Abstract

1. Introduction

Medicinal plants have been the source of remedies for the treatment of several illnesses since earliest times, and people from all continents have practiced the use of botanicals for millenia. Despite the significant growth in synthetic organic chemistry in the 20th century, over 25% of approved drugs in industrialized countries are obtained directly or indirectly from plants (Newman et al., 2000). In recent years, the search for phytochemicals with antioxidant, antimicrobial, or anti-inflammatory properties has been on the rise due to their potential use for the treatment of various chronic and infectious diseases (Halliwell, 1996). Therapeutic plants may be an alternative source of antimicrobial agents with important bioactivity against pathogenic and transmissible microorganisms, with fewer side effects than synthetic antibiotics (Berahou et al., 2007). Plant extracts have numerous secondary metabolites, such as phenolic components, that enhance biological activity. Plant secondary metabolites are known to possess antimicrobial and antioxidant properties, and some of them are categorized as generally recognized safe substances (Proestos et al., 2005). With the growing interest in these compounds, phytocompounds from therapeutic plants with some biomedicinal activity are in great demand (Chen et al., 2008; Pesewu et al., 2008; Prachayasittikul et al., 2008).

Ferns and their allies are one of the oldest major divisions of the Pteridophyta, and comprise over 12 000 species spread among 250 different genera (Chang et al., 2011). Traditionally, the biomedical system and Ayurvedic systems of medicine, named Sushruta (ca. 100 AD) and Charka (ca. 100 AD), suggested the use of some ferns in the Samhita texts. Pteridophytes are also used by physicians in the Unani system of medicine (Uddin et al., 1998). In the traditional Chinese system of medicine, several ferns are recommended by native doctors (Kimura and Noro, 1965). In more recent times, ethnobotanical and advanced pharmacological studies have been carried out on ferns and their allies by several investigators (Dhiman, 1998; Vasudeva, 1999; Reddy et al., 2001; Singh L et al., 2001; Gogoi, 2002; Singh M et al., 2008a, 2008b; Chen JJ et al., 2005; Chen K et al., 2005).

2. Phytochemicals of ferns and their distribution in other plant groups

The secondary metabolites, flavonoids, have anti-inflammatory properties through the inhibition of the cyclo oxygenase (COX) pathway (Liang et al., 1999). They were also found to have antioxidant, anti-cancer, and antimicrobial properties (Lin et al., 2008; Yoshida et al., 2008; Amaral et al., 2009; Lopez-Lazaro, 2009; Govindappa et al., 2011). Spider brake fern (Pteris multifida) has various bioactive flavonoids with heat-clearing, antipyretic, detoxification, antibiotic, anti-inflammatory, and antimutagenic activity (Lee and Lin, 1988). The entire plant of P. multifida contains various bioactive compounds including: luteolin-7-O-glucoside (Murakami and Machashi, 1985; Lu et al., 1999), 16-hydroxy-kaurane-2-β-D-glucoside (Liu and Qin, 2002), luteolin, palmitic acid, apigenin 4-O-α-L-rhamnoside (Lu et al., 1999; Qin et al., 2006), quercetin, hyperin, isoquercitrin, kaempferol, rutin (Lu et al., 1999; Wang et al., 2010; Hoang and Tran, 2014), and apigenin-7-O-β-D-glucoside (Lu et al., 1999; Hoang and Tran, 2014). Also, the cytotoxic bioactive compounds, pterosin sesquiterpenes, have been isolated from P. multifida (Shu et al., 2012). Bioactive terpenoids, especially the monocyclic sesquiterpene α-caryophyllene, were found in an ethanolic extract of Pteris tripartita (Baskaran and Jeyachandran, 2010). Sesquiterpenes form a significant group of secondary metabolites and have a varied range of medicinal activity, including anti-cancer, anti-inflammatory, cytotoxic, plant growth-regulatory, and antimicrobial properties (Baruah et al., 1994).

The anti-inflammatory activity of fatty acids such as myristic, palmitic, stearic, oleic-linoleic, and eicosatrienoic acids are widely known (Bremner and Heinrich, 2002). Stearic acid has been shown to have both anti-inflammatory and hepatoprotective effects (Pan et al., 2010). Baskaran and Jeyachandran (2010) found octadecanoic acid (a stearic acid) in an ethanol extract of P. tripartita. Pteridium aquilinum, thought to be a fern with potent anti-cancer properties, contains p-coumaric, p-hydroxybenzoic, caffeic, ferulic, vanillic, and protocatechuic acids (Michael and Gillian, 1984). Hydroxycinnamic acid, anthocyanins, total polyphenols, and flavonoids have been quantified in Stenochlaena palustris (Chai et al., 2012). Some bioactive flavones such as amentoflavone, robustaflavone, biapigenin, hinokiflavone, podocarpusflavone A, and ginkgetin, in Selaginella sp. were reported to have antioxidant, antivirus, and anti-cancer activity (Ma et al., 2001; Shi et al., 2008; Liu et al., 2011; Li S et al., 2014). Both the whole plant and mature spores of Lygodium japonicum are used for medical purposes in traditional Chinese medicine. For over 2000 years, L. japonicum has been used in China for the treatment of gorge gall, skin eczema, enteritis diarrhea, nephritis dropsy, urine calculus, and infection (Wynne et al., 1998). The foremost phenolic components, namely 4-hydroxycinnamic acid (p-coumaric), 3-methoxy-4-hydroxycinnamic acid (ferulic), 3,4-dihydroxycinnamic acid (caffeic), 3-methoxy-4-hydroxybenzoic, acid and 3-caffeoilquinic acid (chlorogenic), have been found in Polypodium leucotomos extracts (Gombau et al., 2006). The free radical scavenging bioactive principles viz. flavan-4-ol glycosides, abacopterins, huperzine A, isoquercetin, di-E-caffeoyl-meso-tartaric acid, flavaspidic acid PB, flavaspidic acid AB, flavan-3-ol, kaempferol, A-type proanthocyanidins, and afzelechin, have been derived from a few ferns including Abacopteris penangiana, Huperzia selago, Equisetum arvense, and Dryopteris crassirhizoma (Lee et al., 2003; Staerk et al., 2004; Zhao et al., 2007; Mimica et al., 2008). Fig. ​Fig.11 and Table ​Table11 list the distribution of numerous bioactive compounds present in pteridophytes.

