cell lines (Manojlovic et al. 2012).

Cyclodextrins are used to make complexes with compounds that are poorly soluble in aqueous solutions. Fumarprotocetraric acid 20 formulated in cyclodextrin was shown to be inactive against the proliferation of malignant cell lines (T-47D, Panc-1 and PC-3) (Kristmundsdottir et al. 2005). Weak cytotoxicity of fumarprotocetraric acid has been found using various cancer cell lines, including L1210 (murine lymphocytic leukaemia, [IC.sub.50] = 82.3 [micro]g/ml or 174.2 [micro]M), 3LL (murine Lewis lung carcinoma, [IC.sub.50] = 75.9[micro]g/ml or 160.7 [micro]M), DU145 (human brain metastasis of a prostate carcinoma, [IC.sub.50] = > 100 [micro]g/ml or 211.7 [micro]M), MCF7 (human breast adenocarcinoma, [IC.sub.50] = > 100 [micro]g/ml or 211.7 [micro]M), K-562 (human chronic myelogenous leukaemia, [IC.sub.50] = > 100 [micro]g/ml or 211.7 [micro]M) and U251 (human glioblastoma, [IC.sub.50] = > 100 [micro]g/ml or 211.7 [micro]M) (Bezivin et al. 2004) as well as FemX ([IC.sub.50] = 30.67 [micro]g/ml or 64.9 [micro]M) and LS174 ([IC.sub.50] = 41.23 [micro]g/ml or 87.3 [micro]M) cell lines (Kosanic et al. 2014). Apart from the potent effect of fumarprotocetraric acid on the gram-negative bacterium Klebsiella pneumoniae (MIC = 65.63 [micro]M or 31 [micro]g/ml) (Misic et al. 2008), this lichen substance has a weak antimicrobial activity against the bacteria species: Bacillus cereus, B. subtilis, B. mycoides, Staphylococcus aureus, Escherichia coli and Listeria monocytogenes and the fungi Aspergillus flavus, A. fumigatus, Candida albicans, Penicillium purpurascens and P. verrucosum with MICs over 100 pM (Kosanic et al. 2014; Yilmaz et al. 2004). Moreover, fumarprotocetraric acid shows better antioxidant activity in the superoxide anion scavenging assay than the known antioxidant quercetin (Lohezic-Le Devehat et al. 2007) but still weaker activity than ascorbic acid (Kosanic et al. 2014). The antioxidant activity of fumarprotocetraric acid has also been tested using an in vivo mouse model where oral administration of fumarprotocetraric acid 50 mg/kg resulted in increased inhibition (81%) of lipid peroxidation compared to the negative control (de Barros Alves et al. 2014). An expectorant activity of fumarprotocetraric acid has also been found using male Albino mice as a model in the same study, where the activity was evaluated by tracheal output of phenol red indicating mucus secretion. However, it should be noted that the doses of fumarprotocetraric acid (25, 50 and 100 mg/kg or 0.053, 0.106 and 0.212 mmol/kg) used was considerably higher than the reference compound/positive control (ambroxol: 1 mg/kg or 2.64 [micro]mol/kg).

No promising bioactivity of stictic acid 21 has been discovered, except for its antiviral activity against plant pathogenic Tobacco Mosaic Virus (Ramirez et al. 2012). Stictic acid did neither show cytotoxicity against cancerous (HL-60 and HeLa) up to 10 [micro]M nor the non-cancerous cell line (Vero) up to 150 [micro]M (Schinkovitz et al. 2014). Using lecithin liposome assay, linoleic acid emulsion assay and DPPH radical scavenging assay, stictic acid (0.65 mM, 0.65 mM and 1.29 mM) showed weaker antioxidant activity than the known antioxidant BHT (1.13 mM, 1.13 mM and 2.27 mM), while norstictic acid 23 ([IC.sub.50] = 566 [micro]M) exhibits stronger antioxidant activity than quercetin ([IC.sub.50] = 754 [micro]M) and stictic acid using superoxide anion scavenging assay (Atalay et al. 2011; Lohezic-Le Devehat et al. 2007). Antimycobacterial activity of norstictic acid against Mycobacterium tuberculosis has also been reported with MIC value of 62.5 [micro]g/ml (168 [micro]M) (Honda et al. 2010).

Antioxidant activity of salazinic acid 24 has been evaluated using DPPH radical scavenging assay and linoleic acid peroxidation assay (Gaikwad et al. 2014), and it shows weaker activity in the first assay ([IC.sub.50] = 227 [micro]M or 88 [micro]g/ml) than a reference antioxidant butylated hydroxyanisole (BHA) ([IC.sub.50] = 366 [micro]M or 66 [micro]g/ml), and also stronger activity in the second assay ([IC.sub.50] = 278 [micro]M or 108 [micro]g/ml) than BHA ([IC.sub.50] = 749 [micro]M or 135 [micro]g/ml). The study also showed a growth promoting effect of salazinic acid towards a strain of human intestinal lactic acid bacteria: Lactobacillus casei, which is estimated by the increasing bacterial dry mass compared to control. Cytotoxicity of salazinic acid has been tested in FemX ([IC.sub.50] = 39.02 [micro]g/ml or 100.5 [micro]M) and LS174 ([IC.sub.50] = 35.67 [micro]g/ml or 91.9 [micro]M) cell lines (Manojlovic et al. 2012).

