The genus Trollius-review of pharmacological and chemical research.

PHYTOTHERAPY RESEARCH Phytother. Res. 29: 475–500 (2015) Published online 9 January 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5277

REVIEW

The Genus Trollius—Review of Pharmacological and Chemical Research Ewa Witkowska-Banaszczak* Department of Pharmacognosy, Poznan University of Medical Sciences, Poland

Three species of the genus Trollius (Ranunculaceae) are traditionally used to treat upper respiratory tract infections, pharyngitis, tonsillitis, bronchitis, cold with fever, acute tympanitis, aphthae, mouth sore, hemorrhage and pain of gums, acute lymphangitis and acute periostitis. However, only a few studies support its traditional use. These are studies of the biological activity of extracts and/or compounds of selected species of Trollius, but there are no clinical studies proving the effectiveness or possible toxic effects. Until now, the following activity of extracts and/or compounds from certain species of Trollius used in traditional medicine has been proven: antiviral, antibacterial, antiinflammatory and antioxidant. The review showed that flavonoids, mainly C-glycosides, were characteristic of the species Trollius. Furthermore, other main groups of compounds are carotenoids, organic acids, terpenes, alkaloids, sterols, lactones and carbohydrates. The essential oil mainly contains compounds from the group of benzenoids, nitrogen-containing compounds, monoterpenoids and sesquiterpenoids, irregular terpenes and macrocyclic epoxide. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: Trollius; antiviral; antioxidant; flavonoids; phenolic acids; essential oil.

INTRODUCTION The genus Trollius belongs to the most numerous family from Magnoliophyta, i.e. the family Ranunculaceae. It consists of about 30 species of plants (Jasiewicz, 1985; Pałczyński et al., 1994; Jasnowska et al., 1995; Rajewski and Waszak 1998, www. crescentbloom.com) native to temperate and arctic regions of Asia, Europe and North America, which usually grow in peatlands, swamps, wet meadows and banks of reservoirs as well as in mountain areas, up to the alpine zone (Palewski et al., 2006; Doroszewska, 1974; Jasiewicz, 1985; Antkowiak, 1999, www.crescentbloom.com). Taxonomic studies have shown differences between the species, thus making it possible to divide the genus Trollius into sections. Doroszewska has grouped the species into seven sections on the basis of the differences in the morphological structure and geographical distribution. Further morphological studies, and palynological ones in particular, have suggested some changes in the division of the species into sections on the basis of pollen types Table 1 (Doroszewska, 1974; Lee and Blackmore, 1992). Many species from the genus Trollius are found in the Far East, for example, T. chinensis Bng, T. ledebouri Reichb and T. macropetalus F. Schm., all used in medicine (Doroszewska, 1974; Li et al., 2002; Xie et al., 2001; Després et al., 2003; Zou et al., 2004). In Europe, locations of T. europaeus L. and T. altissimus Cranz, sometimes considered a subspecies of globe-flower, have been reported (Piękoś–Mirkowa and Mirek, 2003; Doroszewska, 1974; Maciejewska-Rutkowska et al., 2007). In Poland, Trollius * Correspondence to: Ewa Witkowska-Banaszczak, Department of Pharmacognosy, Poznan University of Medical Sciences, ul. Święcickiego 4, 60-781 Poznań, Poland. E-mail: [email protected]

Copyright © 2015 John Wiley & Sons, Ltd.

is a protected species due to an alarming decrease in its habitats, probably resulting from progressive land amelioration and cropland fertilisation (Piękoś–Mirkowa and Mirek, 2003; Antkowiak, 1999). T. laxus is found in central and north-eastern parts of the USA (Scanga and Leopold, 2012; Scanga, 2009) and in New England, in North Marble Dale of Litchfield County, Connecticut (Jones, 2000). Occurrence of T. laxus is limited to boggy locations, peatlands and swamps rich in limestone. Due to the decreasing number of habitats, T. laxus is ‘a candidate for listing under the US Federal Endangered Species Act’ (Scanga and Leopold, 2012; Scanga, 2009). Coexistence between T. europaeus and insects Chiastocheta spp. has been observed; their larvae feed on Trollius flowers, which stimulates the plant to produce adonivernite (Jaeger and Després 1998; Després et al., 2002; Pompanon et al., 2006; Després et al., 2007)

Traditional uses Flowers of the Asian species T. ledebourii and T. chinensis are used in Chinese folk medicine to treat upper respiratory tract infections, tonsillitis, influenza and acute myringitis. Flowers of T. ledebourii, a species found in northern regions of China, are used to treat common cold (Zhou et al., 2005). T. chinensis is widely cultivated in China and Mongolia. Flowers of this species (Flos trolli) are used to prepare tea as well as to treat many ailments, such as upper respiratory tract infections, bronchitis, cold with fever, pharyngitis, acute tympanitis, tonsillitis and, also, aphthae, mouth sore, swelling, hemorrhage and pain of the gum, acute periostitis and acute lymphangitis (Sun et al., 2011; Wang et al., 2010; Zhou et al., 2011). Received 23 July 2014 Revised 30 September 2014 Accepted 25 November 2014

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E. WITKOWSKA-BANASZCZAK

Due to their ability to lower temperature and remove toxins, flowers of T. macropetalus are also used to treat upper respiratory tract infections, tonsillitis, acute otitis and lymphangitis, conjunctivitis, appendicitis and dysentery. In folk medicine, flowers of T. europaeus have been used to treat scurvy as they contain large amounts of vitamin C (Gruenwald et al., 2004).