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Fig. 1

Bioactive compounds in pteridophytes

Table 1

Distribution of bioactive compounds in pteridophytes

No.	Pteridophyte	Bioactive compounds	Source(s)
1	Pteris multifida	Luteolin-7-O-glucoside, 16-hydroxy-kaurane-2-β-D-glucoside, luteolin, palmitic acid, apigenin4-O-α-L-rhamnoside, quercetin, hyperin, isoquercitrin, kaempferol, rutin, apigenin-7-O-β-D-glucoside, and pterosin	Murakami and Machashi, 1985; Lu et al., 1999; Liu and Qin, 2002; Qin et al., 2006; Wang et al., 2010; Shu et al., 2012; Hoang and Tran, 2014
2	Pteris tripartita	α-Caryophyllene and octadecanoic acid	Baskaran and Jeyachandran, 2010
3	Abacopteris penangiana	Flavan-4-ol, glycosides, and abacopterins	Zhao et al., 2007
4	Pteridium aquilinum	p-Coumaric acid, p-hydroxybenzoic acid, caffeic acid, ferulic acid, vanillic acid, protocatechuic acid, kaempferol, quercetin, and apigenin	Michael and Gillian, 1984
5	Selaginella sp.	Amentoflavone, robustaflavone, biapigenin, hinokiflavone, podocarpusflavone A, and ginkgetin	Ma et al., 2001; Shi et al., 2008; Liu et al., 2011; Li S et al., 2014
6	Equisetum arvense	Isoquercetin, quercetin 3-O-glucoside, quercetin 3-O-(6''-O-malonylglucoside), 5-O-caffeoyl meso-tartaric acid, monocaffeoyl meso-tartaris acid, monocaffeoyl meso-tartaris acid, di-E-caffeoyl-meso-tartaric acid, hexahydrofarnesyl acetone, cis-geranyl scetone, thymol, and trans-phytol	Radulovic et al., 2006; Milovanovic et al., 2007; Mimica et al., 2008
7	Polypodium leucotomos	4-Hydroxycinnamic acid (p-coumaric), 3-methoxy-4-hydroxycinnamic acid (ferulic), 3,4-dihydroxycinnamic acid (caffeic), 3-methoxy-4-hydroxybenzoic acid, and 3-caffeoilquinic acid (chlorogenic)	Gombau et al., 2006
8	Adiantum capillus-veneris	Adiantone, adiantoxide, astragalin, β-sitosterol, caffeic acids, caffeylgalactose, caffeylglucose, campesterol, carotenes, coumaric acids, coumarylglucoses, diplopterol, epoxyfilicane, fernadiene, fernene, filicanes, hopanone, hydroxy-adiantone, hydroxy-cinnamic acid, isoadiantone, isoquercetin, kaempferols, lutein, mutatoxanthin, naringin, neoxanthin, nicotiflorin, oleananes, populnin, procyanidin, prodelphinidin, quercetins, querciturone, quinic acid, rhodoxanthin, rutin, shikimic acid, violaxanthin, and zeaxanthin	Taylor, 2003
9	Dryopteris crassirhizoma	Flaspidic acid PB and flavaspidic acid AB	Lee et al., 2003
10	Cyathea gigantea	β-Sitosterol	Woyengo, 2009
11	Cibotium barometz	Pterosins, terpenoids, sterides, flavones, glucosides, aromatic, and pyrone compounds	Wu et al., 2007; Xu et al., 2012
12	Cyathea phalerata	Kaempferol-3-neohesperidoside, 4-O-β-D-glucopyranosyl caffeic acid, 4-O-β-D-glucopyranosyl p-coumaric acid, 3,4-spyroglucopyranosyl protocatechuic acid, sitosterol β-D-glucoside, β-sitosterol, kaempferol, and vitexin	Hort et al., 2008
13	Pteris vittata	Rutin, kaempferol monoglycoside, kaempferol diglycoside, quercetin monoglycoside, and quercetin diglycoside	Salatino and Prado, 1998; Singh et al., 2008b
14	Polypodium leucotomos	3,4-Dihydroxybenzoic acid, chlorogenic acid, 4-hydroxybenzoic acid, chlorogenic acid, vanillic acid, caffeic acid, 4-hydroxycinnamic acid, 4-hydroxycinnamoyl-quinic acid, and ferulic acid	Garcia et al., 2006
15	Angiopteris evecta	Angiopterioside	Twentyman et al., 1989
16	Onoclea sensibilis	Kaempferol and quercetin	Harada and Saiki, 1955
17	Matteuccia struthiopteris	Kaempferol and quercetin
18	Equisetum ramoissimum	Apigenin and luteolin
19	Lycopodium japonicum	Lycopodine-type alkaloids	He et al., 2014
20	Lycopodium sieboldii	Sieboldine A	Hirasawa et al., 2003
21	Lycopodium casuarinoides	Huperzine B and N-demethylhuperzinine	Shen and Chen, 1994
22	Selaginella tamariscina	Caffeic acid, ferulic acid, vanillic acid, syringic acid, adenosine, umbelliferone, and amentoflavone	Bi et al., 2004; Zheng et al., 2004; Woo et al., 2005
23	Selaginella moellendorfii	Moellenoside B and selaginellic acid	Wang et al., 2009b; Feng et al., 2011
24	Selaginella doederleinii	Apigenin and hordenine	Chao et al., 1987; Chen et al., 1995
25	Dicranopteris linearis	Afzelin, quercitrin, isoquercitrin, astragarin, rutin, kaempferol 3-O-(4-O-p-coumaroyl-3-O-α-lrhamnopyranosyl)-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside, and (6S,13S)-6-[6-O-acetyl-β-D-glucopyranosyl-(1→4)-α-L-rhamnopyranosyloxy]-13-[α-lrhamnopyranosyl-(1→4)-β-D-fucopyranosyloxy]cleroda-3,14-diene	Raja et al., 1995; Zakaria et al., 2008
26	Psilotum nudum	Quercetin, kaempferol, amentoflavone, hinokiflavone, vicenin-2 psilotin, and 3'-hydroxypsilotin	Cambie and Ash, 1994
27	Huperzia selago	Huperzine A	Staerk et al., 2004
28	Huperzia serrata	Alkaloids: huperzine A and B	Liu et al., 1986
29	Pityrogramma tartarea	2'6'-dihydroxy-4,4'-dimethoxydihydrochalcone, kaempferol 7-methyl ether, and apigenin 7-methyl ether	Star and Mabry, 1971
30	Pityrogramma calomelanos
31	Cheilanthes concolor	7-O-Glycosides of apigenin, aglycone, 7-O-glycosides of luteolin, 7-O-glycosides of chrysoeriol, 3-O-glycosides of kaempferol, 3-O-glycosides of kaempferol, and 3-O-glycosides of quercetin	Salatino and Prado, 1998
32	Cheilanthes flexuosa
33	Cheilanthes goyazensis
34	Doryopteris ornithopus
35	Pellaea cymbiformis
36	Pellaea gleichenioides
37	Pellaea pinnata
38	Pellaea riedelii
39	Pteris altissima
40	Pteris angustata
41	Pteris decurrens
42	Pteris deflexa
43	Pteris denticulata
44	Pteris plumula
45	Pteris podophylla
46	Pteris splendens
47	Pteris propinqua
48	Cyrtomium fortunei	Protocate chaldehyde, woodwardinsaure methylester, physcion, pimpinellin, ursolic acid, sitost-4-en-3-one, betulin, 3',4',5-trihydroxy-3,7-dimethoxyflavone, woodwardinic acid, sutchuenoside A, kaempferol-3,7-O-α-L-dirhamnoside, (−)-epicatechin, (+)-catechin hydrate kaempferol, crassirhizomoside A, and kaempferol-3-O-(3-O-acetyl-α-L-rhamnopyranoside	Yang et al., 2013

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Marchantiophyta have a cellular oil body which produces numerous mono-, sesqui-, and di-terpenoids, aromatic compounds like bibenzyl, bis-bibenzyls, and acetogenins. Most sesqui-and di-terpenoids isolated from non-vascular plants (liverworts) are enantiomers of those present in vascular plants (Asakawa et al., 2013). Since 1960, studies have begun to identify triterpenoids in ferns too. Moreover, flavonoids are present in more than one genus of ferns and also occur in fern allies (Berti and Bottari, 1968). Pteridophytes are known to produce proanthocyanidins which are present in a polymerized molecular form, as tannins. Proanthocyanidins in higher groups of plants are formed by dihydroflavonol-4-reductase (DFR) using dihydroflavonols as substrate. The DFR enzyme has not been described in pteridophytes, but the genomic characterization of ferns has begun. DFR has been obtained from duplicate genes linked with primary metabolism; in this instance, nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductases are related to steroid metabolism (Baker and Blasco, 1992). Moreover, three divisions of the flavonoid pathway well-known in the bryophytes are also found in pteridophytes including procyanidins, prodelphinidins, and flavonols like kaempferol, quercetin, and myricetin (Markham, 1988). Acylphloroglucinol compounds are found only in the genus Dryopteris, which has been used in chemosystematic and phylogenetic studies (Widen, 1971; Widen and Britton, 1971a, 1971b). Flavonoids and phenolic compounds are the most general group of bioactive principles in plants, occurring in almost all plant parts, but mainly in photosynthesizing cells. These compounds are the main producers of the colors of blooming plants (Koes et al., 2005). In early studies, myricetin, quercetin, kaempferol, apigenin, luteolin, and gallic acid were reported in angiosperms including the Hamamelidae, Rutaceae, Eriocaulaceae, Lythraceae, and Velloziaceae (Grieve and Scora, 1980; Giannasi, 1986; Salatino et al., 2000). Several phenolic compounds, such as p-coumaric acid, caffeic acid, ferulic acid, protocatechuic acid, gallic acid, vanillic acid, and flavonoids like luteolin, apigenin, have also been identified in seagrasses (Subhashini et al., 2013). Apigenin, kaempferol, luteolin, myricetin, quercetin, and rutin were identified in some Iranian flowering plants from different families including the Leguminosae, Polygonaceae, Euphorbiaceae, Resedaceae, and Cyperaceae (Mitra, 2012). The bioactive flavonoids, kaempferol, luteolin, quercetin, quercitrin, isoquercitrin, hyperoside, and guaijaverin, have been derived from methanol extracts of Hypericum brasiliense (Rocha et al., 1995). In addition, kaempferol, myricetin, catechin, vitexin, orientin, isoquercitin, hyperside, isovitexin, luteolin-7-glucoside, rutin, kampferol-7-neohesp-eridoside, quercitin, luteolin, and apigenin have been identified in the angiosperm families Lytheraceae, Acanthaceae, Chenopodiaceae, Caprifoliaceae, Euphorbiaceae, Verbenaceae, Zygophyllaceae, Moraceae, Asteraceae, Urticaceae, Scrophulariaceae, Verbenaceae, and Mimosaceae (Khan et al., 2012). The evolution of flavonoids in land plants has been discussed from an enzymatic point of view. In ferns and their allies, proanthocyanidin and NADPH reductase are present for flavonoid synthesis while anthocyanidin and pterocarpan synthase have been reported in gymnosperms and angiosperms. Moreover, at two different levels, chalcone synthase, chalcone isomerase, anthocyanidin synthase, flavonol synthase, isoflavone synthase, and NADPH reductase are also involved in flavonoid synthesis (Stafford, 1991). These studies show that all land plants are related based on the evidence of shared secondary metabolites. The genetic relationships among genes in response to phytochemical synthesis in vascular and non-vascular plant groups should be studied further to understand their phytochemical evolution.