Antibacterial activity of physodic acid 27 against multi-drug resistant strains of Staphylococcus aureus ranges from MIC of 34-68 [micro]M, weaker than hybocarpone (MIC 8.13-16.3 [micro]M) and (+)-usnic acid (MIC 23.3-46.5 [micro]M) (Kokubun et al. 2007). Contradictory result can be found in Turk et al. (2006) and Rankovic et al. (2008), where the MIC values are as high as 53.1 and 2.13 mM, respectively. Physodic acid has also been indicated as a weak antimicrobial agent towards both bacteria and fungi with MIC values between 1.06 and 2.13 mM Rankovic et al. (2008). Differences of the strain in study and the concentration of microbial cells could contribute to the discrepancy between the MIC values. Interestingly, a derivative of physodic acid, 3-hydroxyphysodic acid, has a far stronger antimicrobial activity than physodic acid against bacterial and fungal pathogens (Turk et al. 2006; Yilmaz et al. 2005). Physodic acid displays no mutagenicity (Shibamoto and Wei, 1984) and anti-mutagenicity activity in Salmonella typhimurium TA98 treated with indirect mutagens, but no activity towards direct mutagens directed mutations (Osawa et al. 1991). Physodic acid was shown to be less pronounced in anti-proliferative activity towards rat thymocytes than physodalic acid with increased ROS production and decreased MMP levels (Pavlovic et al. 2013). Physodic acid also shows a low anti-proliferative activity ([IC.sub.50] = 171 [micro]g/ml or 363.4 [micro]M) against HeLa cell line (Stojanovic et al. 2014).

Carotenoids

Carotenoids are naturally occurring colorants widespread from higher plants to algae, fungi and bacteria (Lesellier et al. 1993), while the carotenoids in lichen are not extensively studied. The reasons might be the time-consuming sample preparation steps to avoid oxidation and limited taxonomic value since they are not specific to lichens. Nonetheless, carotenoid composition of lichen thalli has been applied to taxonomic research (Czeczuga 1988). Merely three cetrarioid lichens have been investigated for their carotenoid composition: [beta]-carotene 32, zeaxanthin 34, lutein 35, mutatoxanthin 39, [beta]-cryptoxanthin 41, lutein epoxide 42, antheraxanthin 43 and 3'-epilutein 44 in Cetrariella delisei; [alpha]-carotene 31, [beta]-carotene 32, [epsilon]-carotene 33, zeaxanthin 34, lutein 35, violaxanthin 36, lutein epoxide 42 and antheraxanthin 43 in Flavocetraria nivalis, and [beta]-carotene 32, zeaxanthin 34, lutein 35, astaxanthin 37, canthaxanthin 38, luteoxanthin 40, [beta]-cryptoxanthin 41 and lutein epoxide 42 in Cetraria islandica. The total carotenoids are present at low contents in lichen thalli as reported: 13.13, 29.7 and 37.64 [micro]g/g dry weight in Flavocetraria nivalis, Cetraria islandica and Cetrariella delisei, respectively (Czeczuga and Jacobsen 1993; Czeczuga and Kristinsson 1992). Pharmaceutical potential of carotenoids found in lichens are beyond the scope of this paper since they are not specific compounds in lichens.

Terpenoids and steroids

Only a few old studies have been carried out on the terpenoid and steroid profiles of cetrarioid lichens. Known terpenoids from lichens are all shared with higher plants or marine organisms, including monoterpenoid (-)-carvone 45, sesquiterpenoid bakkenolide A/fukinanolide A 46 from Cetraria islandica (Solberg 1986), triterpenoids [alpha]-amyrin 47, friedelan-3[beta]-ol/epifriedelinol 48, lupeol 49 and ursolic acid 50 from Flavocetraria nivalis (Bruun 1969) and zeorin 51 in the Vulpicida genus (Randlane et al. 2001). Cetrariella delisei is the only investigated cetrarioid species containing two steroids: ergosta-7,22-dien-3[beta]-ol/dihydroergosterol 52 and [beta]-sitosterol 53 (Solberg 1987). The bioactivity of the discovered compounds subject to this section has been well-studied. For example, the dietary triterpenoid lupeol, which is found in common vegetables and fruits, exhibits remarkable anti-inflammation activity in both in vitro and in vivo conditions via multiple mechanisms without toxicity to normal murine and human cells (Saleem 2009). The anti-inflammatory activity of the sterol ergosta-7,22-dien-3[beta]-ol, isolated from sea-star Marthasterias glacialis, via the inhibition of the NF-[kappa]B (nuclear factor kappa-B) pathway has also been recognized (Pereira et al. 2014).

Dibenzofuran

Undoubtedly usnic acid is the most studied lichen substance, which is present as two enantiomers: (-)-usnic acid 54 and (+)-usnic acid 55. Their chemistry, bioactivities and applications have been comprehensively reviewed by Ingolfsdottir (2002) and Cocchietto et al. (2002). The popularity of usnic acid is not only due to its pronounced bioactivities, but also its high content in lichen thallus up to 8% of thallus dry weight in Flavocetraria nivalis (Bjerke et al. 2005) and its wide distribution in many closely or even distantly related species. To date, usnic acid has been discovered in at least seven cetrarioid lichen genera, spanning Allocetraria, Cetreliopsis, Flavocetraria, Nephromopsis, Tuckneraria and Vulpicida (Randlane et al. 2001). Among the well-known usnic acid-containing lichens, it has been reported that Flavocetraria nivalis and Flavocetraria cucullata contain both (+)- and (-)-usnic acids (Kinoshita et al. 1997). More recently the presence of both isomers was also found in Cladonia stellaris, where (-)-usnic acid was found in much higher yield than (+)-usnic acid (Smeds and Kytoviita 2010).