compounds from groups of fatty acid derivatives, benzenoids, nitrogen containing compounds, irregular, mono and sesqui-terpenoids have been identified in the essential oil from T. europaeus. The reported compounds from the species of the genus Trollius have been presented in Table 2. Biological and pharmacological activity

Chemical constituents Phytochemical studies of species from the genus Trollius L have so far been conducted mainly for the following Asian species: T. chinensis Bunge, T. ledebouri Reichb and T. macropetalus F. Schmidt and, to some extent, the European species T. europaeus L. The most numerous group of compounds found in the investigated species from the genus Trollius are flavonoids, mainly flavone C-glycosides, derivatives of orientin, vitexin, isoswertisin and flavonoid O-glycosides (flavonols). Organic and phenolic acids, especially benzoic acid derivatives, terpene compounds, carotenoids and alkaloids, have also been described. Phytoecdysteroids were also found in T. europaeus and T. pumilus (Dinan et al., 2002). Fifty three

Antiviral activity. Results of in vitro studies into antiviral activity of the 2″-O-(2′″-methylbutyryl) isoswertisin, trollisin I, trollisin II and vitexin galactoside from T. chinensis showed moderate antiviral activity of 2″-O(2′″-methylbutyryl) isoswertisin against influenza virus A (IC50 = 74.3 μg/ml) (Cai et al., 2006). An ethanol extract (60%) from flowers of T. chinensis showed moderate activity against parainfluenza virus type 3 (IC50 = 77.5 μg/ml). The following flavonoids isolated from flowers of T. chinensis: orientin (IC50 = 11.7 μg/ml) and vitexin (IC50 = 20.8 μg/ml) demonstrated stronger activity. IC50 of total flavonoids was 74.6 μg/ml. Proglobeflowery acid exhibited weak activity against parainfluenza virus type 3 (IC50 = 184.2 μg/ml) (Li et al., 2002).

Table 1. Division of the Trollius species into sections Species of Trollius T. bhotanicus (Brühl) Mukerjee T. farreri Stapf. T. micranthus Hand.-Mazz. T. pumilus Don. T. ranunculoides Hemsl. T. sikkimensis Brühl T. vaginatus Hand.-Mazz. T. citrinus Miyabe T. papavereus Schipcz. T. yunnanensis (Franch.) Ulbr. ssp. Yunnanensis ssp. Anemonifolius (Brühl) comb. nov. T. acaulis Lindl., Stearn T. afghanicus Hedge et Wandelbo T. lilacinus Bge. T. asaiticus L. T. chinensis Bge. T. hondoensis Nakai T. kytmanovii Reverd. T. ledebouri Reichb. T. macropetalus F. Schm. T. sibiricus Schipcz. T. altaicus C.A.M T. apertus (Perf.) Igosh T. dschungaricus Reg. T. europaeus L. T. ranunculinus (Smith) T. chartosepalus Schipcz. T. membranostylius Hultĕn, T. pulcher Makino, T. riederianus Fisch et Mey T. schipczlinskii Miyabe T. laxcus Salibs. T. chosenesis


Section according to Doroszewska (Doroszewska 1974) Pumilotrollius

Yunnanotrollius

Acaulitrollius

Longipetala

Trollius

Insulaetrollius

Laxotrollius Species endemic in Korea, not assigned to any section

Pollen-type (Lee and Blackmore, 1992) Not investigated T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type Not investigated T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. acaulis-type T. acaulis-type T. acaulis-type T. europaeus-type/T. acaulis-type T. europaeus-type T. europaeus-type not investigated T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. europaeus-type T. acaulis-type T. europaeus-type T. europaeus-type T. europaeus-type Not investigated T. acaulis-type T. chosenensis-type

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THE GENUS TROLLIUS—PHARMACOLOGICAL AND CHEMICAL RESEARCH

477

Antiinflammatory activity. Antiinflammatory activity of the compounds isolated from the ethanol extract of flowers of T. ledebouri: 7-methoxyl 2″-O-(2″′-methylbutyryl) orientin, 2″-O-(2″′-methylbutyryl) isoswertisin, 2″-O(3″′, 4″′-dimethoxybenzoyl) vitexin was investigated on mice with induced oedema of the right ear (TPA15μg/ear). The compounds were administered orally at a dose of 10 mg/kg body weight, after 2 and 12 h. 7-Methoxy 2″O-(2″′-methylbutyryl) orientin showed the strongest activity, inhibiting the rate of the oedema by 58.6%; 2″O-(2″′-methylbutyryl) isoswertisin (35.5%) and 2″-O-(3″′, 4″′-dimethoxybenzoyl) vitexin (27.6%) exhibited weaker antiinflammatory activity (Wu et al., 2006). Antiinflammatory properties were demonstrated by quercetin 3-O-neohesperidoside (Zhou et al., 2005), 7methoxy-2″O-(2″′-methylbutyryl) orientin, 2″-methylbutyryl isoswertisin and 2″-O-(3″′,4″′-dimethoxybenzoyl) vitexin, identified in T. ledebouri (Wu et al., 2006).

