Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Contents lists available at ScienceDirect 2 3 4 5 6 journal homepage: www.elsevier.com/locate/jep 7 8 9 Review 10 11 12 13 14 15 Q1 Sebastian Granica, Jakub P. Piwowarski, Monika E. Czerwińska, Anna K. Kiss n 16 Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, 17 ul. Banacha 1, 02-097 Warsaw, Poland 18 19 20 art ic l e i nf o a b s t r a c t 21 22 Article history: Ethnopharmacological relevance: The Epilobium genus (willowherb) comprises of ca. 200 species of 23 Received 15 May 2014 herbaceous plants distributed around the world. Infusions prepared form willowherbs have been 24 Received in revised form traditionally used externally in skin and mucosa infections and in the treatment of benign prostate 25 26 August 2014 hyperplasia. Nowadays extracts from different Epilobium species are widely used by patients, however Accepted 27 August 2014 26 the lack of clinical studies does not allow to fully establish their efficacy. The present review summarizes 27 published data on phytochemistry, ethnopharmacological use and pharmacological studies concerning 28 Keywords: Q9 willowherb species investigated throughout past few decades. Epilobium L. (Onagracae) 29 Materials and methods: Literature survey was performed using Scopus, PubMed, Web of Science and Traditional uses Reaxys databases looking for papers and patents focused on chemical composition and bioactivity of 30 Oenothein B Epilobium species. Systematic research in ethnopharmacological literature in digitalized sources of 31 Anti-inflammatory academic libraries was also carried out. 32 Anti-proliferative Result: The chemical composition of different Epilobium species and their bioactivities are described. The 33 Benign prostate hyperplasia detailed information on constituents isolated and detected by chromatographic methods is given. The Phytochemistry 34 studies show that polyphenols are main compounds occurring in Epilobium herb among which Flavonoids 35 flavonoids, phenolic acids and tannins (oenothein B and oenothein A) are dominating constituents. 36 The extracts and some isolated compounds from Epilobium sp. were shown to possess antimicrobial, 37 anti-proliferative, anti-inflammatory, analgesic and antioxidative activities. Because many studies 38 suggest that oenothein B as dominating constituent may be responsible for Epilobium sp. pharmacolo39 gical effects, its documented bioactivities were also described. 40 Conclusions: The pharmacological studies performed on Epilobium justify the traditional use of this species in external and in gastrointestinal inflammations. As far as the treatment of benign prostate 41 hyperplasia (BPH) is considered, in the literature, there are some reports indicating that Epilobium 42 extracts have a beneficial effect for this disorder, but the number of in vitro studies is not sufficient and 43 the in vivo studies are not conclusive or too preliminary to draw a final conclusion about the efficacy of 44 Epilobium preparations. More in vitro, in vivo and clinical studies to confirm this mode of action are 45 strongly needed. Epilobium’s extracts have also documented antioxidative and potential anti46 inflammatory properties. Oenothein B can be considered as responsible for some of Epilobium 47 48 49 50 51 52 Abbreviations: 1321N1, human astrocytoma cell line; ABTS, 2,20 -azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid); ACE, angiotensin-converting enzyme; ATE, ascetic 53 Q8 tumor of Ehrich cells; BPH, benign prostate hyperplasia; COX-1, cycloxygenase-1; COX-2, cycloxygenase-2; CUPRAC, cupric reducing antioxidant capacity; DPPH, 2,254 diphenyl-1-pikrylhydrazyl; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; f-MLP, N-formyl-L-methionyl-L-leucyl-L-phenylalanine; FRAP, ferric reducing ability/ 55 antioxidant power assay; GPx, glutathione peroxidase; HEC293, human embryonic kidney 293 cells; HHDP, hexahydroxydiphenic group; HMEC, human mammary epithelial 56 cells; HPV-7, 18, human papillomavirus 7, 18; IL-6, 8, interleukin 6, 8; LNCaP, androgen-sensitive human prostate adenocarcinoma cells; LPS, lipopolysaccharide; LTB4, 57 leukotriene B4; MDA, malonyldialdehyde; MIC, minimum inhibitory concentration; MRSA, methycylin resistant Staphylococcus aureus; MTT, 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide; NEP, neutral endopeptidase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NQO1, NADPH quinine oxireductase 1; 58 PC-3, human androgen-independent prostate cancer cells; PGD2, prostaglandin D2; PGE2, prostaglandin E2; PGI2, prostacyclin; PMA, phorbol myristate acetate; PPAR α, γ, 59 peroxisome proliferator-activated receptor alpha, gamma; PSA, prostate specific antigen; PZ-HPV-7, human papillomavirus 7 transformed epithelial cells; RAW 264.7, mouse 60 leukemic monocyte macrophage cell line; RIA, radioimmunoassay; ROS, reactive oxygen species; SK-N-SH, human neuroblanstoma cells; TBA, thiobarbituric acid reactive 61 substances assay; THP-1, human monocytic cell line; TNF-α, tumor necrosis factor alpha; TPC, total polyphenol content n Corresponding author. Tel.: þ 48 22 57 20 942; fax: þ48 22 57 20 985. 62 E-mail address: [email protected] (A.K. Kiss). 63 64 http://dx.doi.org/10.1016/j.jep.2014.08.036 65 0378-8741/& 2014 Published by Elsevier Ireland Ltd. 66

Journal of Ethnopharmacology

Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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pharmacological properties. Because of the lack of clinical data further studies are needed to provide an evidence base for traditional uses of plant materials belonging to the Epilobium genus. & 2014 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botanical profile and taxonomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Traditional uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Phenolic acids and their derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Tannins and related compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Steroids and triterpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Other constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Pharmacological reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Anti-proliferative activity and potential effect on prostate cells growth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Anti-inflammatory activity and analgesic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antioxidative activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Antimicrobial, antifungal and antiviral activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Effects on gastrointestinal tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Documented bioactivities of oenothein B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Toxicity and safety. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The Epilobium genus (Onagraceae) consists of approximately 200 species distributed worldwide (Raven, 1976b). Twenty-six different species can be found and identified in Europe (Raven, 1976a). Some of these species have been used as medicinal plants due to their beneficial attributes towards human health. In Europe, extracts from the herb of different plants belonging to the Epilobium genus: small-flowered species such as Epilobium parviflorum Schreb. (small-flower willowherb), Epilobium montanum L. (mountain willowherb), Epilobium roseum Schreb. (pink willowherb), Epilobium collinum C.C.Gmelin (hill willowherb) and large-flowered species such as Epilobium angustifolium L. (¼ Chamerion angustifolium Scop.) (rosebay willowherb, fireweed, great-willowherb) and Epilobium hirsutum L. (villous willowherb) have been used for the treatment of benign prostate hyperplasia (BPH) (Treben, 1984; Wichtl, 2004). Native Americans used the herb, a root of some Epilobium species, externally to treat skin infections and rectal bleeding due to its astringent properties (Raymond, 1945; Shikov et al., 2006). In Russia, the aerial parts of Epilobium are commonly consumed untreated or fermented in a form of infusion (often called Ivan tea, Kapor tea or Russian tea) to treat stomach ulceration, gastritis and sleeping disorders (Shikov et al., 2006; Kosman et al., 2013). In the last few decades there has been a growing interest in phytochemical composition of plant materials belonging to the Epilobium genus. At first it was due to the chemotaxonomic reasons as different Epilobium species contain a wide variety of flavonoids, which are often considered as valuable chemotaxonomic markers (Averett et al., 1978; Averett et al., 1979; Hiermann, 1983, 1995; Ducrey et al., 1995; Hevesi Toth et al., 2006). It was observed that infusions prepared from the Epilobium herb display some positive effects in the prevention and treatment of early stages of BPH, which is why many studies focus efforts to prove

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the efficacy of Epilobii herba preparations and their actual mechanism of action in the context of their application for prostatic ailments (Lesuisse et al., 1996; Ducrey et al., 1997; Vitalone et al., 2001; Vitalone et al., 2003; Kiss et al., 2006a, b; ; Kujawski et al., 2010b; Coulson et al., 2013; Stolarczyk et al., 2013a). The ubiquitous presence of at least in vitro biologically active ellagitannin oenothein B in all Epilobium species suggests the important role of this constituent in the preparations’ efficacy (Ducrey et al., 1997; Kiss et al., 2011; Granica et al., 2012). The aim of this paper is to give a comprehensive review on the chemical composition, traditional uses, documented biological activities as well as possible future applications of plant materials belonging to the Epilobium genus. It shall also discuss the activity and the role of oenothein B as a dominating polyphenolic compound of polar extracts prepared from the herb of Epilobium sp.

2. Botanical profile and taxonomy Plants belonging to the Epilobium genus are erect perennial herbs often flowering in the first year, distributed on all continents except Antarctica (Raven, 1976a; Wichtl, 2004). The Epilobium genus had already been considered as not homogenous when two groups of closely related plants differing in stemen orientation were recognized by Linnaeus (Sennikov, 2011). The first, smaller group of plants comprising of 8 species with zygomorphic flowers was represented by Epilobium angustifolium. The second, much bigger group of herbs with usually actinomorphic flowers consisted of approximately 165 species. Due to these and some other morphological differences between both groups, it was finally proposed to distinguish two monophyletic sister genera within Epilobium – Chamerion represented by the most common and wide-spread Chamerion angustifolium (formerly Epilobium angustifolium) and Epilobium with many so called small-flowers

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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willowherb species (Wagner and Hoch, 2005; Wagner et al., 2007; Sennikov, 2011). Although many botanists around the world do not separate Chamerion from the Epilobium genus, it is postulated that both genera should be distinguished. In the literature, apart from the name Chamerion, the name Chamaenerion can be found. Both names refer to the separated genus of large-flowered willowherb (Sennikov, 2011). However, in this review we will use the most frequently mentioned Epilobium angustifolium. The identification of species belonging to the Epilobium/ Chamerion genus is considered as taxonomically difficult because of species similarity and frequent interspecific hybridization (Krajsek et al., 2006). The determination of Epilobium species based on the key of Flora Europea (Raven, 1976a) requires samples of all organs, including the seeds (Krajsek et al., 2006). In order to successfully identify sample when all organs are not available, a key based on trichome morphology to determine the 14 most common European Epilobium species was developed (Krajsek et al., 2006). The size, placement and way of filling the mucilage cells of calcium oxalate in the form of raphides may also be useful. Epilobium parviflorum and Epilobium collinum have raphides filling the whole mucilage cells, 100–150 mm long, while Epilobium montanum and Epilobium roseum have 150 mm long raphides which do not fill cells. Raphides in Epilobium angustifolium are placed exclusively along the veins while in other species they are distributed randomly (Wichtl, 2004). This key can be easily used even if the sample of drug or dietary supplement contains only cut or grounded Epilobium aerial parts.

3. Traditional uses The reports concerning the traditional uses of Epilobium species in folk medicine mainly originate from Europe and North America. Traditional names for the most commonly used Epilobium angustifolium are fireweed (USA), North America wickopy, wickup, flowering willow, Indian wickopy, blood vine, blooming sally, herbe de St. Anotine (France), Weidensroeschen, Antoniuskraut, Feuerkraut (Germany), and rosebay willowherb (UK) (Deschauer, 1945). The Potawatomi people (North American Indians) called it Epilobium angustifolium “kêgi’nano’kû k” (sharp pointed weed) and ̂ gi’-bag” ̂ Epilobium adenocaulon “wisi (bitter weed) (Smith, 1933). In Greenland, the dwarf fireweed (Chamerion latifolium) is called “niviaqsiaq” (young girl) and it is the national flower (Aiken et al., 2012). Austrian herbalist Maria Treben recommended the usage of Epilobium herbs (especially Epilobium parviflorum) infusion in the treatment of benign prostate hyperplasia, prostatitis, as well as bladder and kidney diseases. These indications were supported by extensive descriptions of cases where therapy using Epilobium herb occurred to be effective (Treben, 1984). The use of Epilobium angustifolium, Epilobium montanum and Epilobium parviflorum in Austrian folk medicine in the treatment of prostate, kidney and urinary tract diseases was also reported by Vogl et al. (2013). Not only in Europe, but also in North America the traditional use of Epilobium species in the treatment of urinary tract associated ailments is well documented. Miwok and Costanoan people used the herb of Epilobium canum in a form of decoction to treat kidney, bladder and other urinary tract associated problems (Barrett and Gifford, 1933; Bocek, 1984). American herbalist Michael Moore recommended Epilobium angustifolium in the treatment of acute and general prostatitis (Moore, 1994, 1997). Epilobium species were an important remedy in gastrointestinal tract disorders. The infusions from roots were used by North American Indians to treat diarrhea and other gastrointestinal ailments (Smith, 1923, 1933; Turner et al., 1980). The infusions from Epilobium herb (especially Epilobium angustifolium) due to its

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astringent, demulcent and emollient properties, were recommended by American herbalists in the 19th and early 20th century as a very effective agent to treat gastrointestinal diseases such as dysentery and diarrhea of different aetiologies as well as other bowel and intestinal disorders associated with infection, irritation and inflammation (Smith, 1855; King, 1856; Fyfe, 1903; Felter and Lloyd, 1905; Rolla, 1907; Ellingwood, 1909, 1919; Felter, 1909, 1922; Harrison, 1909; ). Some reports point out the usage of Epilobium roots infusion in persistent coughs (Rousseau, 1947) or decoction from herb as a remedy for an infant’s fever by North American Indians (Bocek, 1984). Deschauer (1945) recommended the herb of Epilobium angustifolium to treat whooping cough, hiccough and asthma. Topically the plants from Epilobium species have been used in folk medicine to treat various skin and mucosa diseases as well as for bodily injuries. For North American Indians it was a remedy for infected sores, hemorrhages after parturition and as a wash for swellings (Bocek, 1984; Smith, 1923; Barrett and Gifford, 1933). They also used Epilobium ciliatum (Epilobium adenocaulon) for hip and back pain, especially for pregnant women (Whiting, 1939). In Nepal, paste made from Epilobium brevifolium is a traditional medicine applied for muscular pain (Gewali, 2008). A poultice made from the leaves of Epilobium angustifolium by Gwich’in people (Alaska Native) was applied to burns, bee stings, aches and swelling caused by arthritis (Andre and Fehr, 2002). For rectal hemorrhage, Cheyenne people made tea from pulverized leaves or roots of Epilobium angustifolium (Campbell, 2004). Epilobium angustifolium was called ‘slippery root’ by Chippewa Indians in North America and its leaves were used in treatment of bruises. It was claimed to possess tonic, adstringent, demulcent and emollient properties (Bureau_of_American_Ethnology, 1928). American herbalists recommended the usage of herb infusions in treatment of leucorrhea, menorrhagia, uterine hemorrhage, ophthalmia, ulceration of mouth and throat (King, 1856) and eczema (Ellingwood, 1919). Adstringent, vulnerary and resolving properties were attributable to Epilobium angustifolium (Epilobium spicatum) by XIX century french authors (Adelon et al., 1819). Dictionnaire usuel des sciences médicales from 1892 also mentions vulnerary and detersive properties (Dechambre et al., 1892). Its specific use as a healing agent for ulcers is reported by Egasse and Dujardin-Beaumetz (1889) and Reutter de Rosemont (1923).