The major concern in the application of usnic acid lies in its potential hepatotoxicity. With the advent of hepatotoxic case reports of usnic acid-containing dietary supplements in USA, a variety of toxicity studies using in vitro cell cultures and in vivo animal models have been carried out to elucidate the associated toxic mechanisms of usnic acid, mostly (+)-usnic acid and (+)-usnic acid-containing herbal preparations. Accumulating evidence reveals that the targets of (+)-usnic acid-induced hepatotoxicity may include endoplasmic reticulum, mitochondria and lysosome, leading to energy depletion and stress (Bessadottir et al. 2012; Liu et al. 2012; Pramyothin et al. 2004). For example, in vitro rat primary hepatocytes treated with 10 [micro]M (+)-usnic acid considerably decreased cell viability and cellular activity of oxidative phosphorylation and gluconeogenesis, whereas low concentrations at 1 or 5 [micro]M increased oxidative phosphorylation, implying a cellular adaptive response (Sonko et al. 2011). Significant inhibition of gluconeogenesis was also found using in vivo male albino rat model at low concentrations with [IC.sub.50] values ranging from 1.33 to 3.61 [micro]M (dependent on gluconeogenesis substrate), and higher concentration of 5-10 [micro]M lead to more adverse effects, such as impacted lipid metabolism and mitochondrial impairment (Moreira et al. 2013). Using in vitro HepG2 cell model, Chen et al. (2014) suggest that the hepatotoxicity effect of (+)-usnic acid may well result from a series of inter-correlated pathways, such as caspase-3/7 -mediated cell apoptosis, Akt/mTOR (protein Kinase B/mammalian target of rapamycin)-mediated cell autophagy and MAPK (mitogen-activated protein kinase) pathway, and the complex molecular mechanism remains to be further elucidated.

Decreased toxicity with higher antitumor activity of (+)-usnic acid is reported to be achieved using novel encapsulation technology (da Silva Santos et al. 2006; Ribeiro-Costa et al. 2004). However, reported liver toxicity caused by usnic acid-containing products is more complicated than those research findings, in terms of dosage and possible drug interactions of the enantiomeric forms of usnic acid. First of all, victims in reported cases use a high dose of usnic acid ranging from 300 mg/day to 1350 mg/day, whereas the reference dose in Traditional Chinese Medicine is about 60-120 mg/day (Guo et al. 2008). In addition, those products contained more components than usnic acids, such as caffeine, norephedrin hydrochloride and yohimbine hydrochloride in LipoKinetix[R] and carnitine in UCP-1[R] (Guo et al. 2008), which may involve toxic effects from drug interactions. It might also be a risk by mistakenly using a wrong herbal resource or adulteration, as the lichens of Cladonia species also contain usnic acid but predominantly (-)-usnic acid while the conventionally used Usnea lichens contain (+)-usnic acid (Marcano et al. 1999). (-)-Usnic acid is known to be more effective than (+)-usnic acid for the induction of cell apoptosis in certain cell models like human lymphocytes (Koparal et al. 2006), even though it has quite similar cytotoxicity to (+)-usnic acid in many other cell lines, such as L1210, DU145 (Bazin et al. 2008), Capan-2 and T-47D (Einarsdottir et al. 2010). The hepatotoxicity of (-)-usnic acid has not been evaluated and its possible role in the hepatotoxicity of usnic acid- containing herbal products is not known. Unfortunately, those products are still available on the market with potential risks to public health, even though U.S. FDA has recommended the product withdrawal of LipoKinetix[R] (CFSAN 2001). Since the usnic acid-containing products are marketed as dietary supplements, they are not regulated as drugs and it is the manufacturer and distributor who are responsible for the safety. All in all, more research is still needed to understand the toxicity of (+)- and (-)-usnic acids, their interactions with other drugs and their dose-response relationship.

In addition to hepatotoxicity, no genotoxicity of both enantiomers has been found using Ames Salmonella assay (Shibamoto and Wei 1984) and cytokinesis-block micronucleus assay (Koparal et al. 2006). Cytotoxicity of usnic acids to a large number of cancer and non-cancer cell lines has been reported: for example, (+)-usnic acid against cancer cell lines L1210 ([IC.sub.50] = 26.4 [micro]M), 3LL ([IC.sub.50] = 23 [micro]M), DU145 ([IC.sub.50] = 57.4 [micro]M), MCF7 ([IC.sub.50] = 105.4 [micro]M), K-562 ([IC.sub.50] = 52.8 [micro]M), U251 ([IC.sub.50] = 19.5 [micro]M), Capan-2 ([IC.sub.50] = 15.4 [micro]M) and T-47D ([IC.sub.50] = 12.2 [micro]M), whereas [IC.sub.50] values of (-)-usnic acid are 17.4, 35.1, 45.9, 51.7, 21.8, 19.7, 14.5 and 11.6 [micro]M, respectively (Bazin et al. 2008; Einarsdottir et al. 2010). Inhibition of DNA synthesis has also been found in human cancer cell lines (i.e. Capan-2 and T-47D) under the administration of (+)- and (-)-usnic acids, accompanied by the loss of mitochondrial membrane potential in cells (Einarsdottir et al. 2010). Further research also finds the proton shuttling effect of (+)-usnic acid on lysosomes as well as the formation of autophagosome in cancer cells, where no cell apoptosis is discovered using the same cell lines (Bessadottir et al. 2012). However, the induction of cell apoptosis has been found in human breast cancer cells (MCF-7) through the stimulated formation of reactive oxygen species by (+)-usnic acid (Zuo et al. 2015), murine leukaemia cells (L1210) by (-)-usnic acid (Bezivin et al. 2004) and (+)-usnic acid (Bazin et al. 2008), and also apoptosis in human lymphocytes by both isomers (Koparal et al. 2006), so usnic acid-induced cell apoptosis is rather cell-dependent. Aforementioned cell culture studies and other in vitro assays have shed light on the redox-active nature of usnic acids, and thus usnic acids may exert either pro-oxidant or antioxidant activities dependent on the model and concentration in use (Rabelo et al. 2012). Interestingly, cytotoxicity of (+)-usnic acid seems to be less potent in non-cancer cell lines. Cytotoxic doses of usnic acids in A549 (human lung carcinoma) were not effective in V79 (Chinese hamster lung fibroblast) (Koparal et al. 2006), and cytotoxicity to Vero (monkey kidney epithelial cells, [IC.sub.50] > 150 [micro]M) was much weaker than that in cancer cell lines, such as HL-60 ([IC.sub.50] = 6.4 [micro]M) and HeLa ([IC.sub.50] > 10 [micro]M) (Schinkovitz et al. 2014). However, (+)-usnic acid could inhibit cell growth in the human keratinocyte cell line, HaCaT, at low concentrations ([IC.sub.50] = 2.1 [micro]M) (Kumar and Muller 1999b).

