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

Journal of Ethnopharmacology 156 (2014) 235–270

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Review

Traditional uses, phytochemistry and pharmacological properties of the genus Peucedanum: A review Parisa Sarkhail n Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, 16th Azar Street, PO Box 14155-6451, Tehran 14176, Iran

art ic l e i nf o

a b s t r a c t

Article history: Received 23 April 2014 Received in revised form 25 August 2014 Accepted 25 August 2014 Available online 3 September 2014

Ethnopharmacological relevance: The genus Peucedanum (Apiaceae) comprising more than 120 species is widely distributed in Europe, Asia and Africa. The ethnopharmacologial history of this genus indicated that some extracts of aerial and underground parts of several Peucedanum species have been used in folk medicine for treatment of various conditions, such as cough, cramps, pain, rheumatism, asthma and angina. This review focuses on ethnopharmacological uses of Peucedanum species, as well as the phytochemical, pharmacological and toxicological studies on this genus. Through this review, I intend to highlight the known and potential effects of the Peucedanum species or their isolated compounds and show which traditional medicine uses have been supported by pharmacological investigations. Methods: Information on the Peucedanum species was collected from scientific journals, books, thesis and reports via a library and electronic search (using Google Scholar, Pubmed, Scopus, Web of Science and ScienceDirect). This review covers the available literature from 1970 to the end of September 2013. Results: Although, there are about 120 species in this genus, so far many species have received no or little attention and most of pharmacological studies were performed on just about 20 species. Many phytochemical investigations on this genus confirmed that Peucedanum species are rich in essential oils and coumarins. The present review article shows that Peucedanum species have a wide spectrum of pharmacological activities and the most reported activities of Peucedanum plants come back to the presence of coumarins, flavonoids, phenolics and essential oils. Conclusions: The present review confirms that some Peucedanum species have emerged as a good source of the traditional medicine for treatment of inflammation, microbial infections, cardiopulmonary diseases and provides new insights for further investigations on isolated compounds, especially on praeruptorins, to find novel therapeutics and aid drug discovery. However, for using Peucedanum species to prevent and treat various diseases, additional pharmacological studies to find the mechanism of action, safety and efficacy of them before starting clinical trials are required. & 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical compounds studied in this article: Bergapten (CID: 2355) Columbianadin (CID: 6436246) Imperatorin (CID: 10212) Isosamidin (CID: 442133) ( þ )-trans-kellactone (CID 11436940) Osthole (CID: 10228) Osthrutin (CID: 5281420) Ostruthol (CID: 6441273) Peucedanin (CID: 8616) Praeruptorin A (CID: 38347607) (  )-Praeruptorin A (CID: 38347601) ( þ )-Praeruptorin A or Praeruptorin C (CID: 5320691) Praeruptorin B (CID: 5319259) ( þ )-Praeruptorin B or Praeruptorin D (CID: 25717254) Praeruptorin E (CID: 6440581) Pteryxin (CID: 5281425) Visamminol (CID: 5315249) Xanthotoxin (CID: 4114). Keywords: Peucedanum Apiaceae Traditional uses Phytochemicals Pharmacological effects Coumarins

Contents 1. 2. 3. 4.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Taxonomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnobotanical uses of Peucedanum species. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Coumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4.3. Other compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological and toxicological aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Anti-inflammatory and antipyretic activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Antityrosinase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Anti-microbial, amoebicidal and antihelmintic activities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Cardiopulmonary protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. Neuroprotection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.7. Antidiabetic effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.8. Antiplatelet aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.9. Anti-cancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.10. Phototoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.11. Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.