4. Chemical composition Plant materials belonging to the Epilobium genus are a rich source of secondary metabolites, especially polyphenols including flavonoids, phenolic acids and tannins. Apart from polyphenols, some lipophilic compounds such as steroids, terpenoids and fatty acids have also been isolated and identified from the Epilobium species. Table 1 summarizes the key phytochemicals that can be found in the literature including chemical name of constituent, species name, investigated anatomical parts of the plant and proper citations. Only those chemicals that were properly identified, either by isolation and structure determination or by analysis of plant material preparations with chromatographic methods using chemical standards, are cited in this review. Each phytochemical is numbered from (1) to (103). Figs. 1 to 13 present the chemical structures of compounds 1–101. Compounds 102 and 103 have been isolated from Epilobium angustifolium but due to their high molecular weight, the full chemical structure could not be assigned with available spectroscopic methods; therefore, their chemical structure is not available. Being aware that HPLC–MS is currently one of the most popular methods for elucidation of chemical composition of plant extracts, together with chemical structure of each compound, the molecular weight is given to help

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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Table 1 The overview on the constituents identified in different plant materials belonging to the Epilobium genus. Phytochemical classification

No. Constituent name

Species

Part of plant

References

Flavonoids

1

Epilobium alpestre Epilobium angustifolium

Hiermann (1983) Hiermann (1983), Nowak and Krzaczek (1998a), Reynaud et al. (1982)

Epilobium parviflorum Epilobium angustifolium

Leaves Leaves, herb, flowers, fruits Leaves Leaves, flowers, herb Leaves, flowers, herb Leaves, flowers Flowers, fruits

Hiermann (1983), Rządkowska-Bodalska et al. (1987) Reynaud et al. (1982)

Epilobium alpestre

Flowers

Hiermann (1983)

Epilobium alpinum¼ Epilobium anagallidifolium Epilobium alsinifolium Epilobium andicolum ¼ Epilobium denticulatum Epilobium angustifolium

Herb

Ducrey et al. (1995)

Root Leaves

Hiermann (1983) Averett et al. (1978)

Leaves, flowers, herb Leaves L Leaves, herb Leaves

Averett et al. Stolarczyk et Averett et al. Averett et al. Averett et al. Averett et al.

Leaves Leaves Leaves, herb Herb Leaves Root, herb

Averett et al. (1978) Averett et al. (1978) Ducrey et al. (1995); Hiermann (1983, 1995) Hiermann (1995) Averett et al. (1978) Barakat et al. (1997), Ducrey et al. (1995), Hiermann (1983, 1995),Nawwar et al. (1997), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978), Ducrey et al. (1995), Hevesi Toth et al. (2009a), Hiermann (1983) Averett et al. (1979) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Ducrey et al. (1995), Hevesi Toth et al. (2009a, 2009b), Hiermann (1983), Rządkowska-Bodalska et al. (1987), Stolarczyk et al. (2013a) Averett et al. (1978) Ducrey et al. (1995). Hevesi Toth et al. (2009a), Hiermann (1983, 1995)

Kaempferol

Epilobium dodonaei Epilobium hirsutum Epilobium montanum

2 3

Kaempferol 8-O-methyl ether Kaempferol-3-Orhamnoside

Epilobium astonii Epilobium canum Epilobium capense Epilobium ciliatum ¼ Epilobium adenocaulon Epilobium clavatum Epilobium coloratum Epilobium dodonaei EEpilobium fleischeri Epilobium galberrimum Epilobium hirsutum Epilobium hornemannii Epilobium minutum Epilobium montanum Epilobium Epilobium Epilobium Epilobium Epilobium

nevadense nivium obcordatum oregonense parviflorum

Epilobium pubens Epilobium roseum

4 5

6

7 8

Leaves Leaves Leaves, flowers, herb Leaves Leaves Leaves Leaves Leaves, flowers, herb

Leaves Leaves, flowers, root, herb Epilobium salignum Herb Epilobium saximontanum Leaves Epilobium stevenii Leaves Epilobium tetragonum Herb Kaempferol-3-O-glucoside Epilobium parviflorum Herb Kaempferol-3-OEpilobium angustifolium Herb arabinoside Epilobium hirsutum Herb Epilobium montanum Herb Epilobium salignum Herb Kaempferol-3-OEpilobium angustifolium Herb glucuronide Epilobium hirsutum Herb Kaempferol-3-O-(6″-pEpilobium angustifolium Herb coumaroyl)-glucoside Quercetin Epilobium alpestre Leaves Epilobium alsinifolium Leaves, flowers Epilobium angustifolium Leaves, herb, flowers, fruits Epilobium dodonaei Leaves Epilobium hirsutum Leaves, flowers, herb Epilobium montanum Leaves, flowers, herb

Hiermann (1983) Barakat et al. (1997), Hiermann (1983), Nawwar et al. (1997) Hiermann (1983)

(1978, 1979), Ducrey et al. (1995), Hiermann (1983, 1995), al. (2013a, 2013b) (1978) (1979) (1978), Ducrey et al. (1995) (1978)

Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1979) Ducrey et al. (1995), Hevesi Toth et al. (2009a) Rządkowska-Bodalska et al. (1987) Ducrey et al. (1995), Hiermann (1995) Ducrey et al. (1995), Barakat et al. (1997) Ducrey et al. (1995) Ducrey et al. (1995) Barakat et al. (1997), Ducrey et al. (1995), Hevesi Toth et al. (2009a); Hiermann (1995), Stolarczyk et al. (2013a) Hiermann (1995); Barakat et al. (1997) Kiss et al. (2004) Hiermann (1983) Hiermann (1983) Hiermann (1983), Reynaud et al. (1982) Hiermann (1983) Barakat et al. (1997), Hevesi Toth et al. (2006), Hiermann (1983), Nawwar et al. (1997) Hiermann (1983)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 Q14 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Q15107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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Table 1 (continued ) Phytochemical classification

No. Constituent name

Species

Part of plant

References

Epilobium parviflorum

Leaves, flowers, herb Leaves, flowers, herb Herb Herb

Hiermann (1983), Rządkowska-Bodalska et al. (1987)

Epilobium roseum

9

Quercetin-3-Orhamnoside

Epilobium tetragonum Epilobium adenocaulon ¼Epilobium ciliatum Epilobium alpestre Epilobium alpinum ¼Epilobium anagallidifolium Epilobium alsinifolium

Epilobium alsinoides Epilobium andicolum ¼ Epilobium denticulatum Epilobium angustifolium

Epilobium astonii Epilobium australe Epilobium brevipes Epilobium brunnescens Epilobium canum Epilobium capense Epilobium chionanthum Epilobium adenocaulon ¼Epilobium ciliatum Epilobium clavatum Epilobium colchicum Epilobium coloratum Epilobium conspersum Epilobium densum¼ Epilobium strictum Epilobium dodonaei

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

fleischeri foliosum glabellum glaberrimum gunnianum hectorii hirsutum

Epilobium hirtigerum Epilobium hornemannii Epilobium hybridum (unresolved name) Epilobium latifolium Epilobium luteum Epilobium melanocaulon Epilobium minutum Epilobium montanum

Epilobium nevadense Epilobium nivium Epilobium obcordatum Epilobium oreganum Epilobium oregonense Epilobium palustre Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum

Leaves, flowers, root Herb

Leaves, flowers, root, herb Leaves Leaves

Leaves, root, flowers, herb

Hiermann (1983)

Hiermann (1995)

Hiermann (1983, 1995) Ducrey et al. (1995); Slacanin et al. (1991)

Hiermann (1983, 1995)

Averett et al. (1978) Averett et al. (1978)

Leaves Leaves Leaves Leaves Leaves Leaves, herb Leaves Leaves

Averett et al. (1979), Ducrey et al. (1995), Hevesi Toth et al. (2009a), Hiermann (1983, 1995), Kiss et al. (2004), Slacanin et al. (1991), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978), Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1978)

Leaves Leaves Leaves Leaves Leaves

Averett Averett Averett Averett Averett

Leaves, flowers, root, herb Leaves, herb Leaves Lleaves Leaves Leaves Leaves Leaves, flowers, root, herb Leaves Leaves Herb

Averett et al. (1979), Ducrey et al. (1995), Hiermann (1983, 1995), Slacanin et al. (1991)

et et et et et

al. al. al. al. al.

(1978) (1979) (1978) (1979) (1978)

Averett et al. (1979); Hiermann (1995) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Ducrey et al. (1995), Hiermann (1983, 1995), Nawwar et al. (1997), Slacanin et al. (1991), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Slacanin et al. (1991)

Leaves Leaves Leaves Leaves Leaves, flowers, root, herb Leaves Leaves Leaves Leaves Leaves Leaves, herb Leaves

Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978), Ducrey et al. (1995); Hevesi Toth et al. (2009a, 2009b), Hiermann (1983, 1995), Slacanin et al. (1991)

Leaves, flowers, root, herb

Averett et al. (1978), Ducrey et al. (1995), Hevesi Toth et al. (2009a, 2009b), Hiermann (1983, 1995), Rządkowska-Bodalska et al. (1987), Slacanin et al. (1991), Stolarczyk et al. (2013a)

Averett Averett Averett Averett Averett Averett Averett

et et et et et et et

al. al. al. al. al. al. al.

(1979) (1979) (1978) (1978) (1978) (1978), Hiermann (1995) (1979)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

5

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 Q16 107 108 109 110 111 112 113 114 115 116 117 118 119 120 Q17 121 122 123 124 125 126 127 128 129 130 131 132

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Table 1 (continued ) Phytochemical classification

No. Constituent name

Species

Epilobium pubens Epilobium rigidum Epilobium roseum

10

11

Part of plant

Leaves Leaves Leaves, flowers, root, herb Epilobium salignum Herb Epilobium saximontanum Leaves Epilobium stereophyllum Herb Epilobium stevenii Leaves Epilobium suffruticosum Leaves Epilobium tetragonum Herb Herb Quercetin-3-O-glucoside Epilobium adenocaulon ¼ Epilobium ciliatum Epilobium alpestre Leaves, root, Epilobium Herb alpinum¼ Epilobium anagallidifolium Epilobium alsinifolium Leaves, root, flowers Epilobium alsinoides Leaves Leaves Epilobium andicolum ¼ Epilobium denticulatum Epilobium angustifolium Leaves, root, flowers, herb Epilobium astonii Leaves Epilobium australe Leaves Epilobium Leaves billardierianum Epilobium brevipes Leaves Epilobium brunnescens Leaves Epilobium canum leaves Epilobium capense Leaves, herb Epilobium clavatum Leaves Epilobium coloratum Leaves Epilobium conspersum Leaves Leaves Epilobium densum¼ Epilobium strictum Epilobium dodonaei Leaves, flowers Epilobium fleischeri leaves Epilobium foliosum leaves Epilobium glaberrimum Leaves Epilobium hectorii Leaves Epilobium hirsutum Leaves, flowers, herb Epilobium hirtigerum Leaves Epilobium hornemannii Leaves Epilobium latifolium Leaves Epilobium luteum Leaves Epilobium melanocaulon Leaves Epilobium minutum Leaves Epilobium montanum Leaves, flowers, root Epilobium nevadense Leaves Epilobium nivium Leaves Epilobium obcordatum Leaves Epilobium oreganum Leaves Epilobium oregonense Leaves Epilobium palustre Leaves, herb Leaves Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Herb Epilobium pubens Leaves Epilobium roseum Herb Epilobium salignum Herb Epilobium saximontanum Leaves Epilobium stevenii Leaves Epilobium suffruticosum Leaves Quercetin-3-O-galactoside Epilobium angustifolium Leaves, root, flowers, herb Epilobium capense Herb Epilobium collinum Herb

References

Averett et al. (1978) Averett et al. (1978) Ducrey et al. (1995), Hevesi Toth et al. (2009a), Hiermann (1983, 1995), Slacanin et al. (1991) Ducrey et al. (1995) Averett et al. (1978) Ducrey et al. (1995) Averett et al. (1979) Averett et al. (1979) Ducrey et al. (1995), Hevesi Toth et al. (2009a),Slacanin et al. (1991) Averett et al. (1978); Hiermann (1995)

Hiermann (1983) Ducrey et al. (1995)

Hiermann, (1983, 1995) Averett et al. (1978) Averett et al. (1978)

Averett et al. et al. (2004), Averett et al. Averett et al. Averett et al.

(1979), Ducrey et al. (1995), Hiermann (1983, 1995), Kiss Slacanin et al. (1991), Stolarczyk et al. (2013a) (1978) (1978) (1978)

Averett Averett Averett Averett Averett Averett Averett Averett

(1978) (1978) (1979) (1978); Ducrey et al. (1995) (1978) (1978) (1979) (1978)

et et et et et et et et

al. al. al. al. al. al. al. al.

Hiermann (1983) Averett et al. (1979) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Hiermann (1983), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Hiermann (1983) Averett Averett Averett Averett Averett Averett Averett

et et et et et et et

al. al. al. al. al. al. al.

(1979) (1979) (1978) (1978) (1978) (1978), Hiermann (1995) (1979)

Rządkowska-Bodalska et al. (1987), Stolarczyk et al. (2013a) Averett et al. (1978) Hiermann (1995) Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1979) Averett et al. (1979) Ducrey et al. (1995), Hiermann (1983, 1995), Kiss et al (2004), Shikov et al. (2006), Stolarczyk et al. (2013a) Ducrey et al. (1995) Hiermann (1995)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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Table 1 (continued ) Phytochemical classification

No. Constituent name

Species

Part of plant

References

Epilobium dodonaei

Leaves, root, flowers, herb Herb Leaves, flowers, herb Leaves, root, flowers, herb Herb Leaves, root, flowers, herb Leaves, root, flowers, herb Herb Herb Herb Herb

Ducrey et al. (1995), Hiermann (1983)

Epilobium fleischeri Epilobium hirsutum Epilobium montanum Epilobium palustre Epilobium parviflorum Epilobium roseum

12

Quercetin-3-Oarabinoside

Epilobium salignum Epilobium stereophyllum Epilobium tetragonum Epilobium adenocaulon ¼Epilobium ciliatum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium astonii Epilobium brevipes Epilobium canum Epilobium capense Epilobium chionanthum Epilobium collinum Epilobium coloratum Epilobium conspersum Epilobium densum¼ Epilobium strictum Epilobium dodonaei Epilobium Epilobium Epilobium Epilobium

fleischeri glaberrimum hectorii hirsutum

Epilobium latifolium Epilobium montanum Epilobium obcordatum Epilobium oreganum Epilobium oregonense Epilobium palustre Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum

13

14

15 16

Quercetin-3-Oglucuronide

Quercetin-3-O-(6″galloyl)-galactoside

Quercetin-3-Orhamnoglucoside Myricetin

dodonaei parviflorum alpestre hirsutum parviflorum

Epilobium alpestre Epilobium alsinifolium

Hiermann (1995) Ducrey et al. (1995), Hiermann, (1983), Rządkowska-Bodalska et al. (1987), Stolarczyk et al. (2013a) Hiermann, (1983), Hevesi Toth et al. (2006), Ducrey et al. (1995), Hiermann (1995) Ducrey et al. (1995) Ducrey et al. (1995) Ducrey et al. (1995) Averett et al. (1978), Hiermann (1995)

Herb Leaves, root, flowers, herb Leaves, root, flowers, herb Leaves Leaves Leaves Herb Leaves Herb Leaves Leaves Leaves

Hiermann (1995) Hiermann (1983, 1995)

Leaves, flowers, herb Herb Leaves Leaves Leaves, root, flowers, herb Leaves Leaves, root, flowers, herb Leaves Leaves Leaves Herb Leaves

Ducrey et al. (1995); Hiermann (1983, 1995)

Leaves, root, flowers, herb Epilobium pubens Leaves Epilobium roseum Leaves, root, flowers, herb Epilobium salignum Herb Epilobium saximontanum Leaves Epilobium stevenii Leaves Epilobium angustifolium Leaves, root, flowers, herb Epilobium hirsutum Leaves, flowers, herb Epilobium parviflorum Leaves, flowers, herb Epilobium angustifolium Herb Epilobium Epilobium Epilobium Epilobium Epilobium

Hiermann (1995) Barakat et al. (1997), Ducrey et al. (1995), Hiermann (1983, 1995), Stolarczyk et al. (2013a) Hiermann (1983), Ducrey et al. (1995)

Herb Herb Herb Herb Herb

Averett et al. (1979), Ducrey et al. (1995), Hiermann (1983, 1995), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Ducrey et al. (1995) Averett et al. (1978) Hiermann (1995) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978)