Antibacterial activity of usnic acid seems to be more specific against Gram-positive strains (Ingolfsdottir 2002). To elucidate the mechanism, a recent study suggests that the antimicrobial activity of (+)-usnic acid against Gram-positive bacteria is primarily due to the inhibition of RNA and DNA synthesis, and inhibitory effects also occur in Gram-negative strains although less potent (Maciag-Dorszynska et al. 2014). Similarly, the antiviral activity of usnic acids is attributed to the inhibition of RNA transcription (Campanella et al. 2002).

Pulvinic acid derivatives

Pinastric acid 56 and vulpinic acid 57 are typical medullary lichen acids with intense yellow color in the genus Vulpicida, and their production is independent of algal partners (Golojuch and Lawrey 1988, Mattsson 1993). Vulpinic acid is found to be the most toxic compound to spores of the moss Funaria hygrometrica over the pH range from 5 to 8 (Gardner and Mueller 1981), but its antimicrobial activity is generally weaker than either enantiomer of usnic acids (Lauterwein et al. 1995), which is in disagreement with results from Lauinger et al. (2013) who found vulpinic acid as the only compound among the selected having inhibitory effects on Staphylococcus aureus (MIC = 32 [micro]M). Antimalarial activity of vulpinic acid has also been investigated against liver stage Plasmodium berghei, showing an [IC.sub.50] value of 10.2 [micro]M but less potent than (+)-usnic acid with [IC.sub.50] of 2.3 [micro]M (Lauinger et al. 2013). Results from both antimicrobial, antimalarial assays and molecular modelling can not fully support the enzymes involved in type II fatty acid biosynthesis pathway as the target (Lauinger et al. 2013).

Xanthones

Although secalonic acids are mostly present in fungi, three of the members, have been isolated from cetrarioid lichens, wherein secalonic acid A 58 from Allocetraria denticulata (Basionym: Cetraria denticulata) (Divakar et al. 2003), Allocetraria ambigua (Basionym: Cetraria ambigua) (Randlane et al. 2001); secalonic acid B 59 from Allocetraria endochrysea (Randlane et al. 2001) and secalonic acid C 60 from Nephromopsis omata (Basionym: Cetraria omata) (Yosioka et al. 1972). They are a group of seven stereoisomers sharing the same skeleton as dimeric phenolic compounds connected with a 2,2'-linkage between the phenolic rings (Aberhart et al. 1965). Currently, few specific studies have been published on the bioactivities of secalonic acid A and C. In contrast, its enantiomer, secalonic acid D, is well documented for food toxicity caused by fungi-induced cereal spoilage (Carlton et al. 1968) and teratogenicity revealed by abnormal fetal development and birth defects of rats (Mayura et al. 1982) and mice (Reddy et al. 1981). Its cytotoxicity has also been reported in cancer cell line B16 (murine melanoma. [IC.sub.50] = 0.28 [micro]M) and non-cancer cell line HaCaT (human keratinocyte, [IC.sub.50] = 3.7 [micro]M) (Millot et al. 2009). Secalonic acid B displayed antimicrobial activities against Gram-positive Bacillus megaterium, fungi Microbotryum violaceum and algae Chlorella fusca, but not Escherichia coli (Zhang et al. 2008). The cytotoxicity of secalonic acid B ([IC.sub.50] = 2.8 [micro]M for B16 and [IC.sub.50] > 10 [micro]M for HaCaT) was less potent than secalonic acid D (Millot et al. 2009). For a detailed record of bioactivities of secalonic acids, it is recommended to consult the review article written by Masters and Brase (2012). Despite the recorded toxicity of secalonic acid D, secalonic acids and their derivatives have been patented for their preparation methods as antibacterial agents (Kurobane et al. 1984) and antitumor agents (Shibukawa et al. 1985), respectively (Table 2).

Putting lichen compounds into the map using the ChemGPS-NP model

As a high-throughput bioactive compound screening approach, the concept of ChemGPS-NP was formally raised by Larsson et al. (2005). It is devised as an attempt to identify and chart the chemical space of biologically active compounds by capturing similarity through a comparison of compounds on the basis of their physicochemical properties (Larsson et al. 2007). ChemGPS-NP model provides a three-dimensional visualization of compounds or groups of compounds within an eight-dimensional chemical space. This model is based on a principal component analysis (PCA) of a set of 35 molecular descriptors calculated on a structurally diverse set of 1779 natural products. This analysis produces a reduction of the dimensionality resulting in eight Principal Components (PCs) or dimensions. In details, PCI correlates to size, shape and polarizability, PC2 to aromaticity, PC3 to lipophilicity and H-bond capacity, and PC4 to flexibility and rigidity. It is thus interesting to see the distribution of lichen compounds in the chemical space and to compare them with bioactive compounds from ChEMBL database (https://www.ebi.ac.uk/chembl/) which present similar pharmacological profile.