3. Activity of ferns

3.1. Antioxidant activity

Most of the pteridophytes are of great economic value, especially in medical, aesthetic, and food applications (Vasudeva, 1999). Table ​Table22 summarizes the antioxidant activity of pteridophytes. The antioxidant activity has been reported for several fern species, namely Polystichum semifertile, Nothoperanema hendersonii, Braomea insignis (Chen K et al., 2005), some Chinese ferns (31 species) (Ding et al., 2008), Selaginella sp. (Gayathri et al., 2005), Polyopodium leucotomus (Garcia et al., 2006; Gombau et al., 2006), E. arvense, Equesitum sylvaticum (Milovanovic et al., 2007), A. penangiana (Zhao et al., 2007), Drynaria fortunei, Pseudodrynaria coronans, Davallia divaricata, Davallia mariesii, Davallia solida, Humata griffithiana (Chang et al., 2007b), Marsilea quadrifolia (Fig. ​(Fig.2c)2c) (Ripa et al., 2009), Cheilanthes anceps Swartz (Chowdhary et al., 2010), Pteris ensiformis Burm. (Chen et al., 2007; Wei et al., 2007), P. multifida (Shyur et al., 2005; Wang et al., 2009a), P. tripartita (Baskaran and Jeyachandran, 2010), Dicranopteris linearis (Fig. ​(Fig.2d)2d) (Zakaria et al., 2011), and Drynaria quercifolia (Fig. ​(Fig.2e)2e) (Milan et al., 2013). Efficient antioxidant properties (0.02–0.12 mg/ml in 2,2-diphenyl-1-picrylhydrazyl (DPPH) activity and 0.03–0.22 mg/ml in activity of 2,2'-azino-bis-(3-ethyl benzthiazoline-6-sulphonie acid diammonium salt (ABTS) radical scavenging) of several fern genera like Davallia, Hypolepis, Pteridium, Cyrtominum, Dryopteris, Polystichum, Dicranopteris, Lycopodium, Osmunda, Adiantum, Coniogramme, Polypodium, Pyrrosia, Pteris, Lygodium, Selaginella, Thelypteris, Athyrium, Matteuccia, Onoclea, and Woodsia have also been reported (Shin, 2010). According to Shin and Lee (2010), scavenging effects on DPPH and ABTS radicals were higher in methanol extracts from rhizomes than in those from aerial parts of Adiantum pedatum, Coniogramme japonica, D. mariesii, Cyrtomium fortunei, D. crassirhizoma, Polystichum polyblepharum, Polystichum lepidocaulon, Dryopteris nipponensis, Pteris cretica, P. multifida, and Polypodium nipponica.

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Fig. 2

Color illustrations of medicinal pteridophytes: (a) P. aquilinum; (b) Lycopodium japonicum; (c) Marsilea quadrifolia; (d) Dicranopteris linearis; (e) Drynaria quercifolia; (f) Cibotium barometz; (g) Blechnum orientale; (h) Hemionitis arifolia

Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article

Table 2

Antioxidant potentials of pteridophytes

No.	Plant name	Family name	Methods used	Source(s)
1	Polystichum semifertile	Dryopteridaceae	Xanthine oxidase, lipoxygenase activity, and ABTS•+ assay	Chen et al., 2005a
2	Nothoperanema hendersonii	Dryopteridaceae
3	Braomea insignis	Blechnaceae
4	Blechnum orientale	Blechnaceae	DPPH assay	Lai et al., 2010
5	Selaginella sp. (n=3)	Selaginellaceae	In vitro lipid peroxidation, hydroxyl radical scavenging activity	Gayathri et al., 2005
6	Polypodium leucotomus	Polypodiaceae	H2O2 and FRAP assays	Garcia et al., 2006; Gombau et al., 2006
7	Equesitum sp. (n=5)	Equisetaceae	Total antioxidant capacity	Milovanovic et al., 2007
8	Abacopteris penangiana	Thelypteridaceae	Trolox equivalent antioxidant capacity (TEAC) assay	Zhao et al., 2007
9	Marsilea quadrifolia	Marsileaceae	DPPH assay	Ripa et al., 2009
10	Cheilanthes anceps	Sinopteridaceae	DPPH assay	Chowdhary et al., 2010
11	Pteris ensiformis	Pteridaceae	DPPH and TEAC assays	Chen et al., 2007; Wei et al., 2007
12	Pteris multifida	Pteridaceae	DPPH, superoxide scavenging activity	Shyur et al., 2005; Wang et al., 2009a
13	Pteris tripartita	Pteridaceae	DPPH, metal chelating activity, phosphomolydenum assay	Baskaran and Jeyachandran, 2010
14	Dicranopteris linearis	Gleicheniaceae	DPPH assay	Milan et al., 2013
15	Selaginella labordei	Selaginellaceae	In vitro xanthine oxidase inhibition	Tan et al., 2009
16	Diplazium polypodioides	Athyriaceae	DPPH assay	Kshirsagar and Upadhyay, 2009
17	Pteris vittata	Pteridaceae	DPPH and ferric reducing power assays	Lai and Lim, 2011
18	Adiantum radianum	Pteridaceae
19	Acrostichum aureum	Pteridaceae
20	Cyathea latebrosa	Cyatheaceae
21	Cibotium barometz	Dicksoniaceae
22	Drynaria quercifolia	Polypodiaceae
23	Blechnum orientale	Blechnaceae
24	Diplazium esculentum	Athyriaceae
25	Nephrolepis biserrata	Nephrolepidaceae
26	Dicranopteris linearis	Gleicheniaceae
27	Dicksonia sellowiana	Dicksoniaceae	In vitro and in vivo antioxidant assays	Bora et al., 2005; Rattmann et al., 2011; Oliveira et al., 2016
28	Microgramma vacciniifolia	Polypodiaceae	In vitro DPPH assay	Peres et al., 2009
29	Polypodium leucotomos	Polypodiaceae	In vitro H2O2 assay	Gombau et al., 2006
30	Davallia mariesii	Davalliaceae	In vitro DPPH, ABTS•+, and total antioxidant assays	Shin, 2010; Delong et al., 2011
31	Cyrtomium fortunei	Dryopteridaceae
32	Dryopteris crassirhizoma	Dryopteridaceae
33	Dryopteris nipponensis	Dryopteridaceae
34	Polystichum lepidocaulon	Dryopteridaceae
35	Polystichum polyblepharum	Dryopteridaceae
36	Dicranopteris pedata	Gleicheniaceae
37	Osmunda cinnamomea var. fokiensis	Osmundaceae
38	Osmunda japonica	Osmundaceae
39	Adiantum pedatum	Pteridaceae	In vitro DPPH, ABTS•+, and total antioxidant assays	Shin, 2010; Delong et al., 2011
40	Pyrrosia lingua	Polypodiaceae
41	Lygodium japonicum	Lygodiaceae
42	Thelypteris acuminate	Thelypteridaceae
43	Athrium niponicum	Athyriaceae
44	Onoclea sensibilis var. interrupta	Onocleaceae
45	Matteuccia struthiopteris	Onocleaceae
46	Aleuritopteris flava	Pteridaceae	DPPH, ABTS•+, ferric reducing power, and metal chelating assays	Gupta et al., 2014
47	Pteris scabristipes	Pteridaceae
48	Adiantum edgeworthii	Pteridaceae
49	Lindsaea odorata	Dennstaedtiaceae
50	Microlepia rhomboidea	Dennstaedtiaceae
51	Microlepia hallbergii	Dennstaedtiaceae
52	Asplenium khasianum	Aspleniaceae
53	Diplazium esculentum	Athyriaceae
54	Athyrium filix-femina	Athyriaceae	Oxygen radical absorbance capacity	Soare et al., 2012a
55	Dryopteris affinis	Dryopteridaceae
56	Dryopteris filix-mas	Dryopteridaceae
57	Dryopteris cochleata	Dryopteridaceae	DPPH, ABTS•+, superoxide, nitric oxide, hydroxide, reducing power, ferrous chelating, and lipid peroxidation assays	Kathirvel et al., 2014