Hiermann (1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Barakat et al. (1997), Ducrey et al. (1995), Hiermann (1983, 1995), Stolarczyk et al. (2013a) Averett et al. (1979) Ducrey et al. (1995), Hiermann (1983, 1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Hiermann (1995) Averett et al. (1979)

Hiermann (1983), Rządkowska-Bodalska et al. (1987), Stolarczyk et al. (2013a) Averett et al. (1978) Hiermann (1983, 1995) Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1979) Ducrey et al. (1995), Hevesi Toth et al. (2009a), Hiermann (1983, 1995), Kiss et al. (2004), Stolarczyk et al. (2013a) Barakat et al. (1997), Hiermann (1983), Nawwar et al. (1997) Hiermann (1983), Stolarczyk et al. (2013a) Ducrey et al. (1995), Hiermann (1995),Kiss et al. (2004), Stolarczyk et al. (2013a) Ducrey et al. (1995) Hiermann (1995), Stolarczyk et al. (2013a) Hiermann (1995) Stolarczyk et al. (2013a) Rządkowska-Bodalska et al. (1987)

Leaves Hiermann (1983) Leaves, flowers Hiermann (1983)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Table 1 (continued ) Phytochemical classification

No. Constituent name

Species

Part of plant

References

Epilobium angustifolium

Leaves, herb, flowers, fruits Leaves Leaves, flowers, herb Leaves, flowers, herb Leaves, flowers, herb Leaves, flowers, herb Herb

Hiermann (1983), Reynaud et al. (1982)

Averett et al. (1978), Hiermann (1995)

Leaves, herb Herb

Hiermann (1983, 1995) Ducrey et al. (1995), Slacanin et al. (1991)

Leaves, root, flowers Leaves

Hiermann (1983, 1995)

Epilobium dodonaei Epilobium hirsutum Epilobium montanum Epilobium parviflorum Epilobium roseum 17

Myricetin-3-Orhamnoside

Epilobium adenocaulon ¼ Epilobium ciliatum Epilobium alpestre Epilobium alpinum¼ Epilobium anagallidifolium Epilobium alsinifolium Epilobium andicolum ¼ Epilobium denticulatum Epilobium angustifolium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

australe brunnescens capense chionanthum clavatum colchicum collinum coloratum curtisiae dodonaei

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

fleischeri foliosum glabellum glaberrimum gunnianum hirsutum

Epilobium hornemannii Epilobium hybridum (unresolved name) Epilobium latifolium Epilobium luteum Epilobium melanocaulon Epilobium minutum Epilobium montanum Epilobium nevadense Epilobium nivium Epilobium obcordatum Epilobium oreganum Epilobium oregonense Epilobium palustre Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum

Epilobium pubens Epilobium rigidum Epilobium roseum

Leaves, herb

Hiermann (1983) Barakat et al. (1997), Hiermann (1983), Nawwar et al. (1997) Hiermann (1983) Hiermann (1983), Rządkowska-Bodalska et al. (1987) Hiermann (1983)

Averett et al. (1978)

Leaves Herb

Ducrey et al. (1995), Hiermann (1983), Slacanin et al. (1991), Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Hiermann (1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979), Ducrey et al. (1995), Hiermann (1983), Slacanin et al. (1991) Averett et al. (1979), Hiermann (1995) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978),Barakat et al. (1997), Ducrey et al. (1995), Hevesi Toth et al. (2006), Hiermann (1983, 1995), Nawwar et al. (1997), Slacanin et al. (1991), Stolarczyk et al. (2013a) Averett et al. (1978) Slacanin et al. (1991)

Leaves Leaves Leaves Leaves Leaves, root, herb Leaves Leaves Leaves Leaves Leaves Herb Leaves

Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978), Ducrey et al. (1995),Hevesi Toth et al. (2006), Hevesi Toth et al. (2009a, 2009b), Hiermann (1983, 1995), Slacanin et al. (1991) Averett et al. (1979) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Hiermann (1995) Averett et al. (1979)

Leaves, herb

Averett et al. (1978), Ducrey et al. (1995), Hevesi Toth et al. (2006, 2009a), Hiermann (1995), Rządkowska-Bodalska et al. (1987), Slacanin et al., 1991, Stolarczyk et al. (2013a) Averett et al. (1978) Averett et al. (1978) Ducrey et al. (1995), Hevesi Toth et al. (2006, 2009a), Hiermann (1983, 1995), Slacanin et al. (1991) Ducrey et al. (1995) Averett et al. (1978) Ducrey et al. (1995) Averett et al. (1979) Averett et al. (1979)

Leaves Leaves Leaves, herb Leaves Leaves Leaves Herb Leaves Leaves Leaves, root, herb Leaves, herb Leaves Leaves Leaves Leaves Leaves, flowers, herb

Leaves Leaves Leaves, flowers, herb Epilobium salignum Herb Epilobium saximontanum Leaves Epilobium stereophyllum Herb Epilobium stevenii Leaves Epilobium suffruticosum Leaves

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Table 1 (continued ) Phytochemical classification

No. Constituent name

18

Myricetin-3-O-glucoside

Species

Part of plant

References

Epilobium tetragonum

Herb

Epilobium adenocaulon ¼Epilobium ciliatum Epilobium alpinum ¼Epilobium anagallidifolium Epilobium alsinifolium Epilobium alsinoides Epilobium andicolum ¼ Epilobium denticulatum Epilobium angustifolium Epilobium astonii Epilobium australe Epilobium billardierianum Epilobium brevipes Epilobium brunnescens Epilobium canum Epilobium capense Epilobium chionanthum Epilobium clavatum Epilobium colchicum Epilobium coloratum Epilobium conspersum Epilobium curtisiae Epilobium dodonaei

Leaves

Hevesi Toth et al. (2006, 2009a), Ducrey et al. (1995), Slacanin et al. (1991) Averett et al. (1978)

Herb

Ducrey et al. (1995), Slacanin et al. (1991)

Herb Leaves Leaves

Hiermann (1995) Averett et al. (1978) Averett et al. (1978, 1979)

Leaves, herb Leaves Leaves Leaves

Averett Averett Averett Averett

Leaves Leaves Leaves Leaves, herb Leaves Leaves Leaves Leaves Leaves Leaves Leaves, herb

Leaves Leaves Herb

Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978); Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978) Averett et al. (1979) Averett et al. (1978) Averett et al. (1979), Ducrey et al. (1995), Hiermann (1993b),Slacanin et al. (1991) Averett et al. (1979), Hiermann (1995) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Ducrey et al. (1995), Hiermann (1995), Slacanin et al. (1991) Averett et al. (1978) Averett et al. (1978) Slacanin et al. (1991)

Leaves Leaves Leaves Leaves Herb Leaves Leaves Leaves Leaves Leaves Leaves, herb Leaves, herb Leaves Leaves Herb Herb Leaves Herb Leaves Leaves Herb Herb

Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1979) Ducrey et al. (1995), Hiermann (1995), Slacanin et al. (1991) Averett et al. (1979) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Hiermann (1995) Averett et al. (1978), Ducrey et al. (1995), Slacanin et al. (1991) Averett et al. (1978) Averett et al. (1978) Ducrey et al. (1995), Hiermann (1995), Slacanin et al. (1991) Ducrey et al. (1995) Averett et al. (1978) Ducrey et al. (1995) Averett et al. (1979) Averett et al. (1979) Ducrey et al. (1995), Slacanin et al. (1991) Hiermann (1995)

Herb Herb Herb Herb Herb Herb Herb Herb Herb

Hiermann (1995) Hiermann (1995) Hiermann (1995), Stolarczyk et al. (2013a) Hiermann (1995) Hiermann (1993a, 1993b) Q18 Hiermann (1995) Barakat et al. (1997), Hiermann (1995), Stolarczyk et al. (2013a) Hiermann (1995) Hiermann (1995)

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

19

fleischeri foliosum glabellum glaberrimum gunnianum hectorii hirsutum

Epilobium hirtigerum Epilobium hornemannii Epilobium hybridum (unresolved name) Epilobium latifolium Epilobium luteum Epilobium melanocaulon Epilobium minutum Epilobium montanum E. nevadense Epilobium nivium Epilobium obcordatum Epilobium oreganum Epilobium oregonense Epilobium palustre Epilobium parviflorum Epilobium pubens Epilobium rigidum Epilobium roseum Epilobium salignum Epilobium saximontanum Epilobium stereophyllum Epilobium stevenii Epilobium suffruticosum Epilobium tetragonum Myricetin-3-O-galactoside Epilobium adenocaulon ¼Epilobium ciliatum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium collinum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium montanum Epilobium palustre

Leaves, herb Leaves Leaves Leaves Leaves Leaves Leaves, herb

et et et et

al. al. al. al.

(1979), Ducrey et al. (1995), Hiermann (1995) (1978) (1978) (1978)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

9

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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Table 1 (continued ) Phytochemical classification

No. Constituent name

20

Species

Epilobium parviflorum Epilobium roseum myricetin-3-O-arabinoside Epilobium alpinum¼ Epilobium anagallidifolium Epilobium angustifolium Epilobium canum Epilobium capense Epilobium ciliatum ¼ Epilobium adenocaulon Epilobium coloratum Epilobium conspersum Epilobium strictum ¼Epilobium densum Epilobium dodonaei Epilobium fleischeri Epilobium glaberrimum Epilobium hectorii Epilobium hirsutum

21

Mirycetin-3-Oglucuronide

22

Mirycetin-3-O-(6″galloyl)-galactoside

Phenolic acids and their derivatives 23 Ellagic acid

Herb Herb Herb

Hiermann (1995), Stolarczyk et al. (2013a) Hiermann (1995) Ducrey et al. (1995)

Leaves, herb Leaves Herb Leaves

Averett et al. (1979), Stolarczyk et al. (2013a) Averett et al. (1979) Ducrey et al. (1995) Averett et al. (1978)

Leaves Leaves Leaves

Averett et al. (1978) Averett et al. (1979) Averett et al. (1978)

Herb Leaves, herb Leaves Leaves Leaves, Herb

Epilobium latifolium Epilobium montanum Epilobium obcordatum Epilobium oreganum Epilobium oregonense Epilobium palustre Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium roseum Epilobium salignum Epilobium saximontanum Epilobium stereophyllum Epilobium stevenii Epilobium tetragonum Epilobium angustifolium

Leaves Herb Leaves Leaves Leaves Herb Leaves

Herb Herb Herb Leaves Herb Leaves Herb Herb

Ducrey et al. (1995); Hiermann (1995); Stolarczyk et al. (2013a) Ducrey et al. (1995) Ducrey et al. (1995) Averett et al. (1978) Ducrey et al. (1995) Averett et al. (1979) Ducrey et al. (1995) Hiermann et al. (1991), Hiermann (1993a, 1995)

Epilobium hirsutum Epilobium adenocaulon ¼ Epilobium ciliatum Epilobium alpinum¼ Epilobium anagallidifolium Epilobium alsinifolium Epilobium capense Epilobium dodonaei Epilobium fleischeri Epilobium palustre Epilobium parviflorum Epilobium roseum Epilobium salignum Epilobium stereophyllum Epilobium tetragonum

Herb Herb

Barakat et al. (1997), Nawwar et al. (1997) Hiermann (1995)

Herb

Ducrey et al. (1995)

Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb

Hiermann (1995) Ducrey et al. (1995) Ducrey et al. (1995), Hiermann (1993a, 1993b) Hiermann (1995) Hiermann (1995) Ducrey et al. (1995), Hiermann (1995) Ducrey et al. (1995), Hiermann (1995) Ducrey et al. (1995) Ducrey et al. (1995) Ducrey et al. (1995)

Epilobium angustifolium Epilobium hirsutum

Herb Herb

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

Herb Herb Herb Herb Herb Herb

Kiss et al. (2004), Shikov et al. (2006), Stolarczyk et al. (2013a) Barakat et al. (1997), Hevesi Toth et al. (2006), Nawwar et al. (1997), Stolarczyk et al. (2013a) Hevesi Toth et al. (2006) Hevesi Toth et al. (2006), Stolarczyk et al. (2013a) Hevesi Toth et al. (2006), Slacanin et al. (1991) Stolarczyk et al. (2013a) Barakat et al. (1997), Nawwar et al. (1997) Barakat et al. (1997), Nawwar et al. (1997)

Herb

Barakat et al. (1997)

Herb

Barakat et al. (1997)

montanum parviflorum roseum angustifolium hirsutum hirsutum

Valoneic acid dilactone

25

Valoneic acidamide dilactone (epilobamide-A) 10 Epilobium hirsutum Monodecarboxyvaloneic acid dilactone Valoneic acid dilactone Epilobium hirsutum dioxine

27

References

Ducrey et al. (1995) Averett et al. (1979) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978), Barakat et al. (1997), Ducrey et al. (1995), Hiermann (1995), Stolarczyk et al. (2013a) Averett et al. (1979), Hiermann (1995) Ducrey et al. (1995) Averett et al. (1978) Averett et al. (1978) Averett et al. (1978) Hiermann (1995) Averett et al. (1979)

24

26

Part of plant

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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11

Table 1 (continued ) Phytochemical classification

No. Constituent name

Species

Part of plant

References

28

Epilobium hirsutum

Herb

Barakat et al. (1997)

Epilobium angustifolium

Herb

tetragonum angustifolium

Herb Herb Herb Herb Herb

Hevesi Toth et al. (2009a), Hiermann and Radl (1998), Slacanin et al. (1991), Stolarczyk et al. (2013a) Hevesi Toth et al. (2009a) Hevesi Toth et al. (2009a); Slacanin et al. (1991) Hevesi Toth et al. (2009a); Slacanin et al. (1991) Hevesi Toth et al. (2009a) Stolarczyk et al. (2013a)

angustifolium

Herb

Stolarczyk et al. (2013a)

angustifolium

Herb

Stolarczyk et al. (2013a)

angustifolium

Herb

Stolarczyk et al. (2013a)

angustifolium angustifolium angustifolium

Herb Herb Herb

Stolarczyk et al. (2013a) Stolarczyk et al. (2013a) Hiermann and Radl (1998); Kiss et al. (2004), Shikov et al. (2006), Stolarczyk et al. (2013a) Barakat et al. (1997), Nawwar et al. (1997), Stolarczyk et al. (2013a) Stolarczyk et al. (2013a) Barakat et al. (1997); Nawwar et al. (1997) Barakat et al. (1997), Nawwar et al. (1997)

29

34 35 36

Epilobium Epilobium E. roseum Epilobium Neochlorogenic acid (5-O- Epilobium caffeoylquinic acid) 3-O-p-coumaroylquinic Epilobium acid 4-O-p-Coumaroylquinic Epilobium acid 5-O-p-Coumaroylquinic Epilobium acid 3-O-Feruoylquinic acid Epilobium 5-O-Feruoylquinic acid Epilobium Gallic acid Epilobium

37 38

Epilobium Epilobium Epilobium Epilobium

hirsutum parviflorum hirsutum hirsutum

Herb Herb Herb Herb

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

angustifolium angustifolium hirsutum parviflorum angustifolium parviflorum parviflorum hirsutum angustifolium parviflorum hirsutum angustifolium parviflorum angustifolium parviflorum angustifolium

Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

capense collinum dodonaei hirsutum montanum parviflorum

Herb Herb Herb Herb Herb Herb

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

roseum salignum stereophyllum tetragonum capense hirsutum hirsutum hirsutum angustifolium hirsutum parviflorum angustifolium