concentrations of 50 μg/ml, 100 μg/ml and 200 μg/ml, respectively, whereas BHT, at the same concentrations, neutralized DPPH radicals by 16.46%, 17.52% and 20.86%, respectively. The examination by the chemiluminescence method made it possible to determine the sequence of the free radicals being scavenged. First, the investigated extract scavenged singlet oxygen 1O.2, then OH., R. and O. 2. At the same time, it was demonstrated that the extract had stronger activity than ascorbic acid (Sun et al., 2011). The high antioxidant activity of the extract from T. chinensis flowers was confirmed by the research carried out in 2013. For the lowest concentration of the extract (50 μg/ml) antioxidant activity was 73.29% and was higher than that of ascorbic acid at the same concentration. Hydroxyl radical scavenging activity was also determined using deoxyribose damage with EDTA model and measured by the TBA method. The tested extract presented slightly stronger antioxidant activity than BHA. At the lowest concentration, it showed 30.64% radical scavenging activity, and at the highest 77.69%. The ability to chelate ferrous ions (lipid peroxidation by the Fenton reaction) by the extract was weak and was 36.36% for the highest concentration (500 μg/ml) (Song et al., 2013a). Orientin and vitexin isolated from T. chinensis dry flowers at a concentration of 40 mg/kg/day demonstrate similar antioxidant capacity as vitamin E at a concentration of 20 mg/kg/day. Studies were conducted on mice which were administered D-galactose intraperitoneally for 8 weeks. D-galactose, as a result of advanced glycation endproducts, accelerates the aging process of the body. Next, vitexin or orientin was administered intragastrically for 8 weeks, with vitamin E used as a control. All of the compounds preferably influenced the health of the aging mice and increased the brain weight. The total capacity of antioxidants and antioxidant enzymes, i.e. superoxide dismutase, catalase and glutathione peroxidase, Na+–K+–ATP, Ca2+–Mg2+– ATP increased in the liver, brain and kidney. Also, a decrease in malondialdehyde (in the liver, brain and kidney) and lipofuscin in the brain was observed, in addition to a beneficial effect on the neurons ultrastructure (An et al., 2012). The protective activity of the ethanol extract from T. ledebouri flowers on genotoxicity in mouse peripheral lymphocytes was demonstrated. The research was conducted on male Swiss mice. The animals were orally administered the extract of T. ledebouri (0.03 g/kg, 0.1 g/kg and 0.29 g/kg) and after 0.5 h potassium dichromate intraperitoneally (20 mg/kg). Potassium dichromate induced DNA damage in mouse lymphocytes. T. ledebouri extract 0.29 mg/kg significantly inhibited the reduction of T-SOD and GSH-Px. The results indicate that the protection of peripheral lymphocyte DNA is associated with activation of natural antioxidant enzymes by the ethanol extract of T. ledebouri (Yang et al., 2008).

Antioxidant activity. Antioxidant activity of an ethanolwater extract from flowers of T. chinensis was investigated by the chemiluminescence technique and with the use of DPPH (2,2-diphenyl-1-picrylhydrazyl). The results suggested significant antioxidant properties in vitro of the alcohol extract from T. chinensis. The tested extract neutralized DPPH free radicals more strongly than BHT (butylated hydroxytoluene). The activity was equal to 57.33%, 72.39% and 87.02% for

Anticancer activity. Anticancer activity of a methanolic extract from T. chinensis flowers was investigated by MTT assay on human gastric carcinoma cells, human melanoma cells and two different cell lines of human breast adenocarcinoma. A strong inhibitory effect on cell proliferation was proved. The activity of the investigated extracts was increased in a dose-dependent manner. The IC 50 values were: 143.72 μg/ml for gastric carcinoma cells, 62.23 μg/ml for melanoma cells and

Trolline isolated from flowers of T. chinensis showed moderate antiviral activity against influenza virus A (IC50 = 56.8μg/ml). The study was conducted on a Madin-Darby canine kidney infected with influenza virus A or B (multiplicity of infection of 0.05 PFU per cell), with the control substance being Ribavirin (Wang et al., 2004). The ethanol extract from flowers of T. chinensis demonstrated antiviral activity against Coxsackie virus (Zhou et al., 2005). The following compounds isolated from flowers of T. chinensis: (2″-methylbutanoyl) isoswertiajaponin (=trollisin I), 2″-(3,4-dimethoxybenzoyl) isoswertiajaponin (=trollisin II), 2″-O-(2″′-methylbutanoyl) isoswertisin and vitexin galactoside were tested to check their antiviral activity. The study was carried out by the in vitro method on Madin-Darby canine-kidney cells, which had been infected with influenza viruses type A and B (0.05PFU/ cell). Ribavirin was used as a control substance. One of the investigated substances—2″-O-(2″′-methylbutyryl) isoswertisin—exhibited moderate activity against influenza virus type A (IC50 = 74.3μg/ml) (Cai et al., 2006). Antibacterial activity. Trolline isolated from the ethanol extract from flowers of T. chinensis was characterized by significant antibacterial activity both against Grampositive and Gram-negative bacteria. The compound showed the strongest activity against Staphylococcus aureus (MIC 32 mg/L); weaker activity was demonstrated against Klebsiella pneumoniae (MIC 128 mg/L) and Streptococcus pneumoniae (MIC 128 mg/L). Streptococcus pyogenes ((MIC 256 mg/L), Pseudomonas aeruginosa (MIC >256 mg/L) and Haemophilus influenzae (MIC >256 mg/L) exhibited little sensitivity to the activity of trolline (Wang et al., 2004). Cirsimaritin, found in flowers of T. chinensis, showed antibacterial activity against Gram-positive and Gram-negative bacteria such as S. aureus and Escherichia coli (Wang et al., 2004).


Phytother. Res. 29: 475–500 (2015)


2″-O-vanilloylvitexin

2

2″-O-feruloylvitexin

Vitexin

3

Name

Flavonoids C-glycosides of flavonoid

1

No.