1. Introduction The genus Peucedanum (Apiaceae) is a large group comprising more than 120 species that are widely distributed in Europe, Asia, Africa and North America (Ciesla et al., 2009; Skalicka-Woźniak et al., 2009a, 2009b). The ethnopharmacological history of Peucedanum indicates that some species have been used in local medicine to treat various conditions, including sore throat, coughs, colds, headaches (Hisamoto et al., 2003; Morioka et al., 2004) asthma, angina (Schillaci et al., 2003), cramps, epilepsy, gastrointestinal disorders, rheumatism, gout, and cardiovascular problems, and as a chemopreventive agent (Leporatti and Ivancheva, 2003) and antifebrile (Ikeshiro et al., 1992). Because of their versatile therapeutic traditional uses, a number of phytochemical investigations have been carried out on Peucedanum plants. To date, comparative phytochemical data are available for nearly 50 Peucedanum species. Several bioactive substances, including coumarins, polyphenols, amines, glycosides, flavonoids, phenolic acids, essential oils, diterpenes and other components, have been isolated from different species of Peucedanum (Fraternale et al., 2000; Hisamoto et al., 2003; Shults et al., 2003; Kapetanos et al., 2008). Coumarins and essential oils are considered to be the main constituents in nearly all Peucedanum plants and can be responsible for many of their biological and pharmacological activities of Peucedanum species (Ciesla et al., 2009; Skalicka-Woźniak et al., 2009a, 2009b). According to The State Pharmacopoeia Commission of P.R. China (2010); Chinese Pharmacopoeia (2010 Edition) some species, such as Peucedanum praeruptorum and Peucedanum japonicum, are highly valued plants because of their pharmacological activities against cancer (Shen et al., 2012), microbes (Yang et al., 2009), diabetes (Nukitrangsan et al., 2012), obesity (Okabe et al., 2011), and reactive oxygen species (Hisamoto et al., 2003). The most important pharmacological properties, including calcium antagonist activity (Chang et al., 1994a); neuroprotection (Yang et al., 2013); anti-asthma, vasorelaxant and antiallergic effects (Aida et al., 1998; Zhao et al., 1999); cardiopulmonary protection (Chang et al., 1994b; Zhao et al., 1999; Wang et al., 2004); hepatoprotection (Song et al., 2011); antitumor activity (Mizuno et al., 1994; Liang et al., 2010; Ren et al., 2013); and anti-platelet aggregation activity (Aida et al., 1995), are related to some khellactone coumarins (praeruptorins) that were identified for the first time in the roots of Peucedanum praeruptorum, Peucedanum japonicum and Peucedanum decursivum. Some praeruptorins have shown strong anti-tumoral activity in various cell lines (Chang-yih et al., 1992; Chang et al., 2008; Liang et al., 2010). Recently, the structure–activity relationship of praeruptorin derivatives has been investigated to find more potent anti-tumor drugs (Fong et al., 2008; Shen et al., 2012).

254 256 256 258 260 260 262 263 263 263 264 265 265 265 266

There are several studies about the pharmacokinetic profile of praeruptorins in human and rat liver microsomes (see the review by Sarkhail et al. (2013b)). The main metabolic pathways of praeruptorins in hepatic microsomes are oxidation, hydrolysis and acyl migration of the C-30 and/or C-40 position (Ruan et al., 2011; Jing et al., 2013). Other known and potential coumarins isolated from Peucedanum plants, for example xanthotoxin, psoralen, and bergapten, have been reported to possess anti-platelet aggregation (Chen et al., 2008) and monoamino-oxidase inhibition activity (Huong et al., 1999). In addition, some of these furanocoumarins are phototoxic in irradiation (Ojala et al., 1999). A number of phenolic acid and flavonoid compounds are the main compounds responsible for anti-tyrosinase and radical scavenging activity (Hisamoto et al., 2003; Sarkhail et al., 2013a). Kuzmanov et al. (1981) used coumarin and flavonoid compounds for chemotaxonomic analysis of six species native to Bulgaria. Furthermore, the study of the essential oil composition of various species of this genus seems valuable for chemotaxonomic classification and for differentiating the individual species with unclear anatomic and morphological structures. The volatile oils of different parts of Peucedanum species usually consist of monoterpenes and sesquiterpene hydrocarbons, oxygenated sesquiterpenes, aliphatic alcohols and esters (Fraternale et al., 2000; Skalicka-Woźniak et al., 2008). The effectiveness of some secondary metabolites or extracts of various Peucedanum plants has been evaluated and supported by pharmacological studies (Aida et al., 1998, Hiermann and Schant, 1998; Skalicka-Woźniak et al., 2010). However, more investigations in vitro, in vivo and in clinical trials are required to determine their safe doses and adverse effects (toxicity) for therapeutic uses. The present review focuses on ethnopharmacological uses of Peucedanum species, as well as the phytochemical, pharmacological and toxicological studies of this genus. It includes many published pharmacological data, not only supporting some local medicine uses but also exposing the lost links between traditional knowledge and new information about Peucedanum plants. This review highlights the importance of some coumarins, such as praeruptorins A and B, for preventing or treating cancer, cardiovascular problems and some inflammatory diseases. All these data warrant further research on Peucedanum species to find the mechanisms behind their pharmacological properties and to identify new potential therapeutic applications and drug discovery.

2. Taxonomy Peucedanum L. (fam. Apiaceae subfamily. Apioideae trib. Peucedaneae) is a large, heterogeneous and polyphyletic genus of more than 120 species distributed in Europe, Asia, Africa and North

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

America. Because of the high degree of heteromorphy the taxonomic value of the genus Peucedanum faces problems, and it has been partly revised (Pimenov and Leonov, 1993). Many species (711 plants) are reported as belonging to the Peucedanum genus, but only 69 species correspond to an accepted scientific name, and others are synonyms or unresolved names (The Plant List, 2013). Of the species listed in this article (see Table 1), 37 of them

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including Peucedanum alsaticum, Peucedanum arenarium, Peucedanum austriacum, Peucedanum carvifolia, Peucedanum cervaria, Peucedanum cervariifolium, Peucedanum coriaceum, Peucedanum delavayi, Peucedanum dissolutum, Peucedanum formosanum, Peucedanum harry-smithii var. subglabrum, Peucedanum japonicum, Peucedanum lancifolium, Peucedanum ledebourielloides, Peucedanum longifolium, Peucedanum longshengense, Peucedanum morisonii,

Table 1 Scientific names, status (Accepted (Ac), Synonym (Syn) and Unresolved (Un)) and synonym(s) of reported Peucedanum species in this article (according to The Plant List (2013)). Peucedanum species

Status

Synonym(s)

Peucedanum alsaticum L.