Herb Herb Herb Herb Herb Herb Herb Herb Leaves, herb Herb Herb Leaves

Shikov et al. (2006) Hiermann and Radl (1998), Shikov et al. (2006) Barakat et al. (1997), Nawwar et al. (1997) Honegr and Pospíšilová (2013) Hiermann and Radl (1998) Honegr and Pospíšilová (2013) Honegr and Pospíšilová (2013) Rakhmadieva et al. (1979) Hiermann and Radl (1998) Honegr and Pospíšilová (2013) Barakat et al. (1997); Nawwar et al. (1997) Hiermann and Radl (1998) Honegr and Pospíšilová (2013) Hiermann and Radl (1998) Honegr and Pospíšilová (2013) Ducrey et al. (1997), Hevesi Toth et al. (2009a); Granica et al. (2012), Kiss et al. (2004), Schepetkin et al. (2009); Shikov et al. (2010), Stolarczyk et al. (2013a) Ducrey et al. (1997) Granica et al. (2012) Ducrey et al. (1997) Ducrey et al. (1997), Granica et al. (2012), Stolarczyk et al. (2013a) Ducrey et al. (1997), Hevesi Toth et al. (2009a), Granica et al. (2012) Ducrey et al. (1997), Hevesi Toth et al. (2009a), Granica et al. (2012), Lesuisse et al. (1996), Stolarczyk et al. (2013a) Ducrey et al. (1997), Hevesi Toth et al. (2009a) Ducrey et al. (1997) Ducrey et al. (1997) Hevesi Toth et al. (2009a) Ducrey et al. (1997) Barakat et al. (1997), Nawwar et al. (1997) Barakat et al. (1997), Nawwar et al. (1997) Barakat et al. (1997), Nawwar et al. (1997) Haddock et al. (1982), Stolarczyk et al. (2013a) Barakat et al. (1997), Nawwar et al. (1997), Stolarczyk et al. (2013a) Stolarczyk et al. (2013a) Haddock et al. (1982)

Epilobium angustifolium

Leaves, herb

Haddock et al. (1982), Stolarczyk et al. (2013a)

Epilobium hirsutum Epilobium parviflorum Epilobium angustifolium

Herb Herb Leaves

Stolarczyk et al. (2013a) Stolarczyk et al. (2013a) Gupta et al. (1982)

Epilobium angustifolium

Leaves, herb

Gupta et al. (1982)

Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium

Herb Herb Herb

Nowak and Krzaczek (1998b) Nowak and Krzaczek (1998b) Nowak and Krzaczek (1998b)

30 31 32 33

39 40

Methyl gallate p-Methoxygallic acid methyl ester Octyl gallate Protocatechuic acid

41 42 43 44 45

Gentisic acid Syringic acid Vanilic acid Isovaloneaic acid Cinnamic acid

46 47

p-Coumaric acid Caffeic acid

48

ferulic acid

49 Tannins and related constituents

Oenothein B

50 51 52 53 54

Oenothein A 6-O-galloylglucose 1,6-di-O-galloylglucose 2,3-di-O-galloylglucose 1,2,6-tri-O-galloylglucose

55

1,2,3,6-tetra-Ogalloylglucose 1,2,3,4,6-penta-Ogalloylglucose

56

57 58 Steroids

2-O-galloyl-3-O-valeneoyl dilactone-(α/β)-4C1glucopyranose Chlorogenic acid (3-Ocaffeoylquinic acid)

59 60 61

1,2,3-tri-O-galloyl-4,6HHDP-glucose 2,3-Di-O-galloyl-4,6HHDP-glucose Cholesterol Campesterol Stigmasterol

montanum parviflorlum

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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Table 1 (continued ) Phytochemical classification

No. Constituent name

62

β-Sitosterol

Species

Part of plant

References

Epilobium angustifolium

Herb, leaves, seeds, stems, flowers Herb Herb, leaves, seeds, stems, flowers Herb, leaves, seeds, stems, flowers Herb, leaves, seeds, stems, flowers Herb, leaves, seeds, stems, flowers Herb, leaves, seeds, stems, flowers Leaves, seeds, flowers Leaves, seeds, flowers Leaves, seeds, flowers Leaves, seeds, flowers Leaves, seeds, flowers Leaves, seeds, flowers Leaves Leaves, flowers Leaves Leaves, flowers Herb, leaves Leaves Leaves Leaves Seeds

Hiermann and Mayr (1985), Huneck (1967), Nowak and Krzaczek (1998b)

Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985) Huneck (1967), Glen et al. (1967) Glen et al. (1967) Glen et al. (1967) Glen et al. (1967) Velasco and Goffman (1999)

Seeds Herb Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Velasco and Goffman (1999) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Seeds Seeds Herb Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al. (1987), Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Seeds Seeds Herb Seeds Seeds

Rządkowska-Bodalska et al. (1987); Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999)

Epilobium obscurum Epilobium parviflorum

63

β-Sitosterol glucoside

Epilobium angustifolium

Epilobium parviflorum

64

β-Sitosterol (6″-O-acetyl)glucoside

Epilobium angustifolium

Epilobium parviflorum

65

β-Sitosterol propionate

Epilobium angustifolium Epilobium parviflorum

66

β-Sitosterol capronate

Epilobium angustifolium Epilobium parviflorum

67

β-Sitosterol caprylate

Epilobium angustifolium Epilobium parviflorum

Teriterpenes

Other compounds

68

β-Sitosterol caprate

69

β-Sitosterol palmitate

70 71 72 73 74

Ursolic acid Corosolic acid Maslinic acid Oleanolic acid Oleic acid

75

76

Linoleic acid

α-linolenic acid

Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium Epilobium

angustifolium parviflorum angustifolium parviflorum angustifolium angustifolium angustifolium angustifolium alpestre

Epilobium alsinifolium Epilobium angustifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium coloratum Epilobium dodonaei

Huneck (1967) Hiermann and Mayr (1985)

Hiermann and Mayr (1985)

Hiermann and Mayr (1985)

Hiermann and Mayr (1985)

Hiermann and Mayr (1985)

Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985) Hiermann and Mayr (1985)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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13

Table 1 (continued ) Phytochemical classification

No. Constituent name

77

78

palmitic acid

stearic acid

79 80 81 82 83 84 85 86 87

Arachidonic acid Eicosenoic acid Palmitoleic acid Caproic acid Caprylic acid Capric acid Llauric acid Myristic acid Arachidic acid

88 89 90 91 92 93

Behenic acid Lignoceric acid Cerotic acid Montanic acid Melissic acid α-Tocopherol

94

γ-Tocopherol

Species

Part of plant

References

Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium angustifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium parviflorum Epilobium angustifolium Epilobium parviflorum Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium parviflorum Epilobium angustifolium E. angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium alpestre Epilobium alsinifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum E. parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium coloratum Epilobium dodonaei Epilobium fleischeri Epilobium hirsutum

Seeds Seeds Seeds Seeds Seeds Seeds

Velasco Velasco Velasco Velasco Velasco Velasco

Herb, seeds Seeds Seeds Seeds Herb Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al. (1987), Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Seeds Seeds Herb Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al. (1987); Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al. (1987); Velasco and Goffman (1999) Velasco and Goffman (1999) Rządkowska-Bodalska et al. (1987) Hiermann and Bucar (1997) Rządkowska-Bodalska et al. (1987) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Rządkowska-Bodalska et al. (1987) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Hiermann and Bucar (1997) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al. (1987),Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

and and and and and and

Goffman Goffman Goffman Goffman Goffman Goffman

(1999) (1999) (1999) (1999) (1999) (1999)

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67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Table 1 (continued ) Phytochemical classification

No. Constituent name

95

δ-Tocopherol

96

Sserine

97

Threonine

98

Ceryl alcohol

99

n-Nonacosan

100 101 102 103

Choline L-ascorbic acid Charenol Chanerozan

Species

Part of plant

References

Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium alpestre Epilobium alsinifolium Epilobium coloratum Epilobium dodonaei Epilobium hirsutum Epilobium lanceolatum Epilobium montanum Epilobium obscurum Epilobium paniculatum ¼ Epilobium brachycarpum Epilobium parviflorum Epilobium tetragonum Epilobium angustifolium Epilobium hirsutum Epilobium montanum E. parviflorum Epilobium angustifolium Epilobium collinum Epilobium hirsutum Epilobium montanum Epilobium parviflorum Epilobium angustifolium Epilobium obscurum Epilobium angustifolium Epilobium obscurum Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium Epilobium angustifolium

Seeds Seeds Seeds Seeds

Velasco Velasco Velasco Velasco

Herb, seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds Seeds

Rządkowska-Bodalska et al., (1987), Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999) Velasco and Goffman (1999)

Herb, seeds Seeds Herb Herb Herb herb Herb Herb Herb Herb Herb Herb Herb Herb Herb Leaves, flowers Herb Flowers Flowers

Rządkowska-Bodalska et al. (1987); Velasco and Goffman (1999) Velasco and Goffman, 1999 Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Bejenaru et al. (2009) Huneck (1967) Huneck (1967) Huneck (1967) Huneck (1967) Puringer (1923) Shikov et al. (2006) Petrova et al. (1974), Pukhalskaya et al. (1970), Pukhalskaya et al. (1975) Pukhalskaya et al. (1975)

compound

R1

R2

MW

1

H

H

286 300

2

H

CH3

3

rhamnoside

H

432

4

glucoside

H

448

5

arabinoside

H

418

6

glucuronide

H

462

7

6-p-coumaroylglucoside

H

494

Fig. 1. Chemical structure and molecular weight of compounds 1–7.

the reader with making comparisons to his/her experimental data in order to preliminarily identify detected constituents. 4.1. Flavonoids Flavonoids have been shown to have great chemotaxonomic value for plant materials belonging to the family of Onagraceae (Howard and Mabry, 1972; Averett et al., 1978; Averett et al., 1979;

and and and and

Goffman Goffman Goffman Goffman

(1999) (1999) (1999) (1999)

Averett and Raven, 1984; Hevesi Toth et al., 2006; Hevesi Toth et al., 2009a). Epilobium species have been proven to contain flavonols including kaempferol (1–7), quercetin (8–15) and myricetin (16–22) derivatives. Most of the reported compounds were identified as monoglycosides containing rhamnose, glucose, galactose, arabinose or glucuronic acid as a sugar moiety. Interestingly in the case of quercetin and myricetin-3-O-(6″-O-galloyl)-galactosides (14, 22) have been reported in some species in contrast to kaempferol for which only 3-O-(6″-p-coumaroyl)-glucoside (7) has been described (Kiss et al., 2004). One diglycoside – quercetin-3-O-rhamnoglucoside (15) has been detected in Epilobium parviflorum (Rządkowska-Bodalska et al., 1987). The comparison of flavonoids content in different species from Epilobium genus showed significant distinction between Epilobium angustifolium in comparison to other species. In the later, quercetin glycosides were dominating while in other species (Epilobium hirsutum, Epilobium dodonaei, Epilobium fleischeri, Epilobium roseum, Epilobium parviflorum, Epilobium montanum, Epilobium adenocaulon, Epilobium palustre, Epilobium alpestre, Epilobium collinum, Epilobium alsinifolium, and Epilobium tetragonum) – myricetin glycosides (Slacanin et al., 1991; Ducrey et al., 1995; Hiermann, 1995; Hevesi Toth et al., 2006; ). Hiermann (1995) in his investigation of Epilobium species (Epilobium angustifolium, Epilobium hirsutum, Epilobium dodonaei, Epilobium fleischeri, Epilobium roseum, Epilobium parviflorum, Epilobium montanum, Epilobium adenocaulon, Epilobium palustre, Epilobium alpestre, Epilobium collinum, Epilobium alsinifolium) has shown that only in Epilobium angustifolium glucuronides of quercetin and myricetin appeared. Kaempferol-3-O-glucuronide was

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67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

compound 8

R H

MW 302

9

rhamnoside

448

10

glucoside

464

11

galactoside

464

12

arabinoside

434

13

glucuronide

478

14

6’’-galloylgalactoside

616

15

rhamnoglucoside

610

Fig. 2. Chemical structure and molecular weight of compounds 8–14.

compound 16

R H

MW 317

17

rhamnoside

464

18

glucoside

480

19

galactoside

480

20

arabinoside

449

21

glucuronide

494

22

6’’-galloylgalactoside

632

Fig. 3. Chemical structure and molecular weight of compounds 15–22.

only present in Epilobium angustifolium and Epilobium hirsutum (Hiermann, 1995). Ducrey et al. (1995) isolated quercetin-3-O-glucuronide (13) and kaempferol-3-O-glucuronide (6) from Epilobium angustifolium, however, no myricetin-3-O-glucuronide (21). The study of Stolarczyk et al. (2013a) supported this finding. This may be explained by very low concentration of myricetin-3-O-glucuronide (21) in Epilobium angustifolii herba, which ranged from 0.008% to 0.026% (Hiermann, 1993a). To make the problem more complex, Barakat et al. (1997) isolated all three types of glucuronides from Epilobium hirsutum, while Stolarczyk et al. (2013a) found kaempferol-3-O-glucuronide in Epilobium parviflorum. However, all authors agree that quercetin-3O-glucuronide is a dominating compound in Epilobium angustifolium (Ducrey et al., 1995; Hiermann, 1995; Kiss et al., 2004; Stolarczyk et al., 2013a). The chemical structures of identified flavonoids and their molecular weights are presented in Figs. 1–3.

15

The first group comprises ellagic acid and its derivatives (23–28). Ellagic acid which is a marker of ellagitannins occurrence has been detected in 5 Epilobium species including the most popular Epilobium angustifolium, Epilobium hirsutum and Epilobium parviflorum (Slacanin et al., 1991; Ducrey et al., 1995; Barakat et al., 1997; Nawwar et al., 1997; Kiss et al., 2004; Hevesi Toth et al., 2006; Shikov et al., 2006; Stolarczyk et al., 2013a). Valoneic acid dilactone (25) has been reported in Epilobium angustifolium and Epilobium hirsutum. Other ellagic acid derivatives including ones characteristic for the Epilobium genus – epilobamide A have only been detected in Epilobium hirsutum (Barakat et al., 1997; Nawwar et al., 1997). The second group of compounds are chlorogenic acids, which classically are described as a family of esters formed between certain trans cinnamic acids, and D-(-)-quinic acid (Clifford et al., 2003). Chlorogenic acid (29) has been found in 5 Epilobium species (Hevesi Toth et al., 2009a) while other quinic acid esters (30–35) have only been detected in Epilobium angustifolium using the HPLC–DAD–MS method (Stolarczyk et al., 2013a). The third group of compounds are benzoic acid derivatives with gallic acid (36) as a typical representative. Nine different benzoic acid derivatives (36–44) have been reported from several Epilobium species (Barakat et al., 1997; Nawwar et al., 1997; Rakhmadieva et al., 1979; Hiermann and Radl, 1998; Shikov et al., 2006; Honegr and Pospíšilová, 2013). Compounds 37 and 38 have been identified as methylated derivatives of gallic acid and should be considered as possible artefacts as the plant material was extracted by the authors with methanol, which facilitates the methylation of free carboxylic groups of compounds occurring in the investigated extract (Barakat et al., 1997). The fourth group of phenolic acids are simple trans cinnamic acid derivatives. Four compounds (45–48) have been described in the Epilobium species (Barakat et al., 1997; Nawwar et al., 1997; Hiermann and Radl, 1998; Honegr and Pospíšilová, 2013). The chemical structures of identified phenolic acids and their derivatives together with their molecular weights are presented in Figs. 4–7. 4.3. Tannins and related compounds Epilobium species have been proven to be a rich source of tannins. Careful phytochemical studies have shown that oenothein B (49) is a major constituent of extract prepared from several Epilobium species (Lesuisse et al., 1996; Ducrey et al., 1997; Schepetkin et al., 2009; Hevesi Toth et al., 2009a; Granica et al., 2012). It has also been proven that oenothein B is a characteristic ellagitannin for other genera in the family of Onagraceae (Granica et al., 2012). The quantity of this compound is high in plant materials and varies from 2% to 14% (Ducrey et al., 1997; Granica et al., 2012). Oenothein B has been claimed to be at least partially responsible for the observed bioactivities of extracts prepared from the Epilobium species (Lesuisse et al., 1996; Kiss et al., 2006a; Schepetkin et al., 2009; Kiss et al., 2011; Ramstead et al., 2012). Apart from oenothein B second macrocyclic ellagitannin – oenothein A (50) has been described in E. capense (Ducrey et al., 1997). Epilobium species, especially Epilobium angustifolium, Epilobium hirsutum and Epilobium parviflorum have been shown to contain not only ellagitannins but also gallotannins, comprising eight galloylglucose derivatives or galloyl-HHDP-glucose derivatives (51–58) (Haddock et al., 1982; Barakat et al., 1997; Nawwar et al., 1997; Stolarczyk et al., 2013a). The chemical structures of identified tannin constituents together with their molecular weights are presented in Figs. 8 and 9.