Table 2. The compounds isolated and identified in the species of Trollius

R1, R3=H, R4, R5=OH, R2=

R1, R3=H, R4, R5=OH, R2=

R1, R2, R3=H, R4, R5=OH

Structure

T. chinensis T. japonicus T. farreri T. altaicus

T. chinensis T. japonicus T. farreri T. altaicus

T. altissimus T. ledebouri

T. japonicas T. farreri T. altaicus T. macropetalus T. europaeus

T. chinensis

T. ledebouri

Source

Wu et al. (2013)

(Continues)

Liu et al. (1992) Witkowska-Banaszczak 2009 Maciejewska-Rutkowska et al. 2007 Maciejewska-Rutkowska et al. 2007 Wu et al. (2013) Zou et al. (2005) Wu et al. (2013)

Wu et al. (2013) Li et al. (2006) Zou et al. (2005) Zhou et al. (2005) Li et al. (2002) Wu et al. (2013) Wang et al. (2004) Li et al. (2002) Wu et al. (2013)

Reference

478 E. WITKOWSKA-BANASZCZAK

Phytother. Res. 29: 475–500 (2015)

6″-O-glucosylvitexin

2″-O-glucosylvitexin

2″-O-acetylvitexin 3″-O-acetylvitexin 6″-O-acetylvitexin 2″-O-β-D-pyranxylosidevitexin

2″-O-β-arabinopyranosylvitexin

2″-O-arabinopyranoside vitexin

2″-O-β-L-galactopyranosylvitexin

2″-O-β-D-xylopyranosyl vitexin

3

4

5 6 7 8


9

10

11

12

R1, R3=H, R4, R5=OH R2=

R1, R3=H, R4, R5=OH, R2=

R1, R3=H, R4, R5=OH, R2=

R1, R3=H, R2=COCH3, R4, R5=OH, R1, R2, R3=H, R4=COCH3, R5=OH R1, R2=H, R3=COCH3, R4, R5=OH, R1, R3=H, R4, R5=OH, R2=

R1, R3=H, R4, R5=OH, R2=

R1, R2=H, R4, R5=OH, R3=

T. chinensis T. farreri T. ledebouri T. altaicus T. chinensis T. ledebouri

T. ledebouri

T. altissimus

T. europaeus

T. japonicus

T. chinensis T. chinensis T. chinensis T. chinensis T. ferreri T. altaicus

T. japonicus T. altaicus

T. chinensis

al. (2013) al. (2013) al. (2013) al. (2013)

Cai et al. (2006) Li et al. (2006)

Wu et al. (2013) Wu et al. (2011) Zou et al. (2005) Wu et al. (2013)

(Continues)

Witkowska-Banaszczak 2009 Maciejewska-Rutkowska et al. 2007 Maciejewska-Rutkowska et al. 2007

Wu et al. (2013)

Wu et Wu et Wu et Wu et

Wu et al. (2013)

Wu et al. (2013) Song et al. 2013b


479

Phytother. Res. 29: 475–500 (2015)

2″-O-(4′″-hydroxybenzoyl) vitexin

2″-O-(2′″-methylbutyryl)vitexin

2″-O-(3′″,4′″-dimethoxybenzoyl)vitexin

3″-O-(2-methylbutyryl)vitexin

Trollisin A

13

14

15

16

17

Table 2. (Continued)


R1, R2, R3=H, R4=C2H5(CH3) CHCO, R5=OH R1=H, R4, R5=OH, R3=

R1, R4, R3=H, R5=OH, R2=

R1, R3=H, R4, R5=OH, R2=C2H5(CH3)CHCO

R1, R3=H, R4, R5=OH R2=

R1, R3=H, R4, R5=OH R2=

T. ledebouri

T. chinensis T. japonicas T. farreri T. altaicus T. chinensis

T. chinensis T. japonicas T. farreri T. altaicus T. ledebouri

T. ledebouri

T. ledebouri

T. macropetalus

Wu et al. (2011)

Li et al. (2009)

Wu et al. (2013) Wu et al. (2006) Zou et al. (2004) Li et al. (2006) Wu et al. (2013)

Wu et al. (2013) Zou et al. (2004) Li et al. (2006) Wu et al. (2013)

Zou et al. (2005)

Liu et al. (1992)

(Continues)


Phytother. Res. 29: 475–500 (2015)


2″-O-β-D-pyranxylosideorientin

22

6″-O-glucosylorientin

20

2″-O-glucosylorientin

Orientin

19

21

Trollisin B

18

R1, R4, R5=OH, R3=H, R2=

R1, R4, R5=OH, R2=H, R3=

R1=OH; R 2, R3=H, R4, R5=OH

R1, R2=H, R4, R5=OCH3, R3=

R5=

T. chinensis

T. altissimus

T. altaicus T. japonicus T. europaeus

T. altissimus T. chinensis

T. macropetalus T. japonicus T. farreri T. altaicus T. europaeus

T. chinensis

T. ledebouri

T. ledebouri

Wu et al. (2013)

(Continues)


Wu et al. (2013)

Witkowska-Banaszczak 2009 Maciejewska-Rutkowska et al. 2007 Maciejewska-Rutkowska et al. 2007 Wu et al. (2013)

Wu et al. (2013) Wu et al. (2011) Li et al. (2006) Zou et al. (2005) Zhou et al. (2005) Li et al. (2002) Wu et al. (2013) Wang et al. (2004) Li et al. (2002) Liu et al. (1992) Wu et al. (2013)

Wu et al. (2011)


481

Phytother. Res. 29: 475–500 (2015)