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According to Kshirsagar and Upadhyay (2009), methanol extracts of Diplazium polypodioides and ethyl acetate or water extracts of Blechnum orientale show strong antioxidant capacity (Lai et al., 2010). Lai and Lim (2011) reported that Pteris vittata, Cyathea latebrosa, Cibotium barometz (Fig. ​(Fig.2f),2f), D. quercifolia, B. orientale (Fig. ​(Fig.2g),2g), Adiantum radianum, Diplazium esculentum, Acrostichum aureum, Nephrolepis biserrata, and D. linearis exhibited strong antioxidant activity ranging from 0.12 to 0.57 mg/ml. The presence of phenolics in extracts of Dicksonia sellowiana may contribute directly to its antioxidant properties (Duh et al., 1999; Bora et al., 2005). Ethanolic and ethyl acetate extracts showed good antioxidant action based on the DPPH radical scavenging assay in Microgramma vacciniifolia (Peres et al., 2009). According to Hort et al. (2008), the antioxidant activity and hepatoprotective potential of crude extracts are based on organic solvents of increasing polarity. Gombau et al. (2006) demonstrated that hexane and chloroform extracts of P. leucotomos had significant inhibitory activity/strong antioxidative properties, based on an H₂O₂ (hydrogen peroxide) assay. The antioxidant properties of methanol extracts of rhizomes and fronds of D. mariesii, C. fortunei, D. crassirhizoma, D. nipponensis, P. lepidocaulon, P. polyblepharum, Dicranopteris pedata, Osmunda cinnamomea var. fokiensis (Fig. ​(Fig.3f),3f), Osmunda japonica, A. pedatum, Pyrrosia lingua, L. japonicum (Fig. ​(Fig.2b),2b), Thelypteris acuminata, Athyrium niponicum, Matteuccia struthiopteris (Fig. ​(Fig.3h),3h), and Onoclea sensibilis var. interrupta were reported by Shin (2010) and Delong et al. (2011).

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Fig. 3

Color illustrations of medicinal pteridophytes: (a) Cyrtomium fortunei; (b) Adiantum capillus-veneris; (c) Cyathea gigantea; (d) Selaginella willdenowii; (e) Selaginella doederleinii; (f) Osmunda cinnamomea; (g) Pyrrosia lingua; (h) Matteuccia struthiopteris

Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article

Methanol leaf extracts of P. multifida showed stronger antioxidant activity than ethanol extracts (Hoang and Tran, 2014). In a DPPH assay of S. palustris, antioxidant activity was higher in mature fertile (2.29 mg TE/mg GAE; TE: Trolox equivalent; GAE: gallic acid equivalent) and sterile (2.07 mg TE/mg GAE) fronds than in young fertile (1.99 mg TE/mg GAE) and sterile (1.80 mg TE/mg GAE) fronds. Moreover, significantly higher metal chelating activity was observed in young sterile fronds (101.22 µg EDTA/mg GAE; EDTA: ethylenediaminetetraacetic acid) and mature fertile fronds (176.37 µg EDTA/mg GAE) than in young fertile fronds (82.14 µg EDTA/mg GAE) and mature sterile fronds (16.54 µg EDTA/mg GAE) (Chai et al., 2012). Methanol extracts from aerial plant parts of eleven different species of pteridophytes from Korea, namely A. pedatum, C. japonica, D. mariesii, C. fortunei, D. crassirhizoma, P. polyblepharum, P. lepidocolon, D. nipponensis, P. cretica, P. multifida, and P. nipponica displayed significant DPPH scavenging activity ranging from 0.05 to 1.66 mg/ml while the activity of rhizome extracts ranged only from 0.02 to 4.99 mg/ml. Using ABTS assays, Zakaria et al. (2011) found 0.06 to 0.53 mg/ml of activity in methanol extracts from aerial plant parts and 0.03 to 1.24 mg/ml in rhizome extracts. In DPPH assays, methanol extracts from leaves of D. linearis exhibited higher antioxidant activity (20 µg/ml) (37.8%) than aqueous (29.3%) or chloroform extracts (13.3%). In D. linearis, superoxide scavenging activity was the highest in methanol extracts (84.2%), moderate in aqueous extracts (62.1%), and the lowest in chloroform extracts (23.2%) (Milan et al., 2013). Methanol extracts of D. polypodiodes displayed only 5.87% antioxidant activity in DPPH assays (Kshirsagar and Upadhyay, 2009). The ethyl acetate, butanol, and water fractions of B. orientale revealed significant free radical scavenging activity (IC₅₀ 8.6–13.0 μg/ml) (Lai et al., 2010). Significant DPPH scavenging (0.12 to 0.14 mg/ml) and ferric reducing power (FRP) (963 to 1417 mg GAE/100 g) were observed in methanol extracts from leaves of C. latebrosa, Cibotium barometz, D. quercifolia, B. orientale, and D. linearis. Adiantum raddianum and P. vittata displayed the highest activity in DPPH scavenging (0.27 and 0.29 mg/ml, respectively) and FRP (842 and 578 mg GAE/100 g, respectively) (Lai and Lim, 2011).

3.2. Anti-cancer, antidiabetic, and antiviral activity

The anti-cancer activity of ferns is listed in Table ​Table3,3, and their antidiabetic and antiviral activity in Table ​Table4.4. Both ethanol and water extracts of Hemionitis arifolia (Burm.) Moore (Fig. ​(Fig.2h)2h) showed hypoglycaemic and antidiabetic properties in rats (Ajikumaran Nair et al., 2006; Kumudhavalli and Jaykar, 2012). The antihyperglycemic and analgesic activity of the leaves of Christella dentata, Adiantum philippense, and Angiopteris evecta has been studied by Paul et al. (2012), Tanzin et al. (2013), and Sultana et al. (2014). Microsorum grossum has been used to cure liver cancer (Petard and Raau, 1972; Defilpps et al., 1988). Pteris polyphylla (Lee and Lin, 1988) and A. evecta (Defilpps et al., 1988) also show anti-cancer activity. In the Chinese traditional medicine system, “Gusuibu” has been used for its anti-cancer and anti-inflammation activity. It is prepared from the rhizomes of various ferns, namely D. fortunei (Kze.) J. Sm., P. coronans (Wall. Ex Mett.) Ching, D. divaricata BL., D. mariesii Moore ex-Bak, D. solida (Forst.) Sw., and H. griffithiana (Hk.) C. Chr. (Cui et al., 1990; Cai et al., 2004; ChPC, 2005; Chang et al., 2007a). M. quadrifolia has been used to treat human breast cancer, diabetes, and snake bites, and as an anti-inflammatory and diuretic (Uma and Pravin, 2013). The bear paw fern, Phlebodium decumanum has been used for anti-cancer, ulcer, and high blood pressure treatments (Punzon et al., 2003). The leaves and rhizomes of H. arifolia (Burm.) Moore and whole plants of Adiantum capillus-veneris L. were used by the tribes of the Valparai hills, Western Ghats, and Tamil Nadu (India) for their hypoglycaemic and anti-cancer activity (Santhosh et al., 2014). Both leaves and rhizomes of A. capillus-veneris L. have been used in the preparation of herbal drugs for treating diabetes in India and Europe. This fern has diverse phytochemical constituents: adiantone, adiantoxide, astragalin, β-sitosterol, caffeic acids, caffeylgalactose, caffeylglucose, campesterol, carotenes, coumaric acids, coumarylglucoses, diplopterol, epoxyfilicane, fernadiene, fernene, filicanes, hopanone, hydroxy-adiantone, hydroxy-cinnamic acid, isoadiantone, isoquercetin, kaempferols, lutein, mutatoxanthin, naringin, neoxanthin, nicotiflorin, oleananes, populnin, procyanidin, prodelphinidin, quercetins, querciturone, quinic acid, rhodoxanthin, rutin, shikimic acid, violaxanthin, and zeaxanthin (Taylor, 2003).