4.2. Phenolic acids and their derivatives 4.4. Steroids and triterpenes It has been shown that apart from flavonoids, Epilobium species are a rich source of phenolic acids. Four different groups of phenolic acids’ derivatives have been described.

In the literature 11 steroid compounds (59–69) including cholesterol, campesterol, stigmasterol, β-sitosterol and its glycosides and

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

Fig. 4. Chemical structure and molecular weight of ellagic acid derivatives compounds 23–28.

compound

R1

R2

R3

29

C

H

H

MW 354

30

H

H

C

354

compound

R1

R2

31

P

H

H

338

45

H

H

MW 148

32

H

P

H

338

46

H

OH

164

33

H

H

P

338

OH

180

F

47

OH

34

H

H

368

OH

H

H

F

OCH3

194

35

48

368

Fig. 5. Chemical structure and molecular weight of quinic acid derivatives compounds 29–35.

Fig. 7. Chemical structure and molecular weight of cinnamic acid derivatives compounds 45–48.

have been found in aerial parts of Epilobium angustifolium but there is a lack of studies considering triterpenes in other Epilobium species (Glen et al., 1967; Huneck, 1967). The chemical structures of identified steroids and triterpenes together with their molecular weights are presented in Figs. 10 and 11. compound

R1

R2

R3

R4

R5

MW

36

H

H

OH

OH

OH

170

37

CH3

H

OH

OH

OH

184 198

38

CH3

H

OH

OCH 3

OH

39

C8H17

H

OH

OH

OH

282

40

H

H

OH

OH

H

154

41

H

OH

H

H

42

H

H

OCH 3

OH

43

H

H

OCH 3

44

H

V

OH

OH

154

OCH3

198

OH

H

168

OH

OH

506

Fig. 6. Chemical structure and molecular weight of benzoic acid derivatives compounds 36–44.

esters have been reported from Epilobium angustifolium, Epilobium parviflorum and Epilobium obscurum (Huneck, 1967; Hiermann and Mayr, 1985; Nowak and Krzaczek, 1998b). Triterpenoid acids (70–73)

4.5. Other constituents The largest group of other compounds detected in Epilobium species is fatty acids. Oleic, linoleic, α-linolenic acids, palmitic and stearic acids (74–78) have been reported from many plants belonging to the Epilobium genus. Other fatty acids (79–92) have been described in Epilobium angustifolium or Epilobium parviflorum (Rządkowska-Bodalska et al., 1987; Hiermann and Bucar, 1997; Velasco and Goffman, 1999). The chemical structures of fatty acids and their molecular weights are given in Fig. 12. Other lipophilic chemicals like α-, γ- and δ-tocopherols have also been identified in several Epilobium plants (93–95) (Rządkowska-Bodalska et al., 1987; Velasco and Goffman, 1999). The rest of Epilobium constituents comprises amino acids (96–97), ceryl alcohol (98), n-nonacosan (99), choline (100), L-ascorbic acid (vitamin C) (101) and two polymers with unidentified structures – charenol (102) and chanerozan (103) which have the molecular weights of nearly 100,000 amu (Puringer, 1923; Huneck, 1967; Pukhalskaya et al.,

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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17

Fig. 8. Chemical structure and molecular weight of oenothein B and oenothein A compounds 48 and 49.

O

O HOR 5 HO

R 4O R 3O

H

H OR2 H

OR1 HO

OH

OH HO

O

OH

G

OH HO

OH

OH

HHDP

compound

R1

R2

R3

R4

R5

MW

50

H

H

H

H

G

332

51

G

H

H

H

G

484

52

H

G

G

H

H

484

53

G

G

H

H

G

636

54

G

G

G

H

G

788

G

G

941

55

G

G

G

56

G

G

G

HHDP

938

57

H

G

G

HHDP

786

Fig. 9. Chemical structure and molecular weight of galloylglucose derivatives compounds 50–57.

1970; Petrova et al., 1974; Pukhalskaya et al., 1975; Bejenaru et al., 2009). The chemical structure of compounds 93–101 and their molecular weights are given in Fig. 13.

5. Pharmacological reports Apart from examination of chemical composition of species belonging to the Epilobium genus, there are many studies investigating the bioactivity of extracts prepared from Epilobium plant materials presented in the literature. An overview of the pharmacological evaluations carried out on several Epilobium species is

described in detail below. Also the authors decided to summarize scientific reports on bioactivity of the macrocyclic ellagitannin oenothein B, as it has been proven to be a major constituent of polar extracts prepared from Epilobium plants and has often been claimed to be responsible for the observed pharmacological effect of extracts. 5.1. Anti-proliferative activity and potential effect on prostate cells growth Epilobium preparation is traditionally recognized as a remedy for prostate impairment, and thus a significant number of studies refer to this application. First study began in the 1990s, Lesuisse et al. (1996) and Ducrey et al. (1997) almost simultaneously investigated the in vitro effect of Epilobium extracts on 5-αreductase and aromatase activity – enzymes responsible for the biosynthesis of testosterone and having a potential role in BPH. Extracts of different polarities from Epilobium parviflorum were examined for their influence on 5-α-reductase activity. Only the aqueous extract, not organic ones, was shown to be active. Bioactivity guided isolation led to the identification of oenothein B as the active principle (Lesuisse et al., 1996). Similar results were obtained by Ducrey et al. (1997), against 5-α-reductase oenothein A had IC50 ¼1.24 μM and oenothein B an IC50 ¼ 0.44 μM. However, the IC50 values were significantly higher than for the reference compound finasteride (5 nM). In in vivo studies on uncastrated and testosterone stimulated castrated rats, the oral administration of water extract of Epilobium angustifolium (40 mg/kg b.w. for 14–20 days) showed an anti-androgenic effect in the first group (significant reduction of seminal vesicles weight) and pro-androgenic effect in the latter (induction of prostate and seminal vesicles

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

18

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

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compound

R

MW

61

H

415

62

glucoside

577

63

(6’’- O-ace tyl)-glucoside

619

64

propionate (C2 H5 CO)

471

65

capronate (C5 H11 CO)

513

66

caprylate (C7 H15 CO)

541

67

caprate (C9 H19 CO)

569

68

palmitate (C15H31CO)

653

Fig. 10. Chemical structure and molecular weight of steroids detected in Epilobium species compounds 58–68.

Fig. 11. Chemical structure and molecular weight of triterpenoids detected in Epilobium angustifolium compounds 69–72.

weights). The lipophilic extract was inactive. Authors did not draw definite conclusion of observed effects. Additionally, there were no positive controls, and only lipophilic hexane extract was characterized chemically by qualitative and quantitative analysis of fatty acids, while the presence of flavonoids in water extracts was only mentioned (Hiermann and Bucar, 1997). The influence of Epilobium angustifolium dry aqueous extract on estrogenic receptors α (ERα) and β (ERβ) in animal model was also examined. The standardized extract containing of total flavonoid (0.44%), polyphenols (9.39%) and sterols (0.18%) was given intragastrically to testosterone (40 mg/kg b.w.) stimulated castrated rats in the concentration of 100 mg/kg b.w. for 21 days, as positive control finasteride (50 mg/ kg b.w.) was used. Presented results indicated that the extract

slightly increased the level of ERα mRNA and decreased the ERβ mRNA in comparison to testosterone treated control and similarly but less pronounced in comparison to finasteride (Kujawski et al., 2010a). Other preliminary results of the same scientific group obtained from with rats and swine receiving the same extract showed a slight anti-androgenic effect. Unfortunately, results were presented only as conference abstracts and no precise information about performed experiments was provided (Koziorowski et al., 2006; Kujawski et al., 2007). On the contrary, Hevesi Toth (2009) tested different preparations (infusion, 80% acetonic and hexane extracts) of chemically characterized Epilobium parviflorum raw material (34.8% of polyphenols, 0.83% of flavonoids and 0.13% of β-sitosterol) on in vitro estrogen and androgen receptors binding

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

O

19

O

HO

HO

75, MW 280

74, MW 282

O OH

O HO

76, MW 278 O

79, MW 304

HO

80, MW 310 O O

HO

HO

81, MW 254

n

compound

n

MW

77

6

256

78

7

284

82

1

116

83

2

144

84

3

172

85

4

200

86

5

228

87

8

312

88

9

340

89

10

368

90

11

396

91

12

424

92

13

452

Fig. 12. Chemical structure and molecular weight of fatty acids detected in Epilobium species compounds 73–92.

R2

O H2N CHC OH CHOH CH3

O H2N CHC OH CH2 OH

R1 HO O

96, MW 105

R3

93, R1 ,R2 ,R3 = CH 3 , MW 431 94, R1 = H, R 2 ,R3 = CH 3 , MW 417 95, R1 ,R2 = H, R 3 = CH 3 , MW 403

N

OH

100, MW 104

HO

97, MW 119

12

11

99, MW 409

98, MW 383 HO H HO HO

O

O OH

101, MW 176 Fig. 13. Chemical structure and molecular weight of tocopherols and other compounds detected in Epilobium species (93–101).

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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activity and showed no effect in a wide concentration range 0.01– 1000 μg/mL. From all of the above studies it is difficult to state if Epilobium extracts may affect the steroids hormone equilibrium. PZ-HPV-7 human epithelial prostate cells derived from normal prostate cells virally transformed by transfection with HPV18 DNA are used as a BPH model in in vitro studies of growth inhibitory responses. Vitalone et al. (2001) have demonstrated a specific and significant anti-proliferative effect of non-chemically characterized Epilobium angustifolium ethanolic extract at concentration as high as 1.9 mg/mL towards this cell line. Further studies conducted on a broader spectrum of Epilobium species (Epilobium hirsutum, Epilobium palustre, Epilobium rosmarinifolium, Epilobium angustifolium, Epilobium tetragonum) demonstrated the potential of ethanolic extracts to inhibit cells proliferation at a high concentration of 1 mg/mL observed as DNA synthesis inhibition and decrease of MTT reduction. However, at this concentration unspecific cytotoxic effect determined by trypan blue exclusion assay was observed. When sub-cytotoxic concentrations of Epilobium angustifolium, Epilobium rosmarinifolium and Epilobium tetragonum were tested (500, 100, 250 μg/mL respectively) DNA synthesis inhibition was observed together with cell cycle arrest, which was determined as a significant increase of cells in G0/G1 phase (to about 40%) however, no apoptosis was observed for the most active Epilobium rosmarinifolium extract at a concentration of 100 μg/mL (Vitalone et al., 2003). To determine the selectivity of anti-proliferative effect, inhibition of DNA synthesis was further examined not only for PZ-HPV-7 but also for other tumor cell lines: LNCaP (androgensensitive human prostate adenocarcinoma cell line), human mammary epithelial cells (HMEC) and 1321N1 (human astrocytoma cell line). There were no significant differences in IC50 values between the cell lines, which suggest that the in vitro effect of Epilobium extracts is not prostate specific. As IC50 values did not show relevant differences between human hormone responsive (LNCaP) and unresponsive (PZ-HPV-7) prostate cell lines, the mechanism of inhibition of proliferation seems to be independent of the androgen receptors. The presented studies are rather inconclusive as there is a lack of characterization of chemical constituents, beside determination of oenothein B content, which was at a very low level: Epilobium rosmarinifolium 0.46%, Epilobium angustifolium 0.03% and Epilobium tetragonum 0.05%. This has probably been the consequence of using liquid ethanolic extracts purchased from the market, as other studies concerning concentration of oenothein B in plant materials of Epilobium sp. revealed the 2–10 percentage of above compound (Ducrey et al., 1997; Granica et al., 2012). Studies comparing activity of nonpolar (ethyl acetate) and polar (water residue) fractions were conducted on PZ-HPV-7 cells. Nonpolar fractions caused concentration dependent inhibition of DNA synthesis, while among polar fractions only one obtained from Epilobium rosmarinifolium expressed significant activity. Similar distribution of effects was observed in the case of cell cycle arrest activity. The contribution of oenothein B in extracts activity was confirmed by examination of Epilobium angustifolium from two different sources. Sources containing 1.34% oenothein B extract from Canadian plant material have shown IC50 towards DNA synthesis by PZ-HPV-7 cells was 40 μg/mL, while the value for European plant material containing 0.03% of oenothein B was 400 μg/mL. Kiss et al. (2006a) conducted studies on Epilobium angustifolium extracts activity regarding its influence on neutral endopeptidase (NEP) activity, the enzyme responsible for reducing peptide mediated cancer progression, and proliferation of SK-N-SH (human neuroblastoma cells) and PC-3 (human androgenindependent prostate cancer cells). Methanolic and aqueous extracts containing 11.5% and 16.4% of oenothein B respectively have shown dose dependent enhancement of NEP activity at a concentration range of 25–100 μg/mL on both models. Apart from this effect, a decrease of cells proliferation was observed with the

IC50 below 50 mg/mL for SK-N-SK and a 25% reduction of proliferation at a concentration of 100 mg/mL for PC-3 cells. Aqueous extracts, due to a higher oenothein B content, had a significantly stronger activity. Studies conducted on LNCaP cell model of extracts from Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum with determined oenothein B content (15.5%, 22.7%, 23.5% respectively) have shown dose dependent inhibition of prostate specific antigen (PSA) secretion and arginase activity at the concentration range of 20–70 μg/mL, which, by changing polyamines metabolism, induces cells proliferation. PSA secretion was inhibited by all aqueous fractions, while for ethyl acetate fractions only one sample obtained from Epilobium parviflorum expressed significant inhibitory activity. In the case of inhibition of arginase activity, aqueous and ethyl acetate fractions acted in a comparable manner. Aqueous extracts from Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum also inhibited LNCaP cells proliferation (IC50 ¼ 44.6, 32.2, 37.3 μg/mL respectively) (Stolarczyk et al., 2013b). Aqueous and ethyl acetate extracts (at concentrations of 20, 50, 70 mg/mL) were also investigated in respect to NEP activity in LNCaP cells. All tested extracts showed a statistically significant induction of enzymatic activity in a concentration-dependent manner (Stolarczyk, 2013). Further studies revealed induction of apoptosis via alteration of the mitochondrial membrane potential and activation of caspase-3. All extracts have shown similar activity (Stolarczyk et al., 2013a). The analysis of dominating compounds (oenothein B, quercetin-3O-glucuronide and myricetin-3-O-rhamnoside) showed significant activity of the first compound in concentrations of 10–40 μM (reduction of cells proliferation by 60–90%). Nevertheless, quercetin-3-O-glucuronide at concentrations of 20 and 40 μM statistically significantly reduced PSA secretion comparably to the positive control flutamide (Stolarczyk et al., 2013b). Although, biological effects seem to be associated with oenothein B, the lack of information on oenothein B bioavailability makes it difficult to estimate the real role of this compound in Epilobium activity. It is noteworthy that compounds (ellagitannin or other constituents) from Epilobium hirsutum herb aqueous extract has been shown to be metabolized by human gut microbiota in in vitro studies to low molecular weight dibenzopyran-6-one derivatives known as urolithins (Stolarczyk et al., 2013b). Urolithins possess good bioavailability and can be present in plasma at low micromolar concentrations (Seeram et al., 2006). Urolithins are able to inhibit LNCaP cells proliferation and PSA secretion in concentration of 10– 40 μM (Stolarczyk et al., 2013b). It has been also proven, that urolithin A has an ability to accumulate in mice prostate glands and to inhibit prostate cell proliferation (Seeram et al., 2007). Further in vivo animal and human studies are highly needed to evaluate the effectiveness and to establish metabolites present in plasma. Additonally, urolithins were proven to possess antioxidant, antiestrogenic, estrogenic, anti-malarial, anti-inflammatory and anticancer activities in several cell models. The proper animal studies supporting these findings are still lacking (Larrosa et al., 2006; Espín et al., 2013). Studies conducted on mice inoculated with leucosis P-388 cells and ascetic tumor of Ehrich (ATE) cells, have shown that i.p. administration of polar extract from Epilobium hirsutum (no information on extract preparation and standardization was provided) in a dose of 1 mg/kg b.w. for 5 subsequent days after tumor inoculation, significantly increased the lifespan (156% and 150% respectively) (Voynova et al., 1991). The only available clinical study of herbal preparation for the management of symptoms of BPH containing Epilobium parviflorum extract (equivalent to 500 mg dry herb), although positive, are not conclusive on Epilobium effectiveness, as the preparation also included Cucurbita pepo oil (160 mg), lycopene (2.1 mg) and Prunus Africana (equivalent to 15 g dry stem, standardized to