The distribution of cetrarioid lichen secondary metabolites in ChemGPS-NP space is shown in Fig. 11. Most of the compounds reside in the same area, except for the aliphatic acid derivatives and terpenes. In fact, these compounds consist of aliphatic scaffolds which separate them from aromatic compounds populating the other classes (increasing PC2 values). In terms of dimensions, the secalonic acids (xanthone group in purple) are isolated in the positive direction of PCI, while quinone molecules include both large and small compounds (brown dots). Depsidones are spread in the chemical area. Namely, they present various physico-chemical properties from low to large dimensions, from hydrophilic to more lipophilic compounds (e.g. salazinic acid and a-collatolic acid, respectively). The advantage of this analysis in ChemGPS-NP map is the intuitive visualization which allows to analyze compound properties in an interactive way and compare different members of a chemical or target class.

An important concept in medicinal chemistry is the relationship between similarity of structural features, physico-chemical properties and biological activity. In other words, it is assumed that similar molecules are likely to present similar biological profiles. If this concept is applied to ChemGPS-NP, it means that close compounds in the chemical space are supposed to present similar pharmacological profiles. In this scenario, we compared lichen compounds with known biological activity to compounds from ChEMBL database which are active on the same targets from the same organism. For example, some depside and depsidone compounds are shown to present anti-inflammatory activity against microsomial prostaglandin E2 synthase-1 (mPGES-1) (Bauer et al. 2012). As an example for comparative study, lichen compounds targeting mPGES-1 are compared with selected active compounds from ChEMBL which modulate mPGES-1 (Fig. 12). A slight overlap between those groups of compounds could be found. Lichen compounds are also found to be quite isolated and unique in the areas they occupy in the chemical space. This comparison was carried out with a subgroup of the lichen acid dataset, due to the limited availability of biological annotation.

Although the chemical diversity of lichen compounds as well as their pharmaceutical potential have been recognized, the potential drug targets of those compounds have rarely been studied. Some of the few examples of an investigation into potential drug targets are acetylcholinesterase (Luo et al. 2013; Pejin et al. 2012) and enzymes from the plasmodial fatty acid biosynthesis (FAS-II) pathway (Lauinger et al. 2013). To accelerate the compound selection, it is anticipated that ChemGPS-NP similarity search could be applied in the selection of lichen substance-based hits and the prediction of their bioactivities.

Concerns to the safety of lichen substances

As best exemplified by the hepatotoxicity of usnic acid-containing dietary supplement, it is not uncommon to find cases of herbal hepatotoxicity caused by either commercial products like herbal teas or other pure compounds like vitamin A (Bunchorntavakul and Reddy 2013; Teschke et al. 2012). It is urgent to employ new causality assessment strategies in place, and accumulate more high-quality data in case reports using recommended CIOMS (Council for International Organizations of Medical Sciences) scale (Teschke et al. 2012).

It is not a new knowledge that some lichen substances can cause allergy. A report from 1965 described the case of allergic contact dermatitis in two forest workers caused by usnic acid (Mitchell 1965). Later on, more lichen compounds were shown to be allergenic, such as atranorin, stictic, fumarprotocetraric and physodic acids (Brasch and Jacobsen 1991; Thune and Solberg 1980). The symptoms may be attributed to the patients' skin sensitivity to sunlight and the photosensitizer nature of aromatic lichen acids, and they can be related to occupational activity (e.g. woodcutters, horticultural workers, etc.) (Aalto-Korte et al. 2005). However, given the popularity of adding natural products in personal care products, the awareness of possible allergens in lichen-derived products is essential for consumers and a "patch testing with the standard lichen acid mix" is highly recommended to confirm allergic contact dermatitis caused by lichen origin (Schalock 2009). Cautions should also be taken in developing novel lichen substance-based sunscreens (Boehm et al. 2009).

The awareness of safety of lichen substances is recently renewed by the discovery of mycotoxin in lichen extracts using an enzyme-linked immunosorbent assay (Burkin and Kononenko 2013, 2014). Among the selected lichens are four cetrarioid lichens, including Cetraria islandica, Flavocetraria nivalis, Melanelia hepatizon and Vulpicida pinastri. Three mycotoxins are commonly encountered in those lichens, namely alternariol, emodin and diacetoxyscirpenol. Their contents vary massively from specimen to specimen. For example, the amount of emodin in Flavocetraria nivalis specimens ranges from 100 ng/g to 27,260 ng/g thalli, averaging at 4610 ng/g (Burkin and Kononenko 2014). Therefore, it is indispensable to determine the contents of mycotoxins while developing lichen-based therapeutics to ensure the safety.

Future-prospects

It is amazing that lichens produce a fruitful pool of bioactive secondary metabolites with a vast chemical diversity. The distribution as well as discovery of those compounds is an indispensable aid together with morphological, molecular and physiological information in species delimitation of closely-related taxa. The resolution of closely-related species could be largely increased by the use of modern analytical and computing techniques, such as LC-MS and principle component analysis. Taking the advantage of molecular phylogenetics, it is anticipated that the elucidation of biosynthetic pathways and prediction of production of particular lichen substances could be facilitated. Ultimately, we expect that more lichen substances with promising pharmaceutical potentials could be discovered by combining molecular phylogenetics and metabolomics.