Table 3

Anti-cancer property of pteridophytes

No.	Plant name	Family name	Methods used	Source(s)
1	Microsorum grossum	Polypodiaceae	Traditional medicine	Petard and Raau, 1972; Defilpps et al., 1988
2	Pteris polyphylla	Pteridaceae	In vitro antimutagenic activity, traditional Chinese medicine	Lee and Lin, 1988; Wang and Zhang, 2008
3	Pteris multifida	Pteridaceae	In vitro MTT method; antimutagenic activity against picrolonic acid-induced mutation
4	Angiopteris evecta	Marattiaceae	Traditional Chinese medicine	Defilpps et al., 1988
5	Drynaria fortunei	Polypodiaceae	Traditional Chinese medicine	Punzon et al., 2003; Cai et al., 2004; ChPC, 2005; Chang et al., 2007a
6	Pseudodrynaria coronans	Polypodiaceae	Traditional Chinese medicine
7	Phlebodium decumanum	Polypodiaceae	In vitro tumour necrosis inhibition
8	Davallia mariesii	Davalliaceae	Korea folk medicine	Cui et al., 1990; Cai et al., 2004; ChPC, 2005
9	Davallia divaricata	Davalliaceae	Traditional Chinese medicine
10	Davallia solida	Davalliaceae
11	Humata griffithiana	Davalliaceae
12	Marsilea quadrifolia	Marsileaceae	In vitro cytotoxic activity on MCF-7	Uma and Pravin, 2013
13	Hemionitis arifolia	Pteridaceae	Traditional Indian medicine	Santhosh et al., 2014
14	Adiantum capillus-veneris	Pteridaceae
15	Blechnum orientale	Blechnaceae	In vitro MTT assay against human colonic adenocarcinoma HT-29, human colonic carcinoma HCT-116, human breast adenocarcinoma MCF-7, human leukemia K562	Lai and Lim, 2010
16	Polypodium nipponica	Polypodiaceae	In vivo two-stage carcinogenesis test on mouse skin papillomas	Konoshima et al., 1996
17	Polypodium formosanum	Polypodiaceae
18	Polypodium vulgare	Polypodiaceae
19	Polypodium fauriei	Polypodiaceae
20	Polypodium virginianum	Polypodiaceae
21	Dryopteris crassirizoma	Dryopteridaceae
22	Adiantum monochlamys	Pteridaceae	In vivo two-stage carcinogenesis test on mouse skin papillomas
23	Oleandra wallichii	Oleandraceae
24	Cyrtomium fortunei	Dryopteridaceae	In vitro MTT assay on MGC-803, PC3, A375 tumor cells	Yang et al., 2013
25	Asplenium polyodon	Aspleniaceae	Traditional Indian medicine	Singh, 1999; Santhosh et al., 2014
26	Asplenium nidus	Aspleniaceae
27	Adiantum capillus-veneris	Pteridaceae
28	Ophioglossum gramineum	Ophioglossaceae
29	Hemionitis arifolia	Pteridaceae
30	Pteridium aquilinum	Dennstaedtiaceae	Anticancer compounds identified	Nwiloh et al., 2014
31	Pityrogramma calomelanos	Pteridaceae	In vitro cytotoxicity against Dalton’s lymphoma ascites tumour cells and Ehrlich ascites tumour cells	Sukumaran and Kuttan, 1991; Shin, 2010; Zakaria et al., 2011; Milan et al., 2013
32	Drynaria quercifolia	Polypodiaceae	Brine Shrimp lethality bioassay
33	Dicranopteris linearis	Gleicheniaceae	In vitro MTT assay on MCT-7, HeLa, HT-29, HL-60, K-562, MDA-MB-231
34	Selaginella willdenowii	Selaginellaceae	In vitro cytotoxic activity on human cancer cell lines	Lee and Lin, 1988; Silva et al., 1995; Sun et al., 1997; Lee et al., 1999; Lin et al., 2000; Su et al., 2000; Chen et al., 2005b; Gao et al., 2007; Li J et al., 2014; Li S 2014; Elda et al., 2015
35	Selaginella lepidophyla	Selaginellaceae	In vitro MTT assay on human colon cancer cell line (HTB-38)
36	Selaginella labordei	Selaginellaceae	In vitro MTT assay on Bel-7402, HeLa, HT-29
37	Selaginella moellendorffii	Selaginellaceae	In vitro cytotoxic activity on human ovarian adenocarcinoma cells; in vitro MTT assay on cervical carcinoma (HeLa), foreskin fibroblast (FS-5), Bel-7402, HeLa, HT-29
38	Selaginella delicatula	Selaginellaceae	In vitro cytotoxic activity on Raji and Calu-1 tumor cell lines; in vitro MTT assay on Bel-7402, HeLa, HT-29
39	Selaginella tamariscina	Selaginellaceae	In vitro MTT assay; in vitro antiproliferative activity in leukemia cells, Bel-7402, HeLa, HT-29; in vivo single dose acute toxicity test
40	Selaginella doederleinii	Selaginellaceae	Antimutagenic activity against picrolonic acid-induced mutation; in vitro antiproliferative against human cancer cells
41	Selaginella uncinata	Selaginellaceae	In vitro MTT assay on Bel-7402, HeLa, HT-29
42	Selaginella remotifolia	Selaginellaceae
43	Selaginella pulvinata	Selaginellaceae
44	Adiantum venustum	Pteridaceae	Ehrlich ascites carcinoma in animal models, in vivo animal study	Woerdenbag et al., 1996; Li et al., 1998, 1999; Viral et al., 2011
45	Pteris semipinnata	Pteridaceae	Human liver adenocarcinoma cell line (HePG II), human lung adenocarcinom a cell line (SPC-A-1), human gastric adenocarcinoma cell line (MGC-803), human nasopharyngeal carcinoma cells; in vitro MTT assay in HL-60 cells; in vivo anticancer activity
46	Pteris multifida	Pteridaceae	In vitro MTT assay in Ehrlich ascites
47	Pteris vittata	Pteridaceae	In vitro MTT assay on MCF-7 breast cancer cells	Chiu et al., 2009; Zhang et al., 2013; Tomsik, 2013; Kaur et al., 2014; Xia et al., 2014
48	Pteridium aquilinum	Dennstaedtiaceae	In vitro MTT assay
49	Davallia cylindrica	Davalliaceae	In vitro MTT assay in A549 cells
50	Stenoloma chusanum	Lindsaeaceae
51	Selaginella frondosa	Selaginellaceae	In vitro MTT assay in A549 cells
52	Thelypteris torresiana	Thelypteridaceae	In vitro MTT assay in lung cancer cell line H1299
53	Selaginella ciliaris	Selaginellaceae	Potato disc-induced method	Sarker et al., 2011
54	Marsilea minuta	Marsileaceae
55	Thelypteris prolifera	Thelypteridaceae
56	Trichomanes reniforme	Hymenophyllaceae	In vivo growth inhibitory activity against ascitic fibrosarcoma in Swiss mice;in vitro cytotoxicity	Guha et al., 1996

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MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Table 4

Antidiabetic, antiviral, anti-inflammatory, and wound healing activity of pteridophytes