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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β-sitosterol) and Serenoe repens extracts (equivalent to 660 mg dry fruits) (Coulson et al., 2013). The presented study was a short-term phase II randomized double-blind placebo controlled clinical trail, conducted on 57 males aged 40–80 years, diagnosed for BPH and having a minimum score of 8 on the international prostate symptom score (IPSS) questionnaire. After 3 months of treatment (1 capsule a day) in the active group there was a significant reduction in IPSS total score 36% as compared to 8% in the placebo group. There was also a significant reduction of day-time and night-time urinary frequency. When compared the traditional preparation of infusion equivalent to 1.5–2 of dry herb twice a day (Wichtl, 2004) it is difficult to evaluate the positive role of this single component of the whole preparation. 5.2. Anti-inflammatory activity and analgesic activities Numerous papers concerning in vitro and in vivo studies of Epilobium focused on anti-inflammatory activity. The first report deals with reduction of the release of pro-inflammatory cytokines PGI2 (6-keto-PGF1α), PGE2 and PGD2 in perfused rabbit ears by an aqueous extract from herb of Epilobium angustifolium (5 mg/mL) (Hiermann et al., 1986; Juan et al., 1988). The reduction of stimulated release of PGE2 and PGI2 in the radioimmunoassay (RIA) was 60% and 98%, respectively (Juan et al., 1988). On the other hand, the methanolic and ethanolic extracts were inactive (Hiermann et al., 1986; Juan et al., 1988). Aqueous extract from Epilobium angustifolium decreased the formation of carrageenininduced rat paw edema, but not dextran-induced edema, suggesting that this effect correlates with the inhibition of proinflammatory prostaglandins synthesis (Hiermann et al., 1986; Juan et al., 1988). Bioguided fractionation led to isolation of myricetin-3-O-glucuronide from leaves of Epilobium angustifolium. This compound, shows significant anti-inflammatory activity in low micromolar range (Hiermann and Radl, 1998), might be responsible for the strong anti-inflammatory activity of the extract, but its very low concentration could suggest the presence of other active constituents (Hiermann et al., 1991). Although Epilobium parviflorum extract was much less active than the Epilobium angustifolium one (Hiermann et al., 1986; Juan et al., 1988), Steenkamp et al. (2006) established inhibitory activity of aqueous and ethanolic extracts (250 μg/mL) from Epilobium parviflorum on COX-1 and COX-2 activity. It turned out that the ethanolic extracts exhibited higher inhibitory effects than the aqueous extracts both on COX-1 and COX-2 enzymatic activity with 90% and  60% inhibition respectively. The aqueous extracts caused inhibition of COX-1 by 59%, whereas the influence on COX-2 was negligible (Steenkamp et al., 2006). Kiss et al. (2011) established weak activity of Epilobium hirsutum, Epilobium parviflorum as well as Epilobium angustifolium aqueous extracts against both cyclooxygenases, however in a 10-time lower concentration than Steenkamp et al. (2006). This inhibitory activity of aqueous preparation in higher concentration on COX-1 activity perhaps may be related to the presence of oenothein B, which was found out to be rather only COX-1 inhibitor, though rather weak in comparison to the inhibitory activity towards hyaluronidase and lipoxygenase (Kiss et al., 2011). The high activity of ethanolic extracts of Epilobium parviflorum is difficult to explain as authors did not perform any phytochemical analysis of their extracts (Steenkamp et al., 2006). Infusion and acetonic extract (80%, v/v) of Epilobium parviflorum inhibited the PGE2 release in macrophage cells RAW 264.7 at a concentration range of 0.45–25 μg/mL (IC50 for infusion 5.5 μg/mL, IC50 for acetone extract 1.4 μg/mL) (Hevesi Toth, 2009; Hevesi Toth et al., 2009b). Authors have suggested that this is related with the direct inhibition of COX activity (Hevesi Toth, 2009; Hevesi Toth et al., 2009b). However, as inhibition of prostaglandin release is unequivocal, the mechanism of this effect

21

is not fully explained and the direct inhibition of COX enzyme (s) seems to be questionable, while the effect of Epilobium extracts on phospholipases A2 has not not been tested till now. Aqueous extracts of the three species of Epilobium mentioned above were shown to inhibit the activity of hyaluronidase and lipooxygenase with IC50 3.3–6.5 μg/mL and 16–28 μg/mL, respectively. All extracts inhibited LTB4 release from stimulated human neutrophils. This effect was more significant than the effect on lipooxygenase activity. No significant difference between extracts chemical composition was observed. Not surprisingly, it correlated with oenothein B that is ubiquitous in Epilobium sp. (Kiss et al., 2011). In the studies by Schepetkin et al. (2009) it was reported that methanolic (80%) extract of Epilobium angustifolium could modulate innate immune function by activation of phagocyte response. It induced ROS production and NF-κB activation in human THP-1 Blue monocytes. The incubation of THP-1 Blue monocytes and PBMCs with extract at a concentration range of 50–200 μg/mL caused the increase of TNFα, IL-8 and IL-6 production. On the other hand, when cells were stimulated by zymosan or PMA, the extract at up to the concentration of 1 μg/mL totally abolished ROS production. Authors isolated oenothein B as the active compound and all of its biological effects were coherent with ones determined for extract (Schepetkin et al., 2009). The effect of extracts (dichloromethane, methanol) from herbs of Epilobium angustifolium, Epilobium parviflorum and Epilobium montanum (10 μg/mL) on the expression of E-selectin and IL-8 in endothelial cells, as well as on the transactivation of nuclear factors, such as PPARα, PPARγ and NF-κB in HEK293 cells, has been recently established. Extracts were not active (o25% of inhibition) in PPARs activation assays. Only a moderate (50–75% of inhibition) ability of dichloromethane extracts of Epilobium angustifolium and Epilobium parviflorum to inhibit NF-κB has been shown. Detannified methanol extract of Epilobium montanum activated PPARs and inhibited NF-κB, whereas dichloromethane extract reduced the expression of E-selectin and IL-8 mRNA after stimulation with TNFα or LPS (Vogl et al., 2013). As the obtained results are not entirely consistent, it seems that active compounds need to be established as the presence of myricetin-3-O-glucuronide may only explain Epilobium angustifolium extracts activity. Other flavonoids present in Epilobium species as myricetine-3-Oglucoside, myricetine-3-O-galactoside, myricetine-3-O-rhamnoside and 3-O-glucuronides of quercetin, and keampferol were not active in carrageenan-induced rat paw edema model (Hiermann et al., 1998). On the other hand, oenothein B present in all species is at least partially responsible for the activity of hydrophilic extracts. Ruszová et al. (2013) have shown the in vitro and in vivo skin protective activity of chemically (HPLC–MS/MS) characterized Epilobium angustifolium extract and its preparation containing 3% extract in carbomer gel. The extract at a concentration of 10 μg/mL inhibited the release of matrix metalloproteinases-1 and -3 together with the tissue inhibitor of matrix metalloproteinases-1 and -2 as well as the gene expression of hyaluronidase 2 in UVirridated human dermal fibroblasts. The application of the gel containing Epilobium angustifolium extract decreased UV-induced erythema in seven of eight volunterers (Ruszová et al., 2013). The anti-inflammatory activity of extracts from Epilobium species was suggested to be associated with the inhibition of prostaglandins synthesis (Hiermann et al., 1986; Hiermann et al., 1991; Hevesi Toth et al., 2009b). Investigations on the possible analgesic and antinociceptive activities of Epilobium angustifolium and Epilobium hirsutum have been carried out. Tita et al. (2001) have examined the analgesic properties of dry extract prepared from 10% ethanolic tincture from Epilobium angustifolium using standard hot plate test and writhing test in male mice. It has been shown that the extract has displayed analgesic properties in both

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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tests conducted. In a hot plate test the examined extract at a dose of 380 mg/kg b.w. s. c. has displayed lower effect than the positive control – morphine (10 mg/kg b.w. s. c.). In the writhing test the Epilobium angustifolium extract used at dosages higher than 190 mg/kg b.w. s. c. has expressed stronger analgesic effect than lysine acetylsalicylate administrated at a dose of 300 mg/kg b.w.s. c. (Tita et al., 2001). In the second study, Pourmorad et al. (2007) have examined the antinociceptive potency of Epilobium hirsutum aerial parts’ methanolic extract using the same two tests with mice. The study has shown that in the writhing test the Epilobium hirsutum extract at a dose of 500 mg/kg b.w. administrated i. p. has exhibited stronger activity than 50 mg/kg b.w. i. p. of diclophenac and 5 mg/kg b.w. i. p. of morphine. In the hot plate test the examined extract in doses within the rage of 200–500 mg/kg b.w. i.p. has shown faster and longer analgesic effect than morphine (5 and 10 mg/kg b.w. i.p.) (Pourmorad et al., 2007). Although both studies have confirmed that preparations from Epilobium species display analgesic activity, there is a lack of proper standardization of used extracts in published papers. Apart from total polyphenol content determination performed for Epilobium hirsutum by Pourmorad et al. (2007) there is no detailed data on either qualitative or quantitative composition of the extracts used. Both authors suggest that further studies elucidating which phytochemicals are responsible for the observed effect are needed. However, to the best of our knowledge up to now no such experiment has been performed. 5.3. Antioxidative activity In screening studies, the antioxidant capacity of plant extracts rich in phenolic compounds, such as Epilobium sp., was determined. Epilobium extracts generally show high antioxidant activity, when tested using different assays such as: ferric reducing ability/antioxidant power (FRAP) assay, cupric reducing antioxidant capacity (CUPRAC), 2,2-diphenyl-1-pikrylhydrazyl (DPPH), 2,20 -azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS), reduction of production of 3-nitrotyrosine and methyl linoleate oxidation (Kähkönen et al., 1999; Katalinic et al., 2006; Wojdyło et al., 2007; Hevesi Toth, 2009; Hevesi Toth et al., 2009a; Stef et al., 2009, 2010). Hevesi Toth et al. (2009a) compared the antioxidant activity of water infusions and acetonic (80%, v/v) extracts of different species of Epilobium, such as Epilobium parviflorum, Epilobium roseum, Epilobium tetragonum, Epilobium montanum, and Epilobium angustifolium. All extracts possessed significantly higher radical scavenging activity (1.71–3.00 μg/mL) in DPPH and ABTS assays comparing to Trolox (EC50 ¼7.96 μM) or ascorbic acid (EC50 ¼14.29 μM). Among samples, Epilobium parviflorum extracts showed the highest antioxidant activity in these cell-free systems (Hevesi Toth, 2009; Hevesi Toth et al., 2009a). Their activity was higher than Trolox or ascorbic acid (Hevesi Toth et al., 2009b). Furthermore, the water and ethanolic extracts of Epilobium parviflorum leaves showed HOd radical scavenging activity above 90% (Steenkamp et al., 2006). It also inhibited lipid peroxidation in TBA assay (IC50 infusion 8.11 mg/mL, IC50 acetone extract 2.37 mg/mL) and protected against oxidative damage of fibroblast cells 143RB (IC50 water 3.3 μg/mL, IC50 acetone 5.2 μg/mL). The cells protective effect was comparable with catalase (250 IU/mL). However, extracts of Epilobium parviflorum at lower concentrations showed prooxidant activity in TBA assay (Hevesi Toth, 2009; Hevesi Toth et al., 2009a, 2009b). Kiss et al. (2011) focused their attention on the antioxidant potential of Epilobium sp. in non-cellular and cellular models. In this study, aqueous extracts of herbs of Epilobium angustifolium, Epilobium parviflorum and Epilobium hirsutum scavenged O2  (IC50 3.5 μg/mL for Epilobium hirsutum, 5 μg/mL for Epilobium angustifolium) and H2O2 (IC50 2.2 μg/mL for Epilobium parviflorum, 3.6 μg/mL for Epilobium angustifolium) and in a less

manner, HClO (IC50 25 μg/mL for Epilobium angustifolium, 33 μg/ mL for Epilobium parviflorum) in cell-free systems and inhibited significantly ROS generation in f-MLP and PMA activated neutrophils with IC50 5 μg/mL and 25 μg/mL, respectively. Additionally, extracts inhibited myeloperoxidase release with IC50 34 μg/mL for Epilobium angustifolium and 26 μg/mL for Epilobium hirsutum, whereas Epilobium parviflorum was less active (IC50 450 μg/ml) (Kiss et al., 2011). On the other hand, Schepetkin et al. (2009) established the dose-dependent inducing activity of Epilobium angustifolium methanolic extract (0.625–20 μg/mL) on ROS production in murine bone marrow leukocytes. Shikov et al. (2006) screened the antioxidant power of five commercial water-soluble extracts of Epilobium angustifolium using in vitro assays, such as iron (III) to iron (II) reducing activity, iron (II) chelation, DPPH scavenging, ascorbate-iron (III)-catalyzed phospholipid peroxidation, non-site-specific and site-specific hydroxyl radical-mediated 2-deoxy-D-ribose degradation. The extracts prepared from non-fermented, as well as fermented plant materials were effective antioxidants in vitro (Shikov et al., 2006). One in vivo experiment performed in rats given for 9 days intraperitonealy 37.5 mg/kg b.w./day of water extract of Epilobium hirsutum showed a statistically significant increase of the protein level and activity of phase II and antioxidant enzymes such as NADPH quinine oxireductase 1 (NQO1) and glutathione peroxidase (GPx) (Karakurt et al., 2013). This is the only report on the potential antioxidant effect in vivo, however, the lack of extract standardization hinders broader discussion of the results. The studies on antioxidant capacity of Epilobium species extracts were supported by total phenol content determination. In few cases, the antioxidant activity was compared with the activity of constituents and/or extract and were characterized phytochemically (Shikov et al., 2006; Hevesi Toth, 2009; Hevesi Toth et al., 2009a; Kiss et al., 2011). There are many studies determining free radical scavenging activity in cell-free systems. However, only a few consider the effect of extracts on ROS production in cellular models. Additionally, some pro-oxidant effects in these models were reported. The summary of literature data on antioxidative activity of extracts from Epilobium species is given in Table 2. 5.4. Antimicrobial, antifungal and antiviral activities The extracts of different polarities from several Epilobium species have been investigated as potential antimicrobial, antifungal and antiviral agents (Villa et al., 1989; Ivancheva et al., 1992; Rauha et al., 2000; Battinelli et al., 2001; Steenkamp et al., 2006; Kosalec et al., 2008; Kunduhoglu et al., 2011; Bartfay et al., 2012; Huttunen et al., 2013; Kosalec et al., 2013; ). Battinelli et al. (2001) investigated the antimicrobial and antifungal activity of ethanolic extracts from five Epilobium species including Epilobium angustifolium and Epilobium hirsutum. It was shown that all the extracts expressed antimicrobial activity with minimum inhibitory concentration (MIC) varying from 81 to 650 mg/mL. Examined extracts were active against Gram-positive bacteria including Staphylococcus aureus, Staphylococcus pyrogenes, Bacillus subtilis, Listeria monocytogenes and Streptococcus sanguis as well as against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumonia and Pseudomonas aeruginosa. Epilobium spp. extracts also inhibited the growth of some fungi belonging to Candida, Microsporum and Trichophyton genera. Compared to the standard antibiotics and chemotherapeutics (tetracycline or miconazole) used in the study which displayed MIC from 0.5 to 50 mg/mL, the activity of examined extracts seemed to be rather weak (Battinelli et al., 2001). Bartfay et al. (2012) proved that investigated crude ethanolic Epilobium angustifolium extract inhibited the growth of a variety of common bacteria including Gram-positive