2″-O-acetylorientin



2″-O-feruloylorientin

25

26

27

28

2″-O-vanilloylorientin

2″-O-β-arabinopyranosylorientin

24

29

2″-O-β-L-galactopyranosylorientin

23


R 1, R4, R5=OH, R3=H, R2=

R1, R4, R5=OH, R2=H, R3=COCH3

R1, R5=OH, R2, R3=H, R4=COCH3

R1, R4, R5=OH, R2=COCH3, R3=H,

R 1, R4, R5=OH, R3=H, R2=

R 1, R4, R5=OH, R3=H, R2=

R1, R4, R5=OH, R3=H, R2=

T. chinensis

T. chinensis T. japonicas T. farreri T. altaicus

T. chinensis T. farreri T. ledebouri T. chinensis T. japonicas T. farreri T. ledebouri T. altaicus T. chinensis T. ledebouri T. ledebouri

T. japonicus T. farreri T. altaicus T. ledebouri T. japonicus

T. ledebouri T. ledebouri

T. farreri

Wu et al. (2013)

Wu et al. (2013) Zou et al. (2005) Wu et al. (2013) Zou et al. (2005) Wu et al. (2013)

Wu et al. (2013)

Wu et al. (2013)

Li et al. (2006) Wu et al. (2013)

Wu et al. (2013) Wu et al. (2011) Li et al. (2006) Zou et al. (2005) Wu et al. (2013)

(Continues)


Phytother. Res. 29: 475–500 (2015)


2″-O-(2′″-methylbutyryl)orientin

7-methoxy-2″-O-(2″′-methylbutyryl) orientin

2″-O-xyloside orientin (adonivernite)

Isoswertisin

31

32

33

34

35

2″-O-(3′″,4′″-dimethoxybenzoyl)orientin

30

R1, R3=H, R2=C2H5(CH3)CHCO, R4=OH, R5=OCH3

R1, R2, R3=H, R4=OH, R5=OCH3

R1, R4, R5=OH, R3=H, R2=

R1, R4=OH, R3=H, R5=OCH3, R2=

R1, R5, R4=OH, R3=H, R2=C2H5(CH3)CHCO

R1, R5, R4=OH, R3=H, R2=

R1, R4, R5=OH, R3=H, R2=

T. japonicus T. farreri T. altaicus T. ledebouri

T. chinensis

T. macropetalus T. ledebouri

T. altissimus T. ledebouri

T. europaeus

T. chinensis T. japonicas T. farreri T. altaicus T. ledebouri

T. ledebouri

T chinensis T. japonicas T. farreri T. altaicus

T. ledebouri

Wu et al. (2013)

(Continues)

Witkowska-Banaszczak 2009 Maciejewska-Rutkowska et al. 2007 Maciejewska-Rutkowska et al. 2007 Ibanez et al. (2009) Gallet et al. (2007) Liu et al. (1992) Wu et al. (2013) Wu et al. (2011) Li et al. (2006) Zou et al. (2004) Wang et al. (2004) Wu et al. (2013) Wu et al. (2013)

Wu et al. (2006)

Wu et al. (2013) Li et al. (2006) Zou et al. (2004) Wu et al. (2013)

Wu et al. (2013) Li et al. (2006) Zou et al. (2004) Wu et al. (2013)


483

Phytother. Res. 29: 475–500 (2015)


Isoswertiajaponin

3″-O-(2-methylbutyryl)isoswertiajaponin

2″-O-(2″′-methylbutyryl)isoswertiajaponin

38

39

40

2″-O-(3″′,4″′-dimethoxybenzoyl) isoswertiajaponin

2″-O-(3″′,4″′-dimethoxybenzoyl) isoswertisin = (2″-O-veratroylisoswertisin)

37

41

3″-O-(2′″-methylbutyryl) isoswertisin

2″-O-(2′″-methylbutyryl) isoswertisin (=2″-O-(2′″-metylbutanoyl) isoswertisin

36


R1, R4=OH, R3=H, R5,=OCH3 R2=

R1, R4=OH, R2=C2H5(CH3)CHCO, R3=H, R5,=OCH3

R1=OH, R2, R3=H, R4=C2H5(CH3)CHCOO, R5=OCH3

R1, R2, R3, R4=H, R5=OCH3

R1, R3=H, R4=OH, R5=OCH3 R2=

R1, R2, R3=H, R4=C2H5(CH3)CHCO, R5=OCH3

japonicus farreri altaicus chinensis ledebouri

ledebouri japonicus farreri altaicus

T. T. T. T. T. T. T. T.

T. T. T. T.

chinensis ledebouri japonicas farreri altaicus japonicas farreri altaicus

japonicus farreri altaicus chinensis

T. chinensis

T. ledebouri

T. T. T. T.

T. chinensis

T. T. T. T. T.

T. chinensis

Wu et al. (2013)

Wu et al. (2013) Li et al. (2009) Wu et al. (2013)

Wu et al. (2013) Wu et al. (2011) Li et al. (2006) Wu et al. (2013) Wang et al. (2004) Wu et al. (2013)

Li et al. (2009) Li et al. (2006) Zou et al. (2004) Wu et al. (2013) Li et al. (2009) Wu et al. (2013)

Li et al. (2006) Zou et al. (2004) Wu et al. (2013) Li et al. (2009) Cai et al. (2006) Wu et al. (2013)

Wu et al. (2006)

(Continues)


Phytother. Res. 29: 475–500 (2015)


Genkwanin 4′-O-rhamnopyranoside (1→2) xylopyranoside

Cirsimaritin Quercetin-3-O-neohesperidoside

46 47

Isoorientin

Trollisin I (=(1S)-1,5-anhydro-1-[2-3,4dihydroxyphenyl)-5-hydroxy-7-metoxy4-oxo-4H-[1]benzopyran-8-yl]-2-O-(2methylbutanoyl)-D-glucitol) (=2″methylbutanoyl) isoswertiajaponin) trollisin II (=(1S)-1,5-anhydro-2-O-[3,4dimethoxyphenyl)carbonyl]-1-[2-(3,4dihydroxyphenyl)-5-hydroxy-7-methoxy-4oxo-4H-[1]-benzopyran-8-yl]-D-glucitol), (=2″(3,4-dimethoxybenzoyl) isoswertiajaponin)