Medicinal use	No.	Plant name	Family name	Methods used	Source(s)
Antiviral activity	1	Hemionitis arifolia	Pteridaceae	In vivo glucose tolerance test and alloxan-induced diabetic rats; in vivo glucose tolerance test in streptozotocin-induced diabetic rats; traditional Indian medicine	Ajikumaran Nair et al., 2006; Kumudhavalli and Jaykar, 2012; Santhosh et al., 2014
	2	Christella dentata	Thelypteridaceae	In vivo glucose tolerance test	Paul et al., 2012; Tanzin et al., 2013; Sultana et al., 2014
	3	Adiantum philippense	Pteridaceae	In vivo study in alloxan-induced diabetic rats
	4	Angiopteris evecta	Marattiaceae	In vivo glucose tolerance test
	5	Adiantum capillus-veneris	Pteridaceae	Traditional Indian medicine; traditional medicine in Amazon; in vivo glucose tolerance test	Jain and Sharma, 1967; Taylor, 2003; Santhosh et al., 2014; Neef et al., 1995
	6	Angiopteris evecta	Marattiaceae	In vivo glucose tolerance test	Miao et al., 1996; Nguyen, 2005
	7	Selaginella tamarascina	Selaginellaceae	In vivo study in alloxan-induced diabetic rats
	8	Asplenium polyodon	Aspleniaceae	Traditional Indian medicine	Singh, 1999; Chand Basha et al., 2013; Santhosh et al., 2014
	9	Asplenium nidus	Aspleniaceae
	10	Adiantum capillus-veneris	Pteridaceae
	11	Ophioglossum gramineum	Ophioglossaceae
	12	Hemionitis arifolia	Pteridaceae
	13	Actiniopteris radiata	Pteridaceae	In vitro chromogenic DNSA method
	14	Blechnum orientale	Blechnaceae	In vitro antiviral activity against hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and murine leukemia virus	Tsai and Hwang, 1999
	15	Woodwardia orientalis	Blechnaceae
	16	Woodwardia unigemmata	Blechnaceae
	17	Athyrium acrostichoides	Athyriaceae
	18	Sphaeropteris lepifera	Cyatheaceae
	19	Cyrtomium fortunei	Dryopteridaceae
	20	Dryopteris crassirhizoma	Dryopteridaceae
	21	Osmunda japonica	Osmundaceae
	22	Lygodium flexuosum	Lygodiaceae	Traditional Indian medicine	Dhiman, 1998
	23	Lygodium japonicum	Lygodiaceae	In vitro antiviral activity against herpes simplex virus, Sindbis virus, and polio virus	Taylor et al., 1996
	24	Asplenium adiantum-negrum	Aspleniaceae	Traditional Indian medicine	Vasudeva, 1999
	25	Microsorum membranifolium	Polypodiaceae	Traditional Fijian medicine	Cambie and Ash, 1994
	26	Pyrrosia lingua	Polypodiaceae	In vitro antiviral activity against Herpes simplex virus	Zheng, 1990
	27	Trichomanes reniforme	Hymenophyllaceae	In vitro antiviral activity against HIV	Guha et al., 1996
	28	Pteris glycyrrhiza	Pteridaceae	In vitro antiviral activity against bovine herpesvirus type	McCutcheon et al., 1995
	29	Polypodium vulgare	Pteridaceae		Husson et al., 1986
	30	Polypodium aureum	Pteridaceae
Antiviral activity	31	Athyrium niponicum	Athyriaceae	In vitro antiviral activity
	32	Selaginella uncinata	Selaginellaceae	In vitro antiviral activity against respiratory syncytial virus, parainfluenza type 3 virus
Anti-inflammatory activity	33	Microsorum grossum	Polypodiaceae	Traditional herbal medicine
	34	Drynaria quercifolia	Polypodiaceae	Traditional Indian medicine
	35	Microsorum scolopendria	Polypodiaceae	Traditional herbal medicine in Tonga
	36	Polypodium leucotomos	Polypodiaceae	Traditional herbal medicine in Bolivia
	37	Ophioglossum vulgatum	Ophioglossaceae	Traditional Indian medicine
	38	Lygodium flexuosum	Lygodiaceae
	39	Adiantum venustum	Pteridaceae
	40	Adiantum caudatum	Pteridaceae	Traditional medicine in Malay Peninsula
	41	Cheilanthes farinosa	Pteridaceae	In vivo anti-inflammatory activity
	42	Pteris ensiformis	Pteridaceae	In vitro anti-inflammatory activity
	43	Christella parasitica	Thelypteridaceae	Traditional Indian medicine
	44	Huperzia serrata	Huperziaceae	Traditional Chinese medicine
	45	Selaginella tamarascina	Selaginellaceae	In vitro anti-inflammatory activity
	46	Selaginella bryopteris	Selaginellaceae	Traditional Indian medicine
	47	Dryopteris sp	Dryopteridaceae	In vivo Carrageenan induced paw oedema method
	48	Blechnum occidentale	Blechnaceae
	49	Alsophila gigantea	Cyatheaceae	Traditional Indian medicine
	50	Cyathea gigantea	Cyatheaceae	In vivo anti-inflammatory activity
	51	Phlebodium decumanum	Polypodiaceae	In vitro anti-inflammatory activity
	52	Phyllitis scolopendrium	Aspleniaceae	Traditional herbal medicine
	53	Dicranopteris linearis	Gleicheniaceae	In vitro anti-inflammatory activity
Wound healing activity	54	Selaginella delicatula	Selaginellaceae	Traditional Indian medicine
	55	Dicranopteris linearis	Gleicheniaceae
	56	Davallia solida	Davalliaceae	Traditional medicine in Hawaii
	57	Polystichum pungens	Dryopteridaceae	Traditional medicine in South Africa
	58	Angiopteris evecta	Marattiaceae	Traditional medicine in Fijian
	59	Nephrolepis cordifolia	Nephrolepidaceae	Traditional Indian medicine
	60	Ophioglossum reticulatum	Ophioglossaceae
	61	Thelypteris arida	Thelypteridaceae
	62	Phyllitis scolopendrium	Aspleniaceae	In vivo method
	63	Pityrogramma calomelanos	Pteridaceae	Traditional medicine
	64	Polypodium ssp.	Polypodiaceae	In vitro assay using platelet activating factor and leukotriene B(4)

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Pterosins, terpenoids, sterides, flavones, glucosides, aromatics, and pyrone compounds derived from C. barometz have antitumour properties (Wu et al., 2007; Xu et al., 2012). Plants in the polyploid genus Pteris contain many chemical compounds like apigenin-7-O-β-D-glucopyranosyl-4'-O-α-L-rhamnopyranoside, luteolin-7-O-β-D-glucopyranoside, apigenin-7-O-β-D -glucopyranoside, apigenin, luteolin, naringenin-7-O-β-D-neohesperidoside, apigenin-7-O-β-D-neohespedoside, apigenin-4'-O-α-L-rhamnopyranoside, (2S,3S)-pterosin C, isovanillic acid, ferulic acid, 2β,16α-dihydroxy-ent-kaurane 2-O-β-D-glucoside, 2β,6β,15α-trihydroxy-ent-kaur-16-ene, 9-hydroxy-15-oxo-ent-kaur-16-en-19-oic acid, 19β-D-glucoside, 2β,14β,15α,16α,17-pentahydroxy-ent-kaurane, and 9-hydroxy-ent-kaur-16-en-19-oic acid (Gong et al., 2007; Ouyang et al., 2008). Extracts of P. multifida have anti-cancer activity (Wang and Zhang, 2008). Ethyl acetate, butanol, and water extracts of B. orientale (Linn.) show notable anti-cancer properties (Lai et al., 2010). The antithiamin substances in brackens, such as astragalin, isoquercitrin, rutin, caffeic acid, and tannic acid have been identified as valuable natural constituents because of their antitumour or antioxidant properties (Kweon, 1986; Cai et al., 2004; Katsube et al., 2006). The ferns P. nipponica, Polypodium formosanum, Polypodium vulgare, Polypodium fauriei, Polypodium virginianum, Dryopteris crassirizoma, Adiantum monochlamys, and Oleandra wallichii have been shown to have anti-cancer activity (Konoshima et al., 1996). A. evecta and Selaginella tamariscina have been shown to have significant antidiabetic activity (Miao et al., 1996; Nguyen, 2005).