Compared with higher plants, lichens are much neglected organisms in search for new drug leads. Accumulating evidence has demonstrated well the pharmaceutical potentials of lichen substances. They are mostly based on in vitro bioassays, in addition to ethnopharmacological uses of cetrarioid lichens which provide valuable hints. However, more research using various in vitro and in vivo models and screening assays are still needed together with careful evaluation of results to avoid over-interpretations of various in vitro assays (Gertsch 2009). Bioactivity assays should be carefully selected with respect to the lichen compounds tested. Given the nature of the assay, several factors, such as the pH value, solubility and stability of compounds used in the assay, which may be easily overlooked, are important variables when determining cytotoxicity of compounds in in vitro models (Gardner and Mueller 1981; Lauinger et al. 2013; Schinkovitz et al. 2014). For example, in evaluating cytotoxicity of lichen substances, water-soluble tetrazolium and trypan blue cytotoxicity assays displayed contradictory results in the beginning where the former assay showed growth-stimulation, while the latter shows the opposite (Schinkovitz et al. 2014). Similar case also happens in antioxidant assay where a particular compound may not be active in DPPH or emulsion assays, but turns out to be more potent in the superoxide anion scavenging assay (Lohezic-Le Devehat et al. 2007), and it is not uncommon that structurally related lichen acids may have different activities (Atalay et al. 2011).

Further research is also needed to understand the exact mode of action of lichen substances from a pharmacological perspective and the possible interactions between those substances (Ingolfsdottir et al. 1997), where molecular docking stimulation is promising to discover functional scaffold, protein-binding patterns and drug targets (Igoli et al. 2014; Lauinger et al. 2013). In addition to natural secondary metabolites, evidence on the bioactivities of their derivatives is also growing. This could be best manifested from a recent study showing the potential of a lichen dye, orcein that is made from decomposed depsides or depsidones, in the treatment of Alzheimer's disease (Bieschke et al. 2011).

Conclusion

Cetrarioid lichens, in particular the lichen Cetraria islandica, has traditionally been used in folk medicine, where their secondary metabolites are associated with remedial effects. The study of those compounds will not only help us define lichen taxa from a taxonomic point of view, but also comprehend their biological actions with regard to pharmaceutical implications. However, up to now, the understanding of their biosynthesis and production is quite limited (e.g. chemotypes, production yield), and the drug discovery screening of natural lichen substances and their modified derivatives is still largely unexplored. To this end, it is expected that the combination of molecular phylogenetics, metabolomics and ChemGPS-NP similarity search could facilitate lichen substance-based hit and lead discovery.

http://dx.doi.Org/10.1016/j.phymed.2016.02.012

ARTICLE INFO

Article history:

Received 11 November 2015

Revised 16 February 2016

Accepted 17 February 2016

Abbreviations: BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; CIOMS, Council for International Organizations of Medical Sciences; COX, cyclooxygenases; DPPH, diphenylpicrylhydrazyl; FAS-11, plasmodial type II fatty acid biosynthesis; ITS, nuclear ribosomal internal transcribed spacer gene region; LC-MS, liquid chromatography-mass spectrometry; LSU, nuclear ribosomal large subunit gene region; MIC, minimum inhibitory concentration; mPGES-1, microsomial prostaglandin E2 synthase-1; PCA, principal component analysis; PKS, polyketide synthase-encoding gene; RATECs, rat adipose tissue endothelial cells; SSU, nuclear ribosomal small subunit gene region; TLC, thin layer chromatography.

Conflict of interest

The authors declare that there are no conflicts of interest. Acknowledgment

The study is financially funded by the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/ under REA grant agreement No. 606895. We thank Dr. Lei Guo, Food and Drug Administration, USA, for the discussion on the toxicity of usnic acid. Professor John A. Elix, Australian National University, Australia, is acknowledged for providing the molecular structures of quaesitic acid and conquaesitic acid.

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Maonian Xu (a), Starri Heidmarsson (b), Elin Soffia Olafsdottir (a), Rosa Buonfiglio (c), Thierry Kogej (c), Sesselja Omarsdottir (a), *

(a) Faculty of Pharmaceutical Sciences, University of Iceland, Hagi, Hofsvallagata 53, IS-107 Reykjavik, Iceland

(b) Icelandic Institute of Natural History, Akureyri Division, 1S-600 Akureyri, Iceland

(c) Chemistry Innovation Centre, Discovery Sciences, AstraZeneca R&D Molndal, Pepparedsleden I, Molndal SE-43183, Sweden

* Corresponding author. Tel.: +354 5255818; fax: +354 5254071.

E-mail address: sesselo@hi.is, sesselo@icloud.com (S. Omarsdottir).

Table 1
Presence of common lichen acids in selected genera of the cetrarioid
lichen core group listed in Randlane et at. (2013) (Esslinger, 2003,
Lai et al. 2009, Lai and Elix, 2002, Randlane and Saag, 2003, Thell et
al., 2002, Wang et al., 2015).

Lichen acid\             Lichesterinic   Protolichesterinic
Genus & Species              acid               acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua                  [check]           [check]
A. endochrysea              [check]           [check]
A. flavonigrescens
A. globulans                [check]           [check]
A. isidiigera
A. madreporiformis          [check]           [check]
A. sinensis                 [check]           [check]
A. stracheyi                [check]           [check]
A. yunnanensis              [check]           [check]
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata                 [check]           [check]
C. ericetorum               [check]           [check]
C. islandica                [check]           [check]
C. laevigata                [check]           [check]
C. muricata                 [check]           [check]
C. nigricans                [check]           [check]
-C. obtusata                [check]           [check]
C. odontella                [check]           [check]
C. sepincola                [check]           [check]
-C. xizangensis             [check]           [check]

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides
C. hypotrachyna
C. laeteflava
C. papuae                                     [check]
C. rhytidocarpa                               [check]
C. thailandica                                [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata                [check]           [check]
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii                    [check]           [check]
-N. hengduanensis           [check]           [check]
N. komarovii                [check]           [check]
N. laii                     [check]           [check]
N. laureri                  [check]           [check]
N. leucostigma              [check]           [check]
N. melaloma                 [check]           [check]
N. morrisonicola            [check]
N. nephromoides             [check]           [check]
N. omata
N. pallescens               [check]           [check]
N. stracheyi
N. togashii                 [check]           [check]
N. yunnanensis              [check]           [check]

Tuckermanella (Esslinger 2003)

T. arizonica                   ?
T. fendleri                    ?
T. pseudoweberi
T. subfendleri
T. weberi

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides                              [check]
T. weii                        ?                 ?