Ac

Peucedanum arenarium Waldst. & Kit. (Peucedanum arenarium var. arenariuma) Peucedanum austriacum (Jacq.) W.D.J.Koch

Ac Ac

Peucedanum cachrydifolia Boiss.b Peucedanum carvifolia Vill.

NRc Ac

Peucedanum caucasicum K. Koch

Un

Peucedanum cervaria (L.) Cusson ex Lapeyr.

Ac

Cervaria alsatica (L.) Gaudin. Cnidium alsaticum (L.) Spreng. Johrenia pichleri Boiss. Ligusticum alsaticum (L.) Link. Peucedanum lubimenkoanum Kotov Pteroselinum alsaticum (L.) Rchb. Selinum alsaticum (L.) Crantz. Xanthoselinum alsaticum (L.) Schur. Peucedanum borysthenicum Klokov. Peucedanum borysthenicum Klokov ex Schischk. Ferula austriaca (Jacq.) Spreng. Ferula elegans Spreng. Ferula montana Spreng. Ferula rablensis Wulfen Pteroselinum austriacum (Jacq.) Rchb. Selinum austriacum Jacq. NR Peucedanum euphimiae Kotov. Peucedanum chabraei var. podolicum Todor. Some data suggest that it is synonymous with Selinum caucasicum M.Bieb. Athamanta cervaria (L.) L. Athamanta decussata Gilib. Athamanta latifolia Viv. Cervaria glauca Gaudin Cervaria laevis Gaudin Cervaria nigra Bernh. Cervaria rigida Moench. Cervaria rivini Gaertn. Ligusticum cervaria (L.) Spreng. Oreoselinum minus Garsault. Oreoselis cervaria (L.) Raf. Peucedanum cervaria (L.) Lap.(Syn) Peucedanum glaucum (Lam.) Dum.Cours. Selinum cervaria L. Selinum glaucum Lam. Peucedanum sintenisii H. Wolff.

Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum

cervariifolium C.A. Mey. Ac chryseum (Boiss. & Heldr.) D.F.Chamb. Un coriaceum Rchb. Ac decursivum (Miq.) Maxim. Syn delavayi Franch. Ac dissolutum (Diels) H. Wolff Ac formosanum Hayata Ac gabrielae R.Frey Un galbanum (L.) Benth. & Hook. f. Syn galbanum (L.) Drude grande C.B.Clarke Un graveolens (L.) C.B. Clarke [Illegitimate] or Peucedanum graveolens (L.) Hiern Syn harry-smithii var. subglabrum (Shan & M.L. Sheh) Shan & M.L. Sheh Ac japonicum Thunb. Ac knappii Bornm. Un

Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum

lancifolium Lange. ledebourielloides K.T. Fu longibracteolatum Parolly & Nordt. longifolium Waldst. & Kit. longshengense Shan & M.L. Sheh luxurians Tamamsch. medium Dunn var. garcile Dunnd ex Shan at Sheh morisonii Besser nebrodense

Peucedanum neumayeri (Vis.) Rchb.f.

Ac Ac Un Ac Ac Un NR Ac Un Syn

Angelica decursiva (Miq.) Franch. & Sav. Sinodielsia delavayi (Franch.) Pimenov & Kljuykov. Peucedanum terebinthaceum subsp. formosanum (Hayata) Kitag. Notobubon galbanum (L.) Magee.

Anethum graveolens L. Peucedanum hirsutiusculum var. subglabrum Shan & M.L. Sheh. Some data suggest that it is synonymous with Zeravschania knappii (Bornm.) Pimenov & Kljuykov. Calestania lancifolia Koso-Pol. Some data suggest that it is synonymous with Dichoropetalum longibracteolatum (Parolly & Nordt) Pimenov & Kljuykov.

NR Peucedanum songoricum Schischk. Some data suggest that it is synonymous with Holandrea nebrodensis (Guss.) Banfi, Galasso & Soldano. Peucedanum arenarium subsp. neumayeri (Vis.) Stoj. & Stef.

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Table 1 (continued ) Peucedanum species

Status

Synonym(s)

Peucedanum obtusifolium Sm.

Ac

Peucedanum officinale L. Peucedanum oligophyllum (Griseb.) Vandas

Ac Ac

Peucedanum oreoselinum (L.) Moench

Ac

Peucedanum ostruthium (L.) W.D.J.Koch

Ac

Peucedanum palimbioides Boiss.