According to Singh (1999) and Lee et al. (2003), Asplenium polyodon, Asplenium nidus, A. capillus-veneris, Ophioglossum gramineum, and H. arifolia have anti-cancer, antidiabetic, and antiviral activity. Chloroform extracts of Actiniopteris radiata (Linn.) have significant antidiabetic activity as shown by the chromogenic DNSA (dinitrosalicylic) colorimetric method, and ethanolic extracts show strong in vitro antidiabetic properties when compared to n-hexane (Chand Basha et al., 2013). Both ethyl acetate and butanol extracts of the rhizome of C. fortunei (J.) Smith (Fig. ​(Fig.3a)3a) exhibit anti-tumour activity (Yang et al., 2013). The phlorophenone derivatives in Dryopteris sp. (Kapadia et al., 1996) and A. capillus-veneris (Fig. ​(Fig.3b)3b) that have anti-cancer activity have also been used as antidiabetic drugs in India and Europe (Jain and Sharma, 1967; Neef et al., 1995). β-Caryophyllene, linalool, geranial and γ-terpinene have also been isolated from the angiosperms Citrus and Croton flavens, revealing antitumour and antioxidant properties (Choi et al., 2000; Sylvestre et al., 2006). Moreover, anti-cancer compounds were detected in the essential oils of P. aquilinum L. Kuhn (Fig. ​(Fig.2a)2a) (Nwiloh et al., 2014). Methanol extracts of Pityrogramma calomelanos, D. quercifolia, and D. linearis exhibit antitumour and cytotoxic activity (Sukumaran and Kuttan, 1991; Shin and Lee, 2010; Zakaria et al., 2011; Milan et al., 2013). Extracts of Adiantum venustum also have anti-cancer activity, as demonstrated by Viral et al. (2011). The lycophytes, Selaginella willdenowii (Fig. ​(Fig.3d),3d), Selaginella lepidophyla, Selaginella labordei, Selaginella moellendorffii, Selaginella delicatula, S. tamariscina, and Sellaginella doederleinii (Fig. ​(Fig.3e)3e) were shown to have cytotoxic and antimutagenic effects due to the presence of bioflavonoids (Lee and Lin, 1988; Silva et al., 1995; Sun et al., 1997; Lee et al., 1999; Lin et al., 2000; Su et al., 2000; Chen JJ et al., 2005; Gayathri et al., 2005; Woo et al., 2005; Gao et al., 2007; Shi et al., 2008; Tan et al., 2009), while Pteris semipinnata (Fig. ​(Fig.4c)4c) and P. multifida have cytotoxic effects due to the presence of diterpenes (Woerdenbag et al., 1996; Li et al., 1998, 1999). Several authors have studied the anti-cancer potentials of ferns and lycopods, namely P. aquilinum, Davallia cylindrical, Stenoloma chusanum, Selaginella frondosa, Thelypteris torresiana, P. vittata, Selaginella ciliaris, Marsilea minuta, and Thelypteris prolifera (Chiu et al., 2009; Sarker et al., 2011; Tomsik, 2013; Zhang et al., 2013; Kaur et al., 2014; Xia et al., 2014).

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Fig. 4

Color illustrations of medicinal pteridophytes: (a) Equisetum ramosissimum; (b) Asplenium bulbiferum; (c) Pteris semipinnata; (d) Woodwardia orientalis; (e) Lygodium flexuosum; (f) Pteris ensiformis

Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article

According to Tsai and Hwang (1999), the hepatitis B virus (HBV) is a prominent infectious disease agent worldwide, especially in Asia and Africa, causing liver cirrhosis and cancer. Blechni rhizome, known for its antiviral (HBV) activity, is prepared from the roots and stems of various ferns including B. orientale, D. crassirhizoma, O. japonica, Woodwardia orientalis (Fig. ​(Fig.4d),4d), Woodwardia unigemmata (Fig. ​(Fig.5b),5b), Athyrium acrostichoides, Sphaeropteris lepifera, and C. fortunei. Likewise, an herbal mixture of Woodwardia species with some other flowering plants has shown anti-HIV-1 (human immunodeficiency virus) activity. Lygodium flexuosum (Dhiman, 1998) and Asplenium adiantum-nigrum (Vasudeva, 1999) have shown significant effects against viral disease and jaundice, while Microsorum membranifolium has shown activity against children’s influenza (Cambie and Ash, 1994). The antiviral and anti-tumor activity shown by Trichomanes reniforme is due to the presence of mangiferin, which can kill cancer cells and has anti-HIV effects (Guha et al., 1996). The antiviral activity of Pteris glycyrrhiza (McCutcheon et al., 1995), P. vulgare, and Polypodium aureum (Husson et al., 1986) has been documented. A new antiviral compound, woodorien, was derived and identified by Xu et al. (1993). A. niponicum is reported to have anti-HIV properties (Mizushina et al., 1998), while Taylor et al. (1996) have shown that L. japonicum has antiviral effects against the Sindbis virus. Zheng (1990) revealed the antiviral activity of P. lingua (Fig. ​(Fig.3g)3g) against the herpes simplex virus. Selaginella uncinata (Fig. ​(Fig.5c)5c) displays antiviral activity against the respiratory syncytial virus (RSV) and parainfluenza type 3 virus (PIV3) (Ma et al., 2003).

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Fig. 5

Color illustrations of medicinal pteridophytes: (a) Selaginella delicatula; (b) Woodwardia unigemmata; (c) Selaginella uncinata; (d) Huperzia serrata; (e) Nephrolepis cordifolia; (f) Pittyrogramma calomelanos; (g) Selaginella involvens; (h) Psilotum nudum

Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article

4. Traditional uses of some pteridophytes

In India, the Gond communities of Badkachhar, Bariaam and Dapka ingest the juice of whole fresh plants to cure cough and diabetes mellitus. Leaves of A. philippense are used to cure fever, cough, asthma, leprosy, and hair loss, while whole plants of B. orientale are used in anathematic and typhoid treatments. Fronds of B. orientale ground in cow’s milk are used in the treatment of asthma, as antibacterials and anthelmintics, and to improve fertility in women. The whole plant of H. zeylanica is considered an intoxicant, anodyne, and is also used as an aphrodisiac. L. flexuosum (Fig. ​(Fig.4e)4e) is used to cure skin diseases, rheumatism, sprains, scabies, eczema, cut wounds, and rheumatism, and as an expectorant. A paste made from the leaves of N. cordifolia is applied to wounds to stop bleeding. Whole plants of S. bryopteris are used as diuretics, and to treat gonorrhoea (Singh and Upadhyay, 2012). A. capillus-veneris is used for antifungal growth and to remove dandruff, and the juice of leaves is drunk to protect against infertility. In addition, A. caudatum is used to cure jaundice, scabies, abdominal pain, and constipation. The young fronds of A. incisum are used to treat malaria and bronchial diseases, while leaves and rhizomes of A. venustum are thought to cure diabetes, and are used to treat liver problems and circulatory disorders. Leaves of Asplenium bulbiferum (Fig. ​(Fig.4b)4b) are applied externally to hemorrhoids, and fronds are taken for liver problems. Decoctions from the rhizomes of P. aquilinum are drunk as a herbal health tea, and the rhizomes of W. unigemmata are used to cure skin diseases. Leaf juices are used as a tea or bath for curing infertility in women, for abdominal pain, constipation and sore throats (Nwosu, 2002). A paste of leaves and rhizomes mixed with lukewarm milk for 30 d is used as an effective tonic. A paste of P. vittata was applied twice to glandular swellings for 15 d (Sharma, 2002). M. grossum is commonly used in Tahiti (Whistler, 1992), H. serrata in China (Zangara, 2003), and S. bryopteris in India (Dhiman, 1998) for their anti-inflammatory activity. A decoction of roots and fronds of D. quercifolia is used as a tonic for the bowels, and aqueous extracts of the rhizomes are applied to wounds and cuts (Anonymous, 1952, 1986; Singh, 1973; Islam, 1983; Jain, 1991). Dried rhizomes of P. aquilinum mixed with milk are used to relieve diabetic disorders, and tender fronds are used as vegetables. Green fronds are used as fodder, make a good soil binder, and are also used in the preparation of manure (Anonymous, 1972, 1986; Islam, 1983; Jain, 1991). A paste made from the rhizomes of O. vulgatum has been externally applied to wounds, dropped in sore eyes as a detergent, and made into an antiseptic. Infusions can be taken internally for vulnerary or to treat bleeding of the nose or mouth, and a decoction has been drunk to treat heart troubles (Anonymous, 1966, 1986; Islam, 1983). In Malaya, a rhizome paste of A. aureum is applied to wounds and boils, and in the Philippines, leaves of A. caudatum are used externally as remedies for skin disease and internally for diabetes. Rhizomes of C. barometz in the Philippines are used to treat wounds and ulcers. Roots and leaves of Lygodium circinnatum are applied to wounds in the Dutch East Indies (Quisumbing, 1951). Tribal people of the Palani hills from South India use A. incisum, C. gigantea, and C. nilgirensis to treat diabetes, while N. cordifolia, H. arifolia, and Microsorum punctatum are applied to cuts and wounds, or used as anti-inflammatories (Sathiyaraj et al., 2015). In the Similipal Biosphere Reserve of Orissa (India), A. evecta, A. caudatum, B. orientale, Ceratopteris thalictroides, M. punctatum, P. biaurita, and P. cretica are used to cure cuts, wounds, and inflammation (Rout et al., 2009).