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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Table 2 Summary of antioxidant studies on Epilobium sp. Species

Part of plant

Solvent

Test model

Effect

Reference

Epilobium angustifolium

Herb

80% Aqueous methanol 80% Aqueous methanol

Oxidation methyl linoleate

TPC: 32.2 mg gallic acid/g ↓90%

Kähkönen et al. (1999)

Herb

Extracts Diod, Express-service, Lotos, nonfermented, Tver

Water

Fresh leaves, stalks, roots

K2HPO4

Seed

50% Methanol 80% Methanol Water

Aerial parts Herb

E. hirsutum

E. montanum

Herb

Murine bone marrow leukocytes Neutrophils ROS scavenging/cell-free systems

FRAP

Leaves



DPPH ABTS Fe (II) chelation

Aerial parts

Methanol

DPPH

Herb

Water

Neutrophils ROS scavenging/cell-free systems

Commercial herb

50% Ethanol 50% Ethanol

FRAP DPPH

Commercial herb

E. parviflorum

80% Aqueous methanol

↓0.63 mg MDA/kg meat (0 days) ↓2.67 mg MDA/kg meat (3 days) 500 mg/kg – 2.5-fold ↓TBARS than 100 mg/kg TPC: 156.76–209.41 mg gallic acid/g dw Reduction Fe(III) to Fe ↓ Fe (III): nonfermented the most (II) effective (  1.7 mmol of ascorbic acid/g) Fe (II) chelation Lotos the most effective Fe (II) chelator (IC50  5 mg/ml) DPPH ↓DPPH: Tver the most effective (IC50  140 μg/ml) ↓Phospholipid-derived TBARS: Ascorbate-Fe (III)nonfermented and Tver the most catalyzed effective (IC50  0.3 mg/ml) phospholipid peroxidation Hydroxyl radical↓2-Deoxy-D-ribose-derived TBARS (nonmediated 2-deoxy-D- site-specific): nonfermented the most effective (IC50  9.0 mg/ml) ribose degradation (Non-site/site↓2-deoxy-D-ribose-derived TBARS (sitespecific) specific): nonfermented and Tver the most effective (IC50  1.5 mg/ml) SOD, CAT, GPX Leaves activity TBARS Total flavonoids: 62.45 mg/mg protein O2  (adrenaline SOD: 17.21 U/mg protein autooxidation) CAT: 11.20 U/mg protein GPX: 11.07 U/mg protein OH (deoxyribose GSH: 0.291 μmol/mg protein degradation) MDA: 4.10 nmol/mg protein O2  : 17.27 nmol/mg protein FRAP OH: 0.63 nmol/mg protein ↓DPPH: 95.57% DPPH FRAP: 4651 μmol Fe2 þ /l DPPH 44.606 μmol Trolox equivalent/100 g Cooked pork patties TBARS

Aerial parts Dried plant

Boiling water Ethanol

Standardized extract



FRAP CUPRAC DPPH

↑ROS production ↓ ROS generation f-MLP induction: IC50 5 μg/ml PMA-induction: IC50 30 μg/ml O2  : IC50 5 μg/ml H2O2: IC50 3.6 μg/ml HClO: IC50 25 μg/ml TPC: 4.03 mg gallic acid/100 g ABTS: 69.6 μM Trolox/100 g DPPH: 2021 μM Trolox/100 g FRAP: 275 μM Trolox/100 g TPC: 92.12 mg gallic acid/g IC50 ¼ 0.49 mg/ml EC50: 0.096 mmol gallic acid equivalent/ mmol DPPH ↓ ROS generation f-MLP induction: IC50 5 μg/ml PMA-induction: IC50 25 μg/ml O2  : IC50 3.5 μg/ml H2O2: IC50 2.3 μg/ml HClO: IC50 26 μg/ml FRAP: 4.28 FeII mmol/l ↓DPPH: 21.87% TPC: 1168 μmol Trolox/g FRAP: 183 μmol Trolox/g CUPRAC: 509 μmol Trolox/g DPPH: 80.2% (after 1 h), 80.9% (after 12 h)

Rabbits skin DHBA

TPC: 37 μg caffeic acid/ml ↓IC50 1.10 μg/ml caffeic acid No effect

DPPH tyrosine nitration

TPC: 115.8 mg gallic acid/100 ml ↓DPPH: 594 μmol catechin/100 ml

ABTS

Rey et al. (2005)

Q3

Shikov et al. (2006)

Stajner et al. (2007)

Q4

Borchardt et al. (2009) Schepetkin et al. (2009) Kiss et al. (2011)

Q5

Wojdyło et al. (2007)

Ebrahimzadeh et al. (2008) Dicu et al. (2010) Kiss et al. (2011)

Stef et al. (2009) Stef et al. (2010)

Arredondo et al. (2004) Morquio et al. (2005) Muselik et al. (2005)

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Q6 Q7

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Table 2 (continued ) Species

Part of plant

Leaves Herb

Herb

Epilobium parviflorum, Epilobium roseum, Herb Epilobium tetragonum, Epilobium montanum, Epilobium angustifolium Epilobium sp. Herb

Solvent

Water or ethanol 80% Aqueous acetone or water

Water

Test model

Effect

HO scavenging

↓Tyrosine nitration: 608 μmol catechin/ 100 ml ↓90%

TBARS fibroblasts 143RB

Neutrophils ROS scavenging/cell-free systems

ABTS DPPH 80% Aqueous acetone Water 98 ºC FRAP

TBARS: IC50 water 8.11 mg/ml IC50 acetone 2.37 mg/ml fibroblasts: IC50 water 3.3 μg/ml IC50 acetone 5.2 μg/ml ↓ROS generation f-MLP induction: IC50 5 μg/ml PMA-induction: IC50 24 μg/mlO2  : IC50 4 μg/ml H2O2: IC50 2.2 μg/ml HClO: IC50 33 μg/ml TPC: 22.3–34.8 g/100 g EC50 1.71–3.00 μg/ml TPC: 841 mg catechin/l 7899 μmo FeII/l

Reference

Steenkamp et al. (2006) Hevesi Toth et al. (2009a); Hevesi Toth et al. (2009b)

Kiss et al. (2011)

Hevesi Toth (2009), Hevesi Toth et al. (2009a) Katalinic et al. (2006)

0

TAC – total antioxidant capacity; ABTS – (2,2 -azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid)); DPPH (2,2-diphenyl-1-pikrylhydrazyl); DHBA – 2,3 dihydroxybenzoic acid; FRAP – ferric reducing/antioxidant power; TPC – total phenolic concentration; MDA – malonyldialdehyde; TBARS – thiobarbituric acid reactive substances.

Micrococcus luteus, Staphylococcus aureus and Gram-negative Escherichia coli and Pseudomonas aeruginosa. The activity was even stronger than the positive controls used in the assays (vancomycin and tetracyclin). These results are in agreement with a previous study by Rauha et al. (2000) which reported that Epilobium angustifolium extract has antibacterial activity towards Staphylococcus aureus and Escherichia coli. Kosalec et al. (2013) have recently studied ethanolic and aqueous extracts from leaves and flowers of Epilobium angustifolium. The study has shown that only ethanolic extracts display antimicrobial activity on several bacteria strains including methycylin resistant Staphylococcus aureus (MRSA) and two yeast species – Candida albicans and Saccharomyces cerevisiae. No differences have been observed between the activity of flowers’ and leaves’ extracts (Kosalec et al., 2013). In the literature it has been shown that not only extracts from raw Epilobium angustifolium aerial parts have antimicrobial activity, but monofloral honey produced from rose bay willow herb is also able to inhibit the growth of Streptococcus pyogenes, Staphylococcus aureus, MRSA and Streptococcus pneumoniae in in vitro studies (Huttunen et al., 2013). A study by Steenkamp et al. (2006) has shown that aqueous and ethanol extracts of Epilobium parviflorum, as well as Epilobium angustifolium are able to inhibit the growth of Escherichia coli. Unfortunately, the activity of those extracts was weak comparing to the positive control – ciprofloxacin. Additionally, the authors suggest that this antimicrobial activity cannot be of clinical interest basing on the extrapolation of experimental data, because after consumption an average amount of home prepared willow herb tee the concentration of absorbed polyphenols in the blood stream is not going to reach the level required for antimicrobial activity. Extracts of different parts: flowers, stems and leaves of Epilobium hirsutum have been investigated by Kunduhoglu et al. (2011) for the activity against several bacteria strains. It has been established that acetone and ethanolic extracts from all parts of the plant are able to inhibit the growth of Grampositive Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis and Sercina lutea. On the other hand, only extracts prepared from flowers of Epilobium hirsutum have been active towards Gram-negative Enterobacter aerogenes, Escherichia coli, Salmonella typhimurium and Shigella ssp. (Kunduhoglu et al., 2011). There are two reports that have been published confirming the antiviral activity of Epilobium angustifolium and

Epilobium hirsutum extracts towards influenza viruses, especially H1N1 and H3N2 using both in vitro models and in vivo mouse model (Villa et al., 1989; Ivancheva et al., 1992). Antimicrobial studies conducted so far confirm that extracts from Epilobium species should be considered as antibacterial and antifungal agents. The results support the traditional usage of Epilobium plant materials as antiseptic remedies useful in the treatment of skin and mucosa infections. On the other hand, no comprehensive data indicating particular extract constituent/constituents responsible for the observed antimicrobial effect are available in the literature. Further studies elucidating the mechanism of antimicrobial action of Epilobium species are strongly needed. 5.5. Effects on gastrointestinal tract In the study by Vitali et al. (2006), ethanolic extracts of Epilobium hirsutum, Epilobium palustre, Epilobium rosmarinifolium, Epilobium angustifolium (Epilobium spicatum) and Epilobium teragonum have been investigated as anti-diarrhoeal remedies in several animal models. Authors have observed that those extracts administrated at a dosage from 5 to 200 mg/kg b.w. possess marked anti-diarrhoeal activity by the inhibition of muscular contractility and mobility. It is suggested that polyphenols, which are the main constituents of used extracts, may be responsible for the observed activity. Authors also have taken into consideration that the observed activity may be caused by unspecific protein denaturation by tannins contained in the examined extracts. The obtained results support the traditional usage of Epilobium species as nonspecific remedy for gastrointestinal disorders but further experiments should be carried out to elucidate the mechanism of their action and principles responsible for their activity. 5.6. Documented bioactivities of oenothein B Oenothein B significantly dominates in polar extracts from Epilbium species. It is considered as the major factor responsible for observed extracts’ biological activities. Studies performed using standardized extracts from Epilobium sp. have clearly shown that the range of effects strongly correlates with the oenothein’s B content (Vitalone et al., 2003; Schepetkin et al., 2009; Kiss et al.,

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Table 3 Summary of investigated bioactivities of oenothein B. Activity

Test model

Effect

Dose/duration

In vivo studies Antitumor

Sarcoma-180 in mice

ILS↑ (235.6%) after 60 days

MM2 and Meth-A in mice Sarcoma-180 in mice

Peritoneal exudate cells (PEC) number ↑ NK cells activity ↑ ILS↑ (196.0%) after 60 days

Single i.p. injection of 5 mg/kg b.w. 4 days before tumor cells inoculation. i.p. injection

Meth-A in mice

Tumor growth inhibition at 10 and 3 mg/kg (64.9%, 60.7% respectively) (dd). Peritoneal exudate cells (PEC) number ↑ Number of regressors ↑ Peritoneal exudate cells (PEC) number ↑ Macrophages’ cytostatic activity and IL-1 like factor secretion ↑ ILS¼ 32.1%

MM2 in female C3H/ He mice S-180 in ICR mice Anti-HIV

Mouse sera after oenothein B administration Immunomodulatory BALB/c mice Anti-inflammatory

In vitro studies Proliferation/ apoptosis

HIV growth↓

Miyamoto et al. (1987) Miyamoto et al. (1992) Single i.p. injection of 10 mg/kg b.w. Miyamoto 4 days before tumor cells inoculation. et al. (1993a) i.p. injection of 10, 3, 1 mg/kg b.w. at 8th Miyamoto to 14th day after cells inoculation (total et al. (1993b) 21 days) i.p. injection 10, 3, 1 mg/kg b.w. 4 days Miyamoto before or 1, 4, 7 days after tumor cells et al. (1993b) inoculation. Single i.p. injection (10 mg/kg b.w.) Wang et al. 3 days before tumor cells inoculation (1999) 1 and 10 μg/mL Okuda et al. (1989)

Neutrophil recruitment to peritoneum↑ (dd) KC (CXCL1) level in peritoneum↑(dd) LPS-induced abnormal behavior in open field↓ LPS-induced microglial activation in the hippocampus and striatum↓ LPS-induced cyclooxygenase (COX)-2 production in the hippocampus and striatum↓

Single i.p. injection of 100 and 400 μg/ 4h 300 mg/kg b.w./day (p.o.) 100 and 300 mg/kg b.w./day (p.o.)

MM2 cell line

Cell viability↓ (culture with serum) Cell viability↓ (culture without serum)

IC50 ¼ 36 μg/mL (23.0 μM)/48 h IC50 ¼ 1.6 μg/mL (1.1 μM)/48 h

34I cell line

Poly(ADP-ribose) glycohydrolase (PARG) activity↓ Dexamethasone induced Mouse mammary tumor virus (MMTV) expression↓ (90% suppression) Dexamethasone-induced endogenous de-poly(ADP-ribosyl)ation of histone H1 and high mobility group (HMG) 14 and 17 proteins↓ Activity↓ (33% inhibition) Activity↓ Cell viability↓ selective index (SI) ¼5.9–1.2

IC50 ¼ 3.8 μM/30 min 50 μM/1 h

LPS treated ICR mice

Ref.

Schepetkin et al. (2009) Okuyama et al. (2013)

100 and 300 mg/kg b.w./day (p.o.)

Miyamoto et al. (1993b) Aoki et al. (1995)

30 μM/1 h

Aromatase 5-α-reductase KB cell line DU-145 cell line HeLa cell line Hep 3B cell line S-180 cell line WISH cell line (normal cells) HL-60 cell line Cell viability ↓ 5-α-reductase Activity↓

50 μM IC50 ¼ 0.44 μM IC50 ¼ 26.8 μg/mL (17.1 μM) IC50 ¼ 54.5 μg/mL (34.7 μM) IC50 ¼ 29.0 μg/mL (18.5 μM) IC50 ¼ 19.0 μg/mL (12.1 μM) IC50 ¼ 11.4 μg/mL (7.3 μM) IC50 ¼ 67.2 μg/mL (42.8 μM)

HeLa S3 cell line

PARG activity↓ (specific, competitive)

IC50 ¼ 3.8 μM

EBV (Epstein Barr virus) DNA polymerase HSC-2 cell line HSG cell line HGF (normal cells) HSC-2 cell line HSG cell line HGF (normal cells) PZ-HPV-7 cell line (normal cells) LNCaP cell line HMEC cel line (normal cells) 1321N1 cell line JB6 Cl41 cell line (mouse epidermal)

Activity↓

IC50 ¼ 62.3 μM/30 min

Cell viability ↓

CC50 ¼ 94 μg/mL (60 μM)/24 h CC50 ¼ 194 μg/mL (120 μM)/24 h CC50 ¼ 393 μg/mL (250 μM)/24 h 130 μM/24 h

Sakagami et al. (2000)

IC50 ¼ 22 μg/mL (14.0 μM)/24 h

Vitalone et al. (2003)

HeLa S3 cell line

Apoptosis induction characterized by DNA fragmentation and caspase activation DNA synthesis↓

30 μg/mL (19.1 μM) IC50 ¼ 22 μM

Ducrey et al. (1997) Wang et al. (1999)

Lesuisse et al. (1996) Maruta et al. (1997) Lee et al. (2000)

IC50 ¼ 28 μg/mL (17.8 μM)/24 h IC50 ¼ 9 μg/mL (5.7 μM)/24 h

EGF-induced: Cell transformation↓ Tyrosine phosphorylation of EGFR ↓ AP-1 activation↓ phosphorylation of ERKs and p38 kinases↓ PI3K activation↓ Akt activation↓ PARG activity↓

IC50 ¼ 64 μg/mL (40.8 μM)/24 h 5 μM

30 μM

Nomura et al. (2005)

Maruta et al. (2007)

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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Table 3 (continued ) Activity

Anti-prostate hyperplasia

Test model

Effect

Dose/duration

Ref.