45

O-glycosides of flavonoid

44

43

42

R1, R2=CH3O, R3, R5=H, R4=OH R1=OH, R2=H, R4,R5=OH, R3=

R1=CH3O, R2, R3, R5=H, R4=

R1, R4=OH, R3=H, R5=OCH3, R2=

R1, R4=OH, R2=CH3CH3CH(CH3)CO, R3=H, R5=OCH3

T. chinensis T. ledebouri

T. altissimus

T. europaeus

T. altissimus

T. europaeus

T. chinensis

T. chinensis

Wang et al. (2004) Zhou et al. (2005)

(Continues)



Cai et al. (2006)

Li et al. (2009) Cai et al. (2006)


485

Phytother. Res. 29: 475–500 (2015)


51

50

Neodiosmin

49

6-Epineoflor

Neoflor

Carotenoids

Acacetin-7-O-neohesperidoside

48


R1=

R2=

R1=

, R2, R3, R5=H, R4=OCH3

, R2, R3=H, R4=OCH3, R5=OH R1=

R1=

T. europaeus

T. europaeus

T. chinensis T. farreri

T. ledebouri

T. chinensis T. ledebouri

(Continues)

Marki–Fischer and Eugster (2004)

Marki–Fischer and Eugster (2004)

Wu et al. (2013) Wu et al. (2011) Wu et al. (2013)

Wu et al. (2013) Wu et al. (2011)


Phytother. Res. 29: 475–500 (2015)


Veratric acid (=3,4-dimethoxybenzoic acid)

54

Caffeic acid

Chlorogenic acid

55

56

Phenolic acids

Proglobeflowery acid (=3-methoxy-4hydroxyl-5-(3′-methyl)-2′butylenzylbenzoic acid)

Neoxanthin (trollixanthin)

53

Organic acids

52

R2=

R1=

R2=

T. europaeus T. altissimus

T. altissimus

T. europaeus

T. chinensis

T. chinensis, T. macropetalus

T. europaeus

(Continues)

Maciejewska-Rutkowska et al. 2007


Wang et al. (2010) Wang et al. (2004)

Wang et al. (2010) Wang et al. (2004) Liu et al. (1992)

Gruenwald et al. (2004) Egger and Dubbagh (1970)


487

Phytother. Res. 29: 475–500 (2015)


Synapic acid

Vanillic acid

p-Hydroxybenzoic acid

Ferulic acid

Syringic acid

p-Hydroxyphenylacetic acid

59

60

61

62

63

64

Protocatechuic acid

p-Coumaric acid

58

65

γ-Resorcylic acid


57

T. europaeus

T. altissimus

T. europaeus

T. altissimus

T. europaeus


T. altissimus

T. europaeus

T. altissimus

T. europaeus


T. altissimus

T. europaeus


(Continues)

Witkowska-Banaszczak 2009










Phytother. Res. 29: 475–500 (2015)


3,5-Dihydroxyphenethyl alcohol 3-Oβ-D-glucopyranoside

3-Methoxy-5-(3-methyl-but-2-enyl)-4-(O-D-β-glucopyranosyl)benzoic acid (trollioside)

68

69

Ledebourene 1 (=8-α, 13R)-epoxy14-labden-6-β, 7-β-diol-7-β-D(4′-acetyl) fucopyranoside

Abscisic acid

70

71

Terpenes

2-(3,4-Dihydroxyphenyl)ethyl-O-β-D-glucopyranoside

3,4-Dihydroxyphenylacetic acid

67

Phenylethanoid glycosides

66

T. europaeus

T. ledebouri

T. chinensis

T. chinensis T. ledebouri T. altaicus

T. chinensis T. ledebouri T. altaicus

T. europaeus

Lipp (1991)

Zou et al. (2006)

Wang et al. (2004)

Wu et al. (2013)

Wu et al. (2013)

(Continues)

Witkowska-Banaszczak 2009 THE GENUS TROLLIUS—PHARMACOLOGICAL AND CHEMICAL RESEARCH

489

Phytother. Res. 29: 475–500 (2015)


Magnoflorine

74

77

Trolliamide (=2-hydroxy-tetracosanoic acid (2,3-dihydroxy-1-hydroxymethyl-heptadec-7enyl)-amide)

Protoanemonin

76

Ceramide

Ranunculin

75

Lactons

Trolline

Proline

73

Alkaloids

72


T. chinensis

T. europaeus

T. europaeus

T. europaeus

T. chinensis

T. europaeus

Wang et al. (2010)

(Continues)

Jürgens and Dötterl (2004) Gruenwald et al. (2004)

Gruenwald et al. (2004)

Hegnauer (1964)

Wang et al. (2004)

Lipp (1991)


Phytother. Res. 29: 475–500 (2015)


Daucosterol

79

Sucrose

Inositol

Fructose

81

82

83

Dodecanoic acid

Tetradecanoic acid

Hexadecanoic acid

1

2

3

Fatty acid and its derivatives

Compounds identified in the essential oil of Trollius europaeus

Sorbitol

80

Carbohydrates

β-Sitosterol

78

Sterols

T. europaeus

T. europaeus T. chinensis


T. hondoensis

T. hondoensis

T. hondoensis

T. hondoensis

T. chinensis

T. chinensis

(Continues)

Witkowska-Banaszczak (2013)