Usnocetraria (Randlane and Saag 2003)

U. oakesiana                [check]           [check]

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Roccellaric   Caperatic   Nephrosterinic
Genus & Species             acid         acid           acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua                              [check]
A. endochrysea
A. flavonigrescens
A. globulans                            [check]
A. isidiigera
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens                         [check]

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata                                           [check]
C. ericetorum
C. islandica               [check]
C. laevigata
C. muricata
C. nigricans
-C. obtusata                            [check]
C. odontella
C. sepincola
-C. xizangensis

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides
C. hypotrachyna
C. laeteflava
C. papuae
C. rhytidocarpa                         [check]
C. thailandica

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon                            [check]
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii                                [check]
-N. hengduanensis                       [check]
N. komarovii
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola                        [check]
N. nephromoides                         [check]
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi                         [check]
T. subfendleri                          [check]
T. weberi                               [check]

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii                                    ?

Usnocetraria (Randlane and Saag 2003)

U. oakesiana                            [check]

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Alectoronic   Collatolic   Fumarprotocetraric
Genus & Species             acid          acid             acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens                                       [check]
A. globulans
A. isidiigera                                            [check]
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica                                             [check]
C. laevigata                                             [check]
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis                                          [check]

Cetrariella (Thell and Moberg 2011)

C. commixta                [check]      [check]
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae                                              [check]
C. endoxanthoides                                        [check]
C. hypotrachyna
C. laeteflava                                            [check]
C. papuae                                                [check]
C. rhytidocarpa                                          [check]
C. thailandica                                           [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis
N. komarovii                                             [check]
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola
N. nephromoides
N. omata                                                 [check]
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi                  [check]

Tuckermannopsis (Randlane and Saag 2003)

T. americana               [check]      [check]
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Protocetraric   Physodic   Physodalic
Genus & Species              acid          acid        acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens          [check]
A. globulans
A. isidiigera               [check]
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica                [check]
C. laevigata
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis             [check]

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae                 [check]                  [check]
C. endoxanthoides           [check]
C. hypotrachyna
C. laeteflava
C. papuae                   [check]
C. rhytidocarpa             [check]
C. thailandica              [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis
N. komarovii
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola
N. nephromoides
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi                                   ?

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Stictic   Constictic   Norstictic
Genus & Species           acid        acid         acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens
A. globulans
A. isidiigera
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica
C. laevigata
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides
C. hypotrachyna                                  [check]
C. laeteflava
C. papuae
C. rhytidocarpa
C. thailandica

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon             [check]                 [check]
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis
N. komarovii             [check]    [check]
N. laii
N. laureri
N. leucostigma
N. melaloma                 *
N. morrisonicola
N. nephromoides
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Succinprotocetraric   Salazinic
Genus & Species                 acid             acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens
A. globulans
A. isidiigera
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica
C. laevigata
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides                               [check]
C. hypotrachyna                                 [check]
C. laeteflava                                   [check]
C. papuae                      [check]          [check]
C. rhytidocarpa                [check]          [check]
C. thailandica                                  [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata                                    [check]
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis
N. komarovii
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola
N. nephromoides
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\                 9[alpha]-0-        Quaesitic  Conquaesitic
Genus & Species          methylsalazinic acid     acid         acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens
A. globulans
A. isidiigera
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica
C. laevigata
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides                                [check]     [check]
C. hypotrachyna
C. laeteflava                                    [check]     [check]
C. papuae                      [check]           [check]     [check]
C. rhytidocarpa                [check]           [check]     [check]
C. thailandica                 [check]           [check]     [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis
N. komarovii
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola
N. nephromoides
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

Lichen acid\             Secalonic   Usnic   Pinastric  Vulpinic
Genus & Species           acid(s)    acid      acid       acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua                [check]   [check]
A. endochrysea            [check]   [check]
A. flavonigrescens                  [check]
A. globulans              [check]   [check]
A. isidiigera             [check]   [check]
A. madreporiformis                  [check]
A. sinensis               [check]   [check]
A. stracheyi              [check]   [check]
A. yunnanensis            [check]   [check]
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica
C. laevigata
C. muricata
C. nigricans
-C. obtusata              [check]
C. odontella
C. sepincola
-C. xizangensis                     [check]

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei
C. fastigiata

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae                         [check]
C. endoxanthoides
C. hypotrachyna                     [check]
C. laeteflava
C. papuae                           [check]
C. rhytidocarpa                     [check]
C. thailandica                      [check]

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata                        [check]
F. nivalis                          [check]
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii                            [check]
-N. hengduanensis                   [check]
N. komarovii                        [check]
N. laii                             [check]
N. laureri                          [check]
N. leucostigma                      [check]
N. melaloma                         [check]
N. morrisonicola                    [check]
N. nephromoides                     [check]
N. omata                  [check]   [check]
N. pallescens                       [check]
N. stracheyi                        [check]
N. togashii                         [check]
N. yunnanensis                      [check]

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana              [check]   [check]

Vulpicida (Thell and Moberg 2011)

V. juniperina                       [check]   [check]   [check]
V. pinastri                         [check]   [check]   [check]

Lichen acid\             Hiascic  Gyrophoric  Olivetoric
Genus & Species           acid       acid        acid