LNCaP cell line

Cell proliferation↓

LNCaP cell line

PSA secretion↓ Arginase activity↓

IC50 ¼ 7.8 μM/72 h IC50 ¼ 21.9 μM/72 h IC50 ¼ 21.9 μM/72 h 20–40 μM/72 h 10–40 μM/72 h

ACE (angiotensinconverting enzyme) NEP (neutral endopeptidase) APN (aminopeptidase N) PC cel line (prostate)

Activity↓

IC50 ¼ 250 μM

Stolarczyk et al. (2013b) Stolarczyk et al. (2013b) Kiss et al. (2004)

PZ-HPV-7 cell line (normal cells) Immunomodulatory Murine macrophages Human peripheral blood macrophages Human neutrophils murine bone marrow leukocytes xanthine/xanthine oxidase assay Murine neutrophils Murine bone marrow leukocytes Human neutrophils Murine neutrophils PMA-differenciated HL-60 cells Human neutrophils THP-1-Blue monocytes Human PBMCs

THP-1-Blue monocytes Bovine γδ T cells Bovine NK cells Human CD3þ T cells, Human γδ T cells Human CD8þ T cells Human NK cells Human γδ T cells Human αβ T cells Human NK cells Bovine PBMCs

Anti-inflammatory

Bovine CD335þ NK cells Human PBMCs Human CD 56þ NK cells Human CD 56þ NK cells Human CD 56þ NK cells Raw 264.7 cell line Human neutrophils Human neutrophils Human neutrophils Xanthine/xanthine oxidase assay H2O2chemiluminescence assay Taurin chlorination assay Hyaluronidase

IC50 ¼ 20 μM IC50 ¼ 165 μM NEP production↑ ACE production (no influence) Cel proliferation↓

10–40 μM

IL-1 like activity↑(dd) IL-1β↑(dd)

10, 3, 1 μg/mL (6.4, 1.9, 0.6 μM)/4 h 10, 3, 1 μg/mL (6.4, 1.9, 0.6 μM)/4 h

PMA induced ROS generation↓ PMA induced ROS generation↓

IC50 ¼ 50 nM IC50 ¼ 90 nM

O2  scavenging

1–50 μM

NADPH oxidase-generated O2  ↑ (dd) ROS↑

10–50 μM 60 min/cell wash 25 μM, 120 min/cell wash

intracellular Ca2 þ flux↑

EC50 ¼25.525 μM EC50 ¼18.3 μM 50 μM

intracellular Ca2 þ flux↑ Chemotaxis↑ NF-κB translocation↑ NF-κB translocation↑ (synergism with LPS) IFN-γ↑ (11 fold) IL-1β↑ (13 fold) GM-CSF↑ (15 fold) TNF-α↑ (31 fold) (dd) IL-6↑ (34 fold) (dd) TNF-α↑ (24 fold) (dd) IL-6↑ (94 fold) (dd) IL-8↑ (98 fold) IL-2Rα expression↑ CD69 expression↑

CD25 expression↑ CD25 expression↑ CD25 expression-no effect IFNγ production- no effect IFNγ production↑ (priming effect) IFNγ production↑ (priming effect)

30–50 μg/mL (19.1–31.9 μM)

Kiss et al. (2006b) Celeste (2008) Miyamoto et al. (1993b) Schepetkin et al. (2009)

EC50 ¼11.8 μM 25–50 μM/18–24 h 25 μM þLPS 100 ng/mL 10 μM

25 μM

20–40 μg/mL (12.7–25.5 μM)/24 h

Ramstead et al. (2012)

40–50 μg/mL (25.5–31.9 μM)/48 h 50 μg/mL (31.9 μM)/48 h 50 μg/mL (31.9 μM)/48 h 40–50 μg/mL (25.5–31.9 μM)/48 h 20 μg/mL (12.7 μM)/42 h

IFNγ production↑ (mainly γδ T cells and CD8þ T cells) IFNγ production↑

40 μg/mL (25.5 μM) þ IL-18/24 h 20–40 μg/mL (12.7–25.5 μM) þ IL-18/24 h 20 μg/mL (12.7 μM)/48 h 20 μg/mL (12.7 μM)/24 h

IFNγ production↑ (priming effect)

20 μg/mL (12.7 μM)þ IL-18/24h

IFNγ production↑ (priming effect)

20 μg/mL (12.7 μM)þ K562 cells/24 h

NO↓ LPS induced NF-κB translocation↓ f-MLP induced LTB4 release↓ f-MLP þ cytochalasin A induced MPO release↓ f-MLP induced ROS generation↓ PMA induced ROS generation↓ O2  scavenging

20 μg/mL (12.7 μM) 25 μg/mL (15.9 μM) IC50 ¼ 7.7 μM IC50 ¼ 0.3 μM IC50 ¼ 5 μM SC50 ¼0.9 μM

H2O2 scavenging

SC50 ¼0.7 μM

HClO scavenging

SC50 ¼0.7 μM

Activity↓

IC50 ¼ 1.1 μM

Chen et al. (2000) Kiss et al. (2011)

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Table 3 (continued ) Activity

Test model

Effect

Dose/duration

lipoxygenase Cyclooxygenase-1 Cyclooxygenase-2 THP-1 cell line

Activity↓ Activity↓ No effect TNF-α induced HAT activity↓ (32.5%) TNF-α reduced HDAC activity↑ LPS induced NO production↓ LPS induced iNOS activity – no effect NO scavenging – no effect TLR4 stimulation induced NO production↓ (dd) TLR2 stimulation induced NO production↓ (dd) IFNγ induced NO production – no effect LPS induced iNOS protein expression↓ (dd) LPS induced iNOS mRNA transcription↓ (dd) LPS induced IL-1β mRNA transcription↓ LPS induced IL-6 mRNA transcription↓ LPS induced TNF-α mRNA ranscription↓ LPS induced NF-κB p50 binding activity↓ LPS or TNF-α induced NF-κB p65 translocation↓ (dd) LPS and TNF-α induced IL-1β production↓ LPS and TNF-α induced IL-12 production↓ LPS and TNF-α induced IL-17 production↓ LPS and TNF-α induced IL-2 production↓ LPS and TNF-α induced IL-4 production↓ Growth↓

IC50 ¼ 15 μM 25 μg/mL (15.9 μM)

RAW 264.7 cell line

iDC cell line

Antibacterial

Helicobacter pylori

2011; Stolarczyk et al., 2013a). In vitro and in vivo studies of oenothein B conducted so far revealed its antitumour, antiprostate hyperplasia, immunomodulatory, anti-inflammatory and antiviral activities (Table 3). The studies on animal in vivo models have shown its effectiveness as the antitumour agent. Its activity after intraperitoneal injection, expressed as an increase in lifespan, towards animals inoculated with different tumor cell lines was shown to be closely associated with enhanced inflammatory response (Miyamoto et al., 1987; Miyamoto et al., 1992; Miyamoto et al., 1993a, 1993b; Wang et al., 1999; Schepetkin et al., 2009). Many studies regarding oenothein B in vitro cytostatic and cytotoxic activity towards different cell lines revealed its high effectiveness towards tumor cell lines (in most studies determined IC50 value below 50 μM) followed by high selectivity observed in studies where parallel examinations on physiological cells were conducted (Wang et al., 1999; Sakagami et al., 2000). The postulated mechanisms of antitumour activity of oenothein B include specific inhibition of poly-(ADP-ribose) glycohydrolase (Aoki et al., 1995; Maruta et al., 2007), 5-α-reductase, and aromatase (Ducrey et al., 1997) as well as induction of neutral endopeptidase in prostate cancer cells (Kiss et al., 2006b). The ability of oenothein B to specifically enhance innate immune system response was shown to be an important component of observed in vivo antitumour effects (Miyamoto et al., 1992; Miyamoto et al., 1993a, 1993b; Schepetkin et al., 2009; Ramstead et al., 2012). Oenothein B was also established to influence the mechanisms of BPH progression. It inhibited PZ-HPV-7 cells proliferation (Vitalone et al., 2003; Celeste, 2008) and to modulate activity of angiotensin-converting enzyme (ACE) and NEP enzymes partially associated with BPH development (Kiss et al., 2004, 2006b). Oenothein B was shown to be a strong anti-inflammatory agent. In vitro and ex vivo studies clearly revealed that it is potent to inhibit enhanced inflammatory response triggered by microbial derived molecules such as f-MLP and LPS as well as directly inhibit inflammation-associated enzymes (Chen et al., 2000; Kiss et al., 2011; Schmid et al., 2012; Yoshimura et al., 2013). Consistent observations were made in vivo on LPS treated mice for orally administered oenothein B, which was shown to inhibit

5 μM IC50 ¼ 17.7 μM/24 h 24 h 24 h

Ref.

Kiss et al. (2012) Schmid et al. (2012)

30–60 μg/mL (19.1–38.2 μM)/24 h

10–60 μg/mL (6.4–38.2 μM)/24 h 20–60 μg/mL 20–60 μg/mL 40–60 μg/mL 30–60 μg/mL 20–60 μg/mL 25 μM

(12.7–38.2 μM) (12.7–38.2 μM) (25.5–38.2 μM) (19.1–38.2 μM) (12.7–38.2 μM) Yoshimura et al. (2013)

100 μM MIC¼ 25–12.5 μg/mL (15.9–8.0 μM)

Funatogawa et al. (2004)

LPS-triggered inflammatory response at the CNS level (Okuyama et al., 2013). The issue, which needs to be raised, is the not fully established bioavailability of oenothein B. No studies have been conducted so far which would have undoubtedly proven its bioavailability. However the experiments performed on in vivo models have demonstrated potential effectiveness of orally administered pure oenothein B (Okuda et al., 1989; Okuyama et al., 2013).

6. Toxicity and safety The extracts from plant materials belonging to the Epilobium genus are considered as nontoxic. This view has been confirmed by the experimental data using different animal models. Roman et al. (2010) have performed an extensive study on cytotoxicity of hydroalcoholic extracts prepared from Epilobium angustifolium, Epilobium hirsutum and Epilobium parviflorum examining their influence on vital organs of Wistar rats after oral administration of 1.5 mL of herbal extract for 10 days. All three extracts showed no cytotoxicity in rats at brain, hypothalamic-hypophyso-adrenal axis, liver, kidneys, spleen and thymus levels. It has also been shown that extracts from Epilobium angustifolium and Epilobium hirsutum had only moderate influence on the increase of oxyreduction enzymes levels in rats’ liver and kidneys (Roman et al., 2010). The extract from Epilobium rosmarinifolium was examined in acute toxicity test in mice by Vitali et al. (2006) showing that LD50 at 4 g/kg i.p. after a 40 h period. In other acute toxicity experiments for Epilobium angustifolium extract the LD50 for mice was established as 1.4 mg/kg b.w. s.c. after 24 h (Tita et al., 2001). Pourmorad et al. (2007) investigated the influence of Epilobium hirsutum extract on viability of mice over a period of one week and have shown that the LD50 value for i.p. administration is 1.5 mg/ kg b.w. Kujawski et al. (2009, 2010b) have investigated the influence of Epilobium angustifolium standardized extract (0.91% of flavonoids, 24.36% of total phenolic compounds, 0.09% of sterols and 0.01% of tannins) on the expression of cytochrome P450–2D2, 7A1 and 3A1. It has been shown that Epilobium angustifolium extract

Please cite this article as: Granica, S., et al., Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): A review. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.08.036i

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administered orally (40 or 100 mg/kg b.w./day) together with or without testosterone causes a slight increase (by 4.6% compared to control) in the expression of CYP2D2 in rats. In the case of CYP3A1 the Authors have observed the statistically significant decrease in expression of this isoenzyme by 20.2% (compared to rats treated with testosterone alone) and by 63.7% (compared to untreated control rats) after the administration of Epilobium angustifolium extract. The authors give no concept of the mechanism responsible for the observed effects. In another study (Karakurt et al., 2013) rats treated intraperitonealy with 37.5 mg/kg b.w./day of water extract of Epilobium hirsutum for 9 days have showed a decrease of CYP2E1 and CYP1A1 expression (  50%). The authors point out that the influence of Epilobium angustifolium and Epilobium hirsutum extracts on investigated cytochromes can cause the potential risk of interactions between phytotherapeutics of similar composition and conventional drugs that are metabolized by these enzymes. In the phase II randomised double-blind placebo controlled clinical trial of herbal preparation containing, beside other components, Epilobium parviflorum extract (equivalent of 500 mg of herb) after 3 months of treatment, it was well tolerated and there were no adverse reactions reported (Coulson et al., 2013).

7. Conclusions In this review, the literature on existing traditional use of plant materials belonging to the Epilobium genus as well as research on their phytochemistry, pharmacology, toxicity and safety have been summarized. The provided data indicates that there are extensive studies concerning the chemical composition of aerial parts of different Epilobium species. It was proven that polyphenols are dominating constituents of polar extracts prepared from willow herbs. Oenothein B has always been the major compound found in these extracts and can be used in standardization procedures as a quality marker. Flavonoids are valuable chemotaxonomic markers for Epilobium. Several analytical systems for the identification of species based on their phytochemical profiles were established. There are limited reports on lypophilic constituents of Epilobium and this field of studies needs further investigations. The pharmacological studies performed on Epilobium justify the traditional use of this species in external and in gastrointestinal inflammations. As far as the treatment of BPH is considered, in the literature, there are some reports indicating that Epilobium extracts have a beneficial effect for this disorder, but the number of in vitro studies is not sufficient and the in vivo studies are not conclusive or too preliminary to draw a final conclusion about the efficacy of Epilobium preparations. More in vitro, in vivo and clinical studies to confirm this mode of action are strongly needed. The biological effect of Epilobium is considered to be associated with the presence of oenothein B that have several bioactivities, which were confirmed in in vitro studies. However, there is lack of information on the bioavailability of this compound after oral administration. On the other hand, there are several reports suggesting that ellagitannins such as oenotehin B are metabolized by gut microbiota to low molecular weight dibenzopyran-6-one derivatives known as urolithins, which are adsorbed in the blood stream and may be responsible for bioactivity of consumed plant extracts. This intestinal metabolism should be taken into account as an important contribution to observe bioactivity of Epilobium extracts after oral administration. The critical role of flavonoids, especially of myricetin-3-O-glucuronide, in bioactivity of Epilobium preparation is suggested but has not been resolved. These hypotheses determine the necessity of properly designed in vivo studies using standardized extracts along with multi-targeted pharmacokinetic analysis, which will allow to get closer to establishment the

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Phytochemistry, pharmacology and traditional uses of different Epilobium species (Onagraceae): a review.

The Epilobium genus (willowherb) comprises of ca. 200 species of herbaceous plants distributed around the world. Infusions prepared form willowherbs h...
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