Un

Peucedanum palustre (L.) Moench

Ac

Ferula obtusifolia (Sm.) Spreng. Malabaila obtusifolia (Sm.) Boiss. Pastinaca obtusifolia (Sm.) DC. Selinum officinale (L.) Vest. Dichoropetalum oligophyllum (Griseb.) Pimenov & Kljuykov. Seseli oligophyllum Griseb. Angelica oreoselinum (L.) M.Hiroe Athamanta diffusa Gilib. Athamanta divaricata Gilib. Athamanta divaricifolia Stokes. Athamanta oreoselinum L. Cervaria oreoselinum (L.) Gaudin. Oreoselinum majus Garsault. Peucedanum bourgaei Lange. Selinum oreoselinum (L.) Crantz. Angelica officinalis Bernh. Angelica ostruthium (L.) Lag. Imperatoria ostruthium L. Ostruthium officinale Link Selinum ostruthium (L.) Wallr. Some data suggest that it is synonymous with Dichoropetalum palimbioides (Boiss.) Pimenov & Kljuykov. Athamanta flexuosa Juss. ex DC. Athamanta pisana Savi. Calestania palustris (L.) Koso-Pol. Callisace schiefereckii Hoffm. Selinum palustre L. Thyselium palustre (L.) Raf. Thysselinum palustre (L.) Hoffm.

Peucedanum paniculatum Loisel. Peucedanum pastinacifolium Boiss. & Hohen. (Peucedanum pastinacifolium Boiss. & Husskne) Peucedanum petiolare Boiss. Peucedanum praeruptorum Dunn Peucedanum rubricaule Shan & M.L. Sheh Peucedanum ruthenicum M.Bieb.

Ac Un Un Ac Ac Ac

Peucedanum salinum Pall. ex Spreng.

Un

Peucedanum schottii Besser ex DC.

Ac

Peucedanum scoparium Boiss.

Un

Peucedanum Peucedanum Peucedanum Peucedanum

Syn Ac Syn Ac

sowa (Roxb. ex Fleming) Kurz tauricum M.Bieb. terebinthaceum var. deltoideum (Makino ex K. Yabe) Makino terebinthaceum (Fisch. ex Trevir.) Ledeb.

Peucedanum turgeniifolium H. Wolff Peucedanum verticillare (L.) W.J.D.Koch ex DC.

Ac Ac

Peucedanum vittijugum Boiss.

Ac

Peucedanum Peucedanum Peucedanum Peucedanum Peucedanum

Ac Ac Ac Un Ac

a

vourinense (Leute) Hartvig wawrae (wawrii) (H. Wolff) Su ex M.L. Sheh in R.H. Shan & M.L. Sheh wulongense Shan & M.L. Sheh zedelmeyeranum Manden. zenkeri Engl.

Some data suggest that it is synonymous with Zeravschania pastinacifolia (Boiss. & Hohen.) Salimian & Akhani.

Callisace ruthenica (M.Bieb.) Fisch. ex Hoffm. Ferula besseriana Spreng. ex DC. Ferula ruthenica (M.Bieb.) Spreng. Athamanta tenuifolia Willd. ex Spreng. Conioselinum humile Turcz. ex Ledeb. Dichoropetalum schottii (Besser ex DC.) Pimenov & Kljuykov. Holandrea schottii (Besser ex DC.) Reduron, Charpin & Pimenov. Trachydium schottii (Besser ex DC.) M.Hiroe. Some data suggest that it is synonymous with Johrenia scoparia Boiss. Anethum graveolens L. Peucedanum deltoideum Makino ex K. Yabe Kitagawia terebinthacea (Fisch. ex Trevir.) Pimenov. Peucedanum paishanense Nakai. Peucedanum terebinthaceum var. paishanense (Nakai) Y. Huei Huang. Peucedanum terebinthaceum var. terebinthaceum Selinum terebinthaceum Fisch. ex Trevir. Peucedanum pulchrum H. Wolff. Angelica verticillaris L. Imperatoria verticillaris (L.) DC. Ostericum verticillare (L.) Rchb. Peucedanum altissimum (Mill.) Thell. [Illegitimate] Selinum verticillare (L.) Vest. Thapsia altissima Mill. Tommasinia altissima (Mill.) Reduron. Bunium minutifolium Janka. Dichoropetalum minutifolium (Janka) Pimenov & Kljuykov Dichoropetalum minutifolium (Janka) Pimenov & Kljuykov Peucedanum minutifolium (Janka) Velen. Peucedanum vittijugum subsp. minutifolium (Janka) Kuzmanov & N.Andreev. Peucedanum longifolium subsp. vourinense Leute Seseli wawrae H. Wolff.