Allocetraria (Randlane and Saag 2003; Wang et al. 2015)

A. ambigua
A. endochrysea
A. flavonigrescens
A. globulans
A. isidiigera
A. madreporiformis
A. sinensis
A. stracheyi
A. yunnanensis
Arctocetraria
A. nigricascens

Cetraria (Horhant et al. 2007; Igoli et al. 2014; Lai et al. 2009;
Thell and Moberg 2011)

C. aculeata
C. ericetorum
C. islandica
C. laevigata
C. muricata
C. nigricans
-C. obtusata
C. odontella
C. sepincola
-C. xizangensis

Cetrariella (Thell and Moberg 2011)

C. commixta
C. delisei               [check]   [check]
C. fastigiata            [check]   [check]

Cetreliopsis (Lai and Elix 2002; Thell et al. 2002; Randlane and
Saag 2003)

C. asahinae
C. endoxanthoides
C. hypotrachyna
C. laeteflava
C. papuae
C. rhytidocarpa
C. thailandica

Flavocetraria (Thell and Moberg 2011; Nguyen et al. 2014)

F. cucullata
F. nivalis
Melanelia
M. hepatizon
M. stygia

Nephromopsis (Thell and Moberg 2011)

N. ahtii
-N. hengduanensis                              [check]
N. komarovii
N. laii
N. laureri
N. leucostigma
N. melaloma
N. morrisonicola
N. nephromoides
N. omata
N. pallescens
N. stracheyi
N. togashii
N. yunnanensis

Tuckermanella (Esslinger 2003)

T. arizonica
T. fendleri
T. pseudoweberi
T. subfendleri
T. weberi                                         ?

Tuckermannopsis (Randlane and Saag 2003)

T. americana
T. ciliaris                                    [check]
T. ulophylloides
T. weii

Usnocetraria (Randlane and Saag 2003)

U. oakesiana

Vulpicida (Thell and Moberg 2011)

V. juniperina
V. pinastri

*: means the acid is inconstantly occur dependent on the chemotype.

-: means the taxonomic position of the lichen is not sufficiently
circumscribed.

?: means insufficient evidence of the presence of the compound.

Table 2
Patents and applications based on substances in cetrarioid lichens.

Patent no.          Metabolites and application      Reference

US4424373           Preparation of secalonic acids   Kurobane et al.
                    for novel antibacterial agents   (1984)

DE3229086           The use of Cetraria islandica    Wichert (1984)
                    in veterinary medicine and
                    feedstuff for the respiratory
                    health of horses

US4556651           Preparation of secalonic acid    Shibukawa et al.
                    derivatives for antitumor        (1985)
                    agents

US5260053           A deodorant composition for      Chappell et al.
                    personal use containing usnic    (1993)
                    acid as a key bactericide

EP0560227A2         Acetone extract of               Miura et al.
                    Nephromopsis omata having high   (1993)
                    inhibitory effect on Epstein-
                    Barr virus activation with a
                    antioncogenic promotor
                    activity

US5447721           Acetone extracts of              Miura et al.
                    Nephromopsis omata (43.1%) and   (1995)
                    Vulpidda canadensis (96.9%)
                    showing superoxide elimination
                    activity for cosmetic uses

US5409702           Methanol extracts of lichen      Higuchi et al.
                    cultures including Cetraria      (1995)
                    juniperina (Basionym of
                    Vulpicida canadensis or V.
                    tubulosus) contain melanin
                    production inhibitors for
                    cosmetic uses

FR2756182           Use of crude extract of          Etienne (1998)
                    Cetraria islandica containing
                    polysacharides and
                    protolichesterinic acid to
                    prevent and treat asthma

WO1999020793        Vulpinic acid and usnic acid     Davies et al.
                    to inhibit eukaryotic protein    1999
                    kinases for investigational
                    and therapeutic uses

US20030068294       Extract from Cetraria            Cabrera and
                    islandica combined with other    Beguer (2003)
                    plant extracts for veterinary
                    medicine (i.e. ear hygiene)

KR100453679         A hair tint composition          Jin (2004)
                    containing Tuckermannopsis
                    ciliaris as a auxiliary
                    component

CN1500520A          An aqueous ethanol extract of    Yao et al. (2004)
                    a non-cetrarioid lichen
                    Parmelia tinctorum containing
                    atranorin, nonstictic acid and
                    salazinic acid produced for
                    antibiotics

WO2006125857        A polymer blend based from       Reijonen (2006)
                    lichen polysaccharides and
                    other polymers for capsule
                    coatings, etc.

W02008077997        A water soluble wood             Reijonen (2008)
                    protection product made from
                    extracts of Cetraria islandica

KR1020110064773 A   A herbicidal composition         Seoun et al.
                    containing vulpinic acid with    (2011)
                    less environmental
                    contamination

US 20120329868      A combination of (+)-            Boustie et al.
                    protolichesterinic acid and      (2012)
                    (+)-lichesterinic acid or
                    their derivatives used for
                    stimulating pigmentation of
                    skin and appendages

WO2012085559 A1     Antibacterial or anti-acne       Eady and
                    skin care formulations contain   Fitzgerald (2012)
                    usnic acid or usnate

JP2013253060        A process to produce a lichen    Takashi et al.
                    extract containing usnic acid    (2013)
                    for skin external agents such
                    as whitening agent

US20150105459       (+)-Lichesterinic acid and its   Boustie et al.
                    derivatives to inhibit the       (2015)
                    pigmentation of human skin and
                    appendages
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Author:Xu, Maonian; Heidmarsson, Starri; Olafsdottir, Elin Soffia; Buonfiglio, Rosa; Kogej, Thierry; Omarsd
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:4EUSW
Date:May 15, 2016
Words:17724
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