Witkowska-Banaszczak (2013) Wang et al. (2010)


Iriki et al. 1978

Iriki et al. 1978

Iriki et al. 1978

Iriki et al. 1978

Wang et al. (2004)

Wang et al. (2004) THE GENUS TROLLIUS—PHARMACOLOGICAL AND CHEMICAL RESEARCH

491

Phytother. Res. 29: 475–500 (2015)


2,4-Dimethylheptan

(E)-3-Hexenol

Heptanal

Octanal

Nonanal

Decanal

Jasmone

8

9

10

11

12

13

14

Hexadecane

Stearic acid

7

16

Oleic acid

6

Pentadecane

Linolenic acid

5

15

10-Hydroxy-hexadecanoic acid

4


T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. chinensis


T. chinensis

T. chinensis

(Continues)

Witkowska-Banaszczak (2013) Jürgens and Dötterl (2004)

Jürgens and Dötterl (2004)

Witkowska-Banaszczak (2013) Jürgens and Dötterl (2004) Ibanez et al. (2010)

Witkowska-Banaszczak (2013) Jürgens and Dötterl (2004) Ibanez et al. (2010) Jürgens and Dötterl (2004)



Jürgens and Dötterl (2004) Ibanez et al. (2010)


Wang et al. (2010)


Wang et al. (2010)

Wang et al. (2010)


Phytother. Res. 29: 475–500 (2015)


Methyl benzoate

1.2-Benzenedicarboxylic acid

22

23

Benzyl benzoate

Methyl salicylate

21

25

Veratrole

20

2-Methoxy-4-vinylphenol

o-Guaiacol

19

24

T. europaeus

Benzenoids Phenyl acetaldehyde

18

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

Eicosane

17

(Continues)




Ibanez et al. (2010)







493

Phytother. Res. 29: 475–500 (2015)


Camphenilone

Terpinolene

30

31

Perillene

Trans-β-ocimene

29

33

α-Pinene

Monoterpenoids 28

Linalool

Methyl anthranilate

27

32

Indole

26

Nitrogen-containing compounds


T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus


(Continues)

Witkowska-Banaszczak (2013) Jürgens and Dötterl (2004) Ibanez et al. (2010)








Phytother. Res. 29: 475–500 (2015)


6-Methyl-5-hepten-2-one

35

(Z)-β-Farnesene

(Z,E)-α-Farnesene

38

39

(E,E)-α-Farnesene

Geranyl acetone

37

40

α-Cis-bergamotene

36

Sesquiterpenoids

Edulan

34

Irregular terpenes

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

(Continues)









495

Phytother. Res. 29: 475–500 (2015)


β-copaene

Germacrene D

β-Selinene

45

46

48

γ-Cadinene

β-Bourbonene

44

50

β-Caryophyllene

43

α-Alaskene

α-Humulene

42

49

β-Santalene

41


T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus

(Continues)











Phytother. Res. 29: 475–500 (2015)


Caryophyllene oxide

δ-Cadinol

53

54

55

Oxacycloheptadec-8-en-2-one

Dendrolasin

52

Macrocyclic epoxide

Cis-nerolidol

51

T. europaeus

T. europaeus

T. europaeus

T. europaeus

T. europaeus







497

Phytother. Res. 29: 475–500 (2015)

498


Figure 1. Reaction of ranunculin changing into anemonin.

244.50 μg/ml and 279.06 μg/ml for cell lines of human breast adenocarcinoma (Song et al., 2013a). The influence of Trollius flavonoids on proliferation of human lung cancer cells and apoptosis of tumor cells was examined. The study of cell proliferation was performed in vitro by CCK-8, whereas apoptosis was determined using agarose gel electrophoresis of DNA. Trollius flavonoids have been shown to inhibit the lung cancer cells depending on concentration and to induce apoptosis of tumor cells (Li et al., 2011). Pharmacokinetics and tissue distribution. Orientin isolated from flowers of T. chinensis was administered to rabbits intravenously, intraperitoneally and intramuscularly to determine pharmacokinetics as well as tissue distribution. The bioavailability after intramuscular administration was lower than the intraperitoneal one which is associated with high vascularization of the abdominal cavity and a fast blood flow there. Tissue distribution was most extensive in the kidney, liver and lungs, and least extensive in the brain (Tan et al., 2013). The HPLC method was developed for the pharmacokinetic study of orientin, after intravenous administration to rabbits. The content of orientin administration of a purified extract from the flowers of T. chinensis in amounts corresponding to 2.69, 5.38 and 10.75 mg/kg of orientin was monitored until complete elimination of the compound. The content of orientin in plasma decreased with time and was dependent on the dose (Li et al., 2007). Quality and purity of plant material. Chen AJ et al., presented results of their studies concerning the risk of fungal infections in medicinal plants used in Chinese medicine in the form of various preparations. Traditional methods of harvesting, processing and storing increase the risk of candidiasis, zygomycosis and aspergillosis in crude herbal drugs. Preparations taken orally made of material infected with fungi may provide harmful mykotoxins, e.g. aflatoxins, ochratoxins A, to the organism. Among the investigated capsules, three batches of T. chinensis bunge capsules contained 12 CFU/g of fungi belonging to the genera Penicillium and Aspergillus (drug hygiene standard in China = 500 CFU/g) (Chen et al., 2012). Toxicology. Many species from the family Ranunculaceae, including T. europaeus, contain ranunculin—a glycoside containing the lactone protoanemonin. Ranunculin is found in the fresh globeflower herb. When the material is harvested and the plant tissues are crushed, the enzyme ranunculase is released, which hydrolyses ranunculin to protoanemonin and a sugar unit (Fig. 1). Protoanemonin is a volatile lactone of a bitter and burning taste. It irritates mucous membranes of the digestive tract, causing gastrointestinal disorders, pain and a burning sensation in the oral cavity, oedema of mucous membranes and sialorrhea. Irritation of the urinary system is also possible. Copyright © 2015 John Wiley & Sons, Ltd.