Both names have been reported by Zheleva et al. (1972, 1976). Actually, the accepted name is Peucedanum arenarium. Peucedanum cachrydifolia Boiss. was not included in The Plant List (2013). Not reported. d This variety (Peucedanum medium Dunn var. garcile Dunn) was not included in The Plant List (2013). e This name have been reported by Movahedian et al. (2010) and Sajjadi et al. (2012). b c

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Peucedanum obtusifolium, Peucedanum officinale, Peucedanum oligophyllum, Peucedanum oreoselinum, Peucedanum ostruthium, Peucedanum palustre, Peucedanum paniculatum, Peucedanum praeruptorum, Peucedanum rubricaule, Peucedanum ruthenicum, Peucedanum schotti, Peucedanum tauricum, Peucedanum terebinthaceum, Peucedanum turgeniifolium, Peucedanum verticillare, Peucedanum vittijugum, Peucedanum vourinense, Peucedanum wawrii, Peucedanum wulongense and Peucedanum zenkeri have been confirmed as accepted scientific names. The last taxonomic revision of this genus showed that many genera, such as Cervaria, Holandrea, Imperatoria, Oreoselinum, Pteroselinum, Thysselinum, Tommasinia and Xanthoselinum, separated from Peucedanum. For example, Peucedanum ostruthium and Peucedanum oreoselinum are referred to as Imperatoria and Oreoselinum, respectively (Spalik et al., 2004). Traditionally fruit characters, both external features and anatomical features, have been used for classification of the family Apiaceae. However, fruit characters of many Peucedanum species have not been supported by recent molecular phylogenetic investigations. Peucedanum spp. are traditionally identified by flattened orthospermus fruits with more and less developed lateral wings, a broad commissure and the lack of prominent dorsal ribs. Because of the great diversity of life forms, leaf and fruit structures, and chemical components, this genus has dissimilar character patterns that show a poor relationship with morphology and are difficult to use for taxonomy (Drude, 1897–1998). For example the boundaries between Peucedanum and Angelica are not clear, and two genera are distinguished from each by commissure width of fruits (Theobald, 1971; Ostroumova and Pimenov, 1997). However, this character seems not to be useful for some plants, e.g., Angelica decursiva, with a quite large commissure, can be referred to as Peucedanum, whereas recent taxonomic revision by Liu et al. (2006) shows that Peucedanum decursivum belongs to genus Angelica and not Peucedanum. The taxonomy of the polymorphous genus Peucedanum has been revised by several techniques, including comparative phytochemical data, immunochemical investigations and sequencing of the internal transcribed spacer of nuclear rDNA (ITS rDNA) (Spalik et al., 2004). For instance Hadacek and Samuel (1994) compared the composition of secondary metabolite of 13 collected Peucedanum species from central Europe, using a high performance liquid chromatography (HPLC) method with ultraviolet–visible (UV) diode array detection. They found that peucedanin, a linear furanocoumarin, is a major compound in HPLC profiles of Peucedanum coriaceum, Peucedanum gabrielae, Peucedanum vourinense and Peucedanum officinale and can be used as a chemotaxonomic marker. Kuzmanov et al. (1981) used coumarin and flavonoid compounds for chemotaxonomic analysis of six native Bulgarian species (Peucedanum officinale, Peucedanum longifolium, Peucedanum ruthenicum, Peucedanum vittijugum, Peucedanum cervifolia and Peucedanum oligophyllum) of two Peucedanum sections, sec. Peucedanum and sec. Palimbioidea. All species of these two sections are similar in their flavonoid content. Peucedanum officinale, Peucedanum longifolium and Peucedanum ruthenicum, but not Peucedanum vittijugum, belonging to sec. Peucedanum, are rich in coumarins, while Peucedanum cervifolia and Peucedanum oligophyllum from sec. Palimbioidea are poor species of coumarins. These findings show that coumarins are valuable chemotaxonomic markers for classification of the genus Peucedanum and that Peucedanum vittijugum can be separated into a new section because of dissimilar coumarin content. Recently, some taxonomic revisions indicated that many Peucedanum species should be transferred to other genera based on morphological, anatomical and molecular evidence. Recent re-classification of several African species of Peucedanum showed that these plants completely separate from the superficially similar Eurasian species. For instance, Peucedanum galbanum was reassigned to the Notobubon

239

genus because it shares the additional rib vittae of Notobubon galbanum fruits and other characters (Winter et al., 2008). This review article discusses the various arguments for and against splitting Peucedanum into more segregates. Although the names of several plants in this review article have not been accepted by The Plant List (2013) database, I decided to use the names reported by the authors in their original works and show their taxonomic validation (scientific names, status and synonyms) in Table 1.

3. Ethnobotanical uses of Peucedanum species A review of books and papers shows that several Peucedanum species are used in local medicine in some Asian and European countries. Although pharmacological investigations of Peucedanum species used in local medicine are not extensive, some studies have identified potential health effects. For example in the Canon of Medicine, one of the most famous traditional medicine books belonging to a Persian scientist named Ibn-Sina (Avicenna), Peucedanum grande was considered a beneficial diuretic herb for destroying, expelling, and preventing kidney calculi (Ibn e Sina, 1920; Faridi et al., 2012). Recently, Aslam et al. (2012a, 2012b) confirmed the nephroprotective action of Peucedanum grande fruits against cadmium and mercuric chloride nephrotoxicity. In Central European local medicine, essential oil fruits of Peucedanum alsaticum and Peucedanum cervaria are used as an expectorant, diaphoretic, diuretic, stomachic, sedative, and antimicrobial agent (Skalicka-Woźniak et al., 2010). Peucedanum galbanum is traditionally used in Africa to treat various ailments, including vesical catarrh, kidney and bladder ailments, prostate problems, swelling of glands and retention of urine and as an abortifacient (Campbell et al., 1994). In Austrian traditional medicine, rhizomes of Peucedanum ostruthium have a long history of treatment of inflammatory diseases (Joa et al., 2011). Peucedanum ostruthium was a valuable plant in 19th-century medical science, and some synonyms have been reported for it such as Imperatoria ostruthium, Selinum ostruthium and Angelica officinalis (see Table 1). The alcohol extract of its rhizome (Radix imperatoriae), named Remedium divinum hoffmannii, has been applied as a diuretic for chronic indigestion, a stimulant, and a stomachicum, as well as for healing typhoid, intermittent fever, and paralytic conditions, and in delirium treatments. Externally, it was applied as a powder for ulcers and cancer (Butenandt and Marten, 1932; Gökay et al., 2010). In Iranian local medicine, the aerial parts of Peucedanum pastinacifolium are commonly used as an antihyperlipidemic vegetable (Movahedian et al., 2009). In Indian local medicine, the essential oil and distilled water of Peucedanum graveolens (a synonym for Anethum graveolens L.) fruits are used to relieve flatulence, hiccup, colic and abdominal pain in children and in adults (Roy and Urooj, 2013). The most frequently employed and investigated Peucedanum species are Peucedanum praeruptorum, Peucedanum japonicum and Peucedanum decursivum. The dried root of Peucedanum praeruptorum, Baihua qianhu, has been one of the most popular herbs in traditional Chinese medicine (TCM) for more than 1500 years and is officially listed in the Chinese Pharmacopoeia (Editorial Committee of Chinese Bencao of the State Administration of Traditional Chinese Medicine,1998; China Pharmacopoeia Committee, 1999). In TCM, Qian-Hu, including the roots of two species of Peucedanum praeruptorum and Peucedanum decursivum, is used for treatment of some respiratory diseases and pulmonary hypertension (Zhao et al., 1999). At present, it is possible to suggest the root and/or rhizome of Peucedanum praeruptorum for the following: (i) to treat respiratory diseases, pulmonary hypertension

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Table 2 The known traditional medical uses and local names of Peucedanum species from different countries. Peucedanum speciesa

Regions

Local names

Uses recorded and references

Formulation/mode of usage

Peucedanum alsaticum (L.) Peucedanum cervaria (L.) Lapeyr. Peucedanum decursivum (Miq.) Maximo.

Polish and CentralEuropean Polish and CentralEuropean China and Korea

NRb

Expectorant, diaphoretic, diuretic, stomachic, sedative, and antimicrobial agent (Skalicka-Woźniak et al., 2010). Expectorant, diaphoretic, diuretic, stomachic, sedative, and antimicrobial agent (Skalicka-Woźniak et al., 2010). Dispels wind-heat, relieves cough and reduce sputum, treatment of colds and headaches, dyspneal fullness and tightness in the chest, respiratory diseases and pulmonary hypertention (Kong, 2010). Treatment of respiratory diseases and pulmonary hypertension (Zhao et al., 1999; Liu et al., 2005). In TCM: remedy for thick phlegm, asthma, and upper respiratory tract infections in traditional (Chen et al., 2008). In Korean medicine as an antitussive, analgesic, antipyretic, and coughs remedy (Zhao et al., 2012). Coughs, fever, headache and excessive sputum caused by colds (Chen et al., 2008).

Fruit

NR Radix Peucedani (Qianhu) Zi-Hue Qian-Hu

Peucedanum formosanum Hayata. Peucedanum galbanum (L.) Benth. & Hook. f. Peucedanum grande C.B. Clark Peucedanum graveolens (L.) C.B Clark. Peucedanum japonicum Thunb.

Taiwan

Taiwan Qian-Hu

South Africa

Mountain celery

India and Iran

India

Japan (in Ryukyu Islands) and Taiwan Korea, Japan, China, and Taiwan.

Abortificient and treatment of vesical catarrh, kidney and bladder ailments, prostate problem, swelling of glands and retention of urine (Campbell et al., 1994). Diuretic, emmenagogue, aphrodisiac, demulscent, deobstruent, Duku (Dughou in Persian), Baphalle, wild urolithotriptic, anti-inflammatory, antidote, oncoctive/maturative (Faridi et al., 2012; Aslam et al., 2012a, 2012b). carrot, Hingupatri Indian name In flatulence, hiccup, colic and abdominal pain in children and Shepu or dill in adults (Roy and Urooj, 2013). Sore throat (Morioka et al., 2004).

Japanese common name: botan-bofu or Shoku-Bohfuu Peucedanum officinale Bulgaria and Italy Samodivska treva (L.) Finocchio di porco (Italy) Europe, UK and Austria Masterwort (Radix Peucedanum imperatoriae) ostruthium (L.) W.D.J. Koch

Peucedanum China and Japan praeruptorum Dunn

Korea Peucedanum pastinacifolium Boiss. & Hausskn. a b

Central and Western Iran

Fruit Root

Root

Root

Infution of plant

Fruit

Essential oil and the distilled water of the fruit Leave and root

Treatment of cough, colds, headaches and as an antifebrile and anodyne (Ikeshiro et al., 1992; Lee et al., 2004; Yang et al., 2009).

Root

Cardio-tonic (Leporatti and Ivancheva, 2003). Astringent, emmenagogue (Leporatti and Ivancheva, 2003)

Root, fruit: decoction Root: infusion

Treatment of inflammatory diseases, tuberculosis, as a stimulant, a stomachicum, a diuretic for chronic indigestion, as well as a therapeutic for typhoid, intermittent fever, paralytic conditions, and in delirium tremens. Externally, the drug was applied as a powder (Butenandt and Marten, 1932; Gökay et al., 2010). Peucedani radix (Baihua Treatment of respiratory diseases, pulmonary hypertension (Zhao et al., Qianhu) 1999; Wu et al., 2003; He et al., 2007), alimentary and bronchial disorders and chest pain, presumably including angina pectoris (Rao et al., 1998). Treatment of coughs with thick sputum and dyspnea, upper respiratory infections and nonproductive cough and as antitussive and mucolytic agents (Chang et al., 2001; He et al., 2007; Song et al., 2011; Liang et al., 2012). Crude drug (Jeon Ho) Used mainly cough and dyspnea in respiratory infections (Ji et al., 2010). Alafe-Tofangchi Anti-hyperlipidemic vegetable (Movahedian et al., 2010; Sajjadi et al., 2012).

Rhizome

Root

Root Aerial parts

The scientific name of plant was reported by the authors in their original works. Not reported.

(Zhao et al., 1999; Wu et al., 2003, He et al., 2007), and chest pain, presumably including angina pectoris (Rao et al., 1998); (ii) to treat symptomatic coughs and dyspnea and as an antitussive and mucolytic agent; and (iii) as an antiseptic in upper respiratory infections (Chang et al., 2001; He et al., 2007; Song et al., 2011; Liang et al., 2012). A number of species from Peucedanum are used for the treatment of asthma, sore throat and angina and cardiovascular problems (Rauwald et al., 1994; Chen et al., 2008; SkalickaWozniak et al., 2010). For instance, Peucedanum japonicum roots are still prescribed against coughs, colds, headaches and antifebrile in Japan and sometimes are applied as a ginseng substitute (Ikeshiro et al., 1992). The root of Peucedanum formosanum, known as “Taiwan Qian-Hu”, has been traditionally used for treating coughs, fever, headache and excessive sputum caused by colds (Chen et al., 2008). The root and fruit decoction of Peucedanum officinale can be used

as a cardio-tonic, astringent and emmenagogue (Leporatti and Ivancheva, 2003). In Table 2, the traditional uses and local names of 12 Peucedanum species from different countries are summarized. However, the reported data in papers and books have no local medicine information regarding most species of Peucedanum.

4. Phytochemicals Like all plants belonging to the Apiaceae family, species of Peucedanum are rich in coumarins and essential oils. In addition, some phenolic acids, flavonoids, terpenoids and other components have been identified in this genus. Thus far, more than 300 molecules have been identified from Peucedanum. The chemical

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241

Table 3 Chemical composition (rel. %) of the essential oils isolated from different parts (aerial parts (A.p), branches (B), flowers (Fl), fruits (Fr), leaves (L), rhizomes/roots (R), seeds (Se) and stems (St)) of Peucedanum species. Peucedanum species

Region

Peucedanum alsaticum Central Balkan

Extraction method(s)a

SD

Austria

Plant part(s) of use Monoterpenes

Sesquiterpenes

Air dried A.p: (  )-α-pinene (6.4%), ( þ )-α-pinene (15.0%), ( þ)-limonene (8.2%). Fr: α-pinene (11–40%), sabinene (16–34%) and β-phellandrene (12–31%).

Air dried A.p: Trace

Poland

HD and HS-SPME

Peucedanum cervariifolium

Iran

HD

Fr (HS-SPME): α-pinene (4.9–27.0%), sabinene (29.3–27.6%), limonene þβ-phellandrene (25.8–13.9%), bornyl acetate (0.3–5.4%) Fr (HD): α-pinene (20.7%), sabinene (22.0%), limonene þ β-phellandrene (18.7%) and bornyl acetate (5.6%). Air dried A.p: (  )-α-pinene (16.5%), ( þ )-α–pinene (8.0%), camphene (8.7%) (  )-limonene (7.6%), tricyclene (7.7%). Air dried A.p: (-)-α-pinene (12.6%), (-)-sabinene (5.5%), ( þ )-β-pinene (10.2%), myrcene (9.1%), ρ-cymene (7.7%), ( þ)-limonene (11.5%). Fr, St and L: β-pinene (7–58%), α-pinene (7–22%), sabinene (up to 22%), and β-phellandrene with limonene (6–21%). R, Fr: α-pinene (SPME, Nb: 32.7%, Gc: 29.4), (HD, N: 31.3%); sabinene (SPME: N: 38.6%, G: 36.9; (HD, N: vs. 31.0%) and β-pinene, (SPME: N:19.4%, G:24.4%), (HD: N:21.7%) –

Peucedanum galbanum Peucedanum japonicum Peucedanum longifolium

South Africa

HD

South Korea Central Balkan

Poland

HD and HS-SPME

Peucedanum austriacum

Central Balkan

NR

Peucedanum cervaria

Central Balkan

NR

Austria

St and L: E-nerolidol (5–22%), spathulenol (up to 18%), dodecanal (up to 7.5%) and caryophyllene oxide (up to 7%). Fr (HS-SPME): β-caryophyllene (8.5%-5.5%), germacrene D (8.7-6.9%). Fr (HD): β-caryophyllene (5.5%), germacrene D (7.9%).

Kapetanos et al. (2008) Chizzola (2012)

Skalicka-Woźniak and Głowniak (2008)

Air dried A.p: (  )-Ecaryophyllene oxide (5.5%).

Kapetanos et al. (2008)

–

Kapetanos et al. (2008)

–

Chizzola (2012)

Skalicka-Woźniak et al. (2009a)

Fresh A.p: ρ-cymene (38.7%).

A.p: α-guaiene (11.9%), γ-muurolene (7.4%), viridiflorene (10.9%), α-selinene (16.3%) and β-selinene (27.4%). Fresh A.p: xanthoxin, psoralen

Campbell et al. (1994)

HD

A.p: α-pinene (24.68%), β-pinene (66.07%).

–

Yang et al. (2009)

HD

Air dried A.p: (-)-α-pinene (36.3%), camphene (7.6%), (-)-limonene (6.7%). A.p.: δ-3-carene (6.38%).

–

Kapetanos et al. (2008) Tepe et al. (2011)

Turkey

Peucedanum neumayeri

Greece

HD

Peucedanum officinale

Serba and Montenegro

NR

Iran

HD

Greece

HD

Central Balkan

Peucedanum oreoselinum Peucedanum oreoselnium

References

Central Balkan Lithuania

SD

Peucedanum ostruthium

Poland

HD

Peucedanum palimbioides

Turkey

HD

A.p: γ-terpinene (32.25%), α-pinene (21.27), β-phellandrene (12.76), limonene (4.71%), ρ-cymene (4.71). L: β-pinene and myrcene, limonene, α-pinene and sabinene. St: β-pinene and myrcene, limonene, α-pinene and sabinene. Fl: α-phellandrene, β-pinene and myrcene, limonene, α-pinene and sabinene R: limonene, α-pinene and sabinene L: fenchone (27.7%), (E)-β-ocimene (18.7%) and β-pinene (8.1%). Se: fenchone (32%), (E)-β-ocimene (17.8%), and (Z)-β-ocimene (9.4%). A.p: bornyl acetate (81.13%) 2, 3, 4-trimethyl benzaldehyde (4.68%)-limonene (2.78%). Air dried A.p: Tricyclene (6.1%), (  )-α-pinene (38.7%), (  )-sabinene (11.5%), β-phellanderene (7.2%), ( þ)-β-pinene (8.0%), myrcene (5.3%). ( þ )-α-pinene (15.2%), (-)-β –pinene (10.1%), (δ)-3-carene (16.9%), Terpinolene (6.9%). Air dried Fr: limonene (44.1–82.4%), γ-terpinene (12.2–17.5%), β-pinene (8.5–14.5%), α-pinene (5.1–8.3%). R: sabinene (35.2%) of which ( þ) sabinene accounts for (96.54%). 4-terpineol (26.6%) of which ( þ) 4-terpineol accounts for (65.8%). Herb: sabinene (4.7%). enantiomers: ( þ ) sabinene (4.7%), (–)-limonene (4.4%), (-) β-pinene (0.4%). A.p: α-pinene (35.45%) and β-pinene (20.19%).

Bazgir et al. (2005)

8-Cedren-13-ol (33.74%), myristicin (8.03%), germacreneD (7.73%). Germacrene-D (2.55) Evergetis et al. (2012)

–

Figuérédo et al. (2009)

–

Jaimand et al. (2006)

–

Evergetis et al. (2012)

–

Kapetanos et al. (2008)

Trace

Kapetanos et al. (2008) Motskutem and Nivinskene (1999)

Air dried Fr: trace amounts.

Herb: β-caryophyllene (16.1%) and α-humulene (15.8%). A coumarin (osthole) detected in both essential oils (5.5% in herb and 5.1% in rhizome oil).

Cisowski et al. (2001)

–

Tepe et al. (2011)

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Table 3 (continued ) Peucedanum species

Peucedanum palustre

Region

Germany

Peucedanum paniculatum

Peucedanum petiolare

Peucedanum ruthenicum

Extraction method(s)a

HD

Iran

HD

Iran Iran (Central)

HD HD

Peucedanum ruthenicum

Iran (North)

HD

Peucedanum scoparium

Iran

HD

Peucedanum tauricum

Poland

HD