5. Mechanisms of action of phytochemicals

In this review we have documented most of the pteridophytes evaluated for phytochemical composition and bioactivity. Tables ​Tables11–5 summarize the presence of phytochemicals and their medicinal uses in pteridophytes. Although there are more than 12 000 species of pteridophytes distributed all over the world, few have been evaluated for their phytochemicals and their pharmacological properties. Most studies have reported only in vitro bioactivity, which suggests to investigate the pteridophytes could exert in vivo bioactivity. In general, phenolic compounds exist in both edible and non-edible plants and have proven bioactive. Phenolics are present in diverse groups of plants and show antimutagenic, anti-cancer, and antioxidant activity, which is beneficial to human life (Li et al., 2006). Due to synergistic effects, mixtures of bioactive compounds such as phenols, flavonoids, tannins, catechins, vitamins C and E, and β-carotene may give better protection/bioactivity than single phytochemicals (Bazzano et al., 2003). Phenolic compounds have been shown to have significant antioxidant effects (Newell et al., 2010). Phenols, flavonoids, anthocyanins, and phenolic acids have been obtained from plants to attain an idyllic structural chemistry for scavenging free radicals. The antioxidant potential of polyphenols may arise from their great reactivity as hydrogen or electron donors. The polyphenol-derived radical stabilize and delocalize the unpaired electron (Chanda and Dave, 2009). The scavenging of DPPH and ABTS radicals may be associated with the hydroxyl groups in caffeic acid and chlorogenic acid. The radical scavenging activity of phenolic compounds is influenced by the number of hydroxyl groups on the aromatic ring (Lazarova et al., 2014). Both rutin and quercetin significantly chelate metal ions and have ferric reducing antioxidant power (Azuma et al., 1999). According to Kim et al. (2004), rutin and quercetin express their anti-inflammatory activity through modulation of the expression of pro-inflammatory genes such as cyclooxygenase-2 and inducible nitric oxide synthase, and via some vital cytokines. Based on these distinctive mechanisms, flavonoids are considered as plausible substances for anti-inflammatory activity. The presence of caffeic acid, chlorogenic acid, rutin, and quercetin has been reported in many pteridophytes, namely P. multifida, P. vittata, P. aquilinum, P. leucotomos, Cyathea phalerata, S. tamariscina, O. sensibilis, M. struthiopteris, D. linearis, P. nudum, E. arvense, and A. capillus-veneris (Table ​(Table11).

Free radicals are generated in cells where they accumulate and react with macromolecules, like lipids, proteins, and nucleic acids, thereby disrupting cellular functions. In addition, oxidative damage to cellular components results in alteration of membrane properties such as fluidity, ion transport, enzyme activity, and protein cross-linking, causing cell death (Chauhan and Chauhan, 2006). Bio-compounds containing antioxidant potential have the capacity to inhibit carcinogenesis (Wang et al., 2011; Firdaus et al., 2013). In earlier studies, apigenin, quercetin, and luteolin were shown to inhibit cancer cell proliferation (Mishra et al., 2013a, 2013b; Fotsis et al., 1997). Moreover, phenolics have been observed to postpone or inhibit the progression of various diseases by preventing peroxidation of lipid membranes (Kumar et al., 2013a, 2013b). Some bioactivity, such as lipoprotective, antiplatelet, and anti-inflammatory activity, is closely associated with antioxidative flavonoids (Kumar et al., 2012). Flavonoids have the potential to be reducing agents and to scavenge free radicals, chelate metal ions and inhibit enzymatic systems (topoisomerases and kinases) responsible for free radical generation (Kumar and Pandey, 2013). Yang et al. (2013) reported the inhibition of cancer cell lines, such as stomach cancer, prostate cancer, malignant melanoma, and mouse fibroblasts, by crude extracts and several isolated compounds (Table ​(Table1)1) of C. fortunei. In addition, apigenin was found to induce apoptosis and suppress insulin-like growth factor I receptor signalling in human prostate cancer (Way et al., 2004; Shukla and Gupta, 2009). Some flavonoids, such as quercetin, apigenin, kaempferol, and rutin in Murraya koenigii, inhibit endogenous 26S proteasome activity in MDA-MB-231 cells (Noolu et al., 2016). Several authors have reported the presence of apigenin, kaempferol, and luteolin in following species, namely P. multifida, P. aquilinum, Selaginella sp., A. capillus-veneris, C. phalerata, P. vittata, O. sensibilis, M. struthiopteris, Equisetum ramoissimum, S. doederleinii, D. linearis, P. nudum, Pityrogramma tartarea, P. calomelanos, Cheilanthes concolor, Cardamine flexuosa, Cardamine goyazensis, Pellaea cymbiformis, P. gleichenioides, P. pinnata, P. riedelii, Pteris altissima, Pteris angustata, Pteris decurrens, Pteris deflexa, Pteris denticulata, Pteris plumula, Pteris podophylla, Pteris splendens, Pteris propinqua, and C. fortunei (Table ​(Table1).1). Synergism between several flavones and flavonols for antimicrobial activity was confirmed in an earlier study. Moreover, quercetin and naringenin were found to significantly inhibit bactericidal motility (Yilmaz and Toledo, 2004). The release of ROS from activated neutrophils and macrophages causes inflammation injury. Excessive production may lead to tissue injury by damaging macromolecules and lipid peroxidation of membranes (Winrow et al., 1993; Gutteridge, 1995). ROS inflammation stimulates the release of cytokines, such as interleukin-1, tumour necrosis factor-α, and interferon-α, which stimulate the production of extra neutrophils and macrophages. However, free radicals are the main mediators promoting the inflammatory process. By neutralizing free radicals, antioxidants can reduce inflammation (Delaporte et al., 2002; Geronikaki and Gavalas, 2006). Therefore, we urge biologists to focus on the mechanisms of action of bioactive compounds from early tracheophytes (pteridophytes) in medicinal applications.

6. Conclusions

Several researchers have studied the phytochemical and medicinal uses of lycophytes and ferns in recent years. These studies have demonstrated the importance of ferns and their allies in plant science fields. We have listed here the medicinal uses of pteridophytes, specifically their antioxidant, antidiabetic, anti-cancer, antiviral, anti-inflammatory, wound healing, antimicrobial, and anti-Alzheimer activity. No significant review papers on medicinal pteridophytes have been published recently, only a few articles with inadequate reports. The medicinal pteridophytes listed in this review belong to the following thirty families: Davalliaceae, Equisetaceae, Lygodiaceae, Ophioglossaceae, Polypodiaceae, Psilotaceae, Pteridaceae, Salviniaceae, Selaginellaceae, Tectariaceae, Woodsiaceae, Aspleniaceae, Athyriaceae, Blechnaceae, Cyatheaceae, Dennstaedtiaceae, Dicksoniaceae, Dryopteridaceae, Hymenophyllaceae, Lindsaeaceae, Thelypteridaceae, Marsileaceae, Nephrolepidaceae, Onocleaceae, Marattiaceae, Oleandraceae, Osmundaceae, Cystopteridaceae, Gleicheniaceae, and Huperziaceae. Our review might encourage an appreciation of the uses of pteridophytes beyond ornamental purposes and, in particular, promote their use and development for medicinal benefits.

7. Future directions

Pteridophytes comprise around 13 000 species that belong to nearly 48 plant families, but only a small number of species from thirty families have been analyzed for their biological activity. Hence, we urge biologists to evaluate the medicinal uses of pteridophytes and their bioactive principles. Using biotechnological tools, the efficacy of bioactive compounds could be increased by studies of in vitro culture, biosynthetic pathways, modes of action, and genetic expression. In addition to studies of their biological activity, pharmacokinetics, and toxicological profiles, multidrug therapies should be developed from early tracheophytes and pteridophytes. Furthermore, the genetic relationships among pteridophytes should be analyzed based on their secondary metabolite synthesis.

Footnotes

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