Irritation, redness, pain or sometimes even blisters and ulcers may be expected after long contact of the freshly harvested herb with the skin or conjunctivas. During drying, protoanemonin spontaneously dimerizes to anemonin, which does not exhibit any toxic properties (Bruneton, 1999; Burda, 1998; Gruenwald et al., 2004).

CONCLUSION Out of 32 species of Trollius, only 3 (T. chinensis, T. ledebouri and T. macropetalus), which are found in the Far East, are traditionally used to treat upper respiratory tract infections, common cold, influenza, tonsillitis, acute tympanitis and aphthae. The use has been justified by the results of pharmacological studies of T. chinensis, T. ledebouri and some compounds isolated from them, which have suggested antiviral activity against parainfluenza virus type 3, influenza virus A and Coxsackie virus as well as antibacterial activity against S. aureus, K. pneumoniae, S. pneumoniae, S. pyogenes, P. aeruginosa and H. influenzae, which frequently cause the aforementioned infections. What is also important for therapy is the antiinflammatory activity proven for compounds isolated from T. ledebouri, of which 7-methoxyl-2″-O-(2″′-methylbutyryl) orientin showed the strongest activity. Results of studies of the chemical constituents of five species from the genus Trollius suggest the presence of ten main compound classes, such as: flavonoids, organic acids, carotenoids, terpenes, ceramides, compounds containing N in the ring, steroid compounds, derivatives of fatty acids, benzenoids and carbohydrates. Flavonoids, in particular flavonoid C-glycosides and terpenes, constitute the most numerous group of compounds. There is strong evidence for the biological importance of certain compounds present in the Trollius species, such as: orientin, vitexin and their derivatives. Detailed studies into the correlation between the biological activity and structure are desirable and would make it possible to develop effective synthetic analogues with medicinal properties. An overview of the literature on the subject shows that various studies into the pharmacological activity have been conducted in vitro for 2 species and/or compounds isolated from them on experimental models. Data on the antiviral activity against influenza virus A, parainfluenza virus type 3 and Coxsackie virus as well as antibacterial activity confirm the effectiveness of extracts from T. chinensis and T. ledebouri in the treatment of respiratory infections. Because of the presence of polyphenolic compounds similar to those found in the Asian species of Trollius, including flavonoid C-glycosides (Maciejewska-Rutkowska et al., 2007; Witkowska-Banaszczak, 2009), T. europaeus may constitute a potential source of natural medicines used to treat infectious diseases of viral and/or bacterial origin. Further research is required to determine the Phytother. Res. 29: 475–500 (2015)


biological activity of the extracts and compounds found in the species. Studies into the activity of the species used in the traditional medicine of the Far East should also be scrutinized; the antimicrobial activity (in particular against strains of drug-resistant microorganisms) should be investigated more accurately as it explains and determines the effectiveness of the selected species in the treatment of respiratory disorders. Despite the long tradition of application, chemical studies and initial pharmacological studies of the Trollius species, their healing properties have not been proven in clinical studies. The need for such studies is evident. The species from the family Ranunculaceae, including Trollius, are characterized by the presence of protoanemonin (which is subject to disintegration); hence, their toxicity cannot be excluded. Protoanemonin may cause skin

499

and mucosa irritation and bleeding from the digestive tract, but it is found in the fresh material, and when drying, enzymatic reactions change it into non-toxic anemonin (Chawla et al., 2012). The genus Trollius is a potential source of new, pharmacologically active compounds. The studies of the chemical compounds found in Trollius and the biological properties conducted so far and the number of the unexplored species suggest that further research is needed and justified.

Conflict of Interest The authors have declared that there is no conflict of interest.

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Ethnomedicinal uses, phytochemistry and pharmacological properties of the genus Boerhavia.

The Genus Phyllanthus: An Ethnopharmacological, Phytochemical, and Pharmacological Review.

The Genus Carissa: An Ethnopharmacological, Phytochemical and Pharmacological Review.

The genus spilanthes ethnopharmacology, phytochemistry, and pharmacological properties: a review.

Chemical and pharmacological profiles of Echinacea complex.

The Chemical Constituents and Pharmacological Actions of Cordyceps sinensis.

Chemical constituents of the plants from the genus Oplopanax.

Chemical constituents of the plants from the genus Phyllanthus.

Chemical constituents of plants from the genus Paris.

Homobatrachotoxin in the genus Pitohui: chemical defense in birds?

Pharmacological potential and conservation prospect of the genus Eucomis (Hyacinthaceae) endemic to southern Africa.

Chemical composition and pharmacological significance of Anethum Sowa L. Root.

Acetylsecohemicholinium: chemical and pharmacological evaluation of an open-ring hemicholinium.

Chemical composition and pharmacological activities of Pisum sativum.

Traditional uses, phytochemistry and pharmacological properties of the genus Peucedanum: a review.

Ethics of pharmacological research involving adolescents.

Chemical, physiological, and toxicological aspects of the essential oil of some species of the genus Bystropogon.

The status of chemical analysis in environmental research and control.

Compartmentalized Platforms for Neuro-Pharmacological Research.

MRI Contrast Agents for Pharmacological Research.

Cryopreserved human tissue in pharmacological research.

Phytoestrogens in postmenopause: the state of the art from a chemical, pharmacological and regulatory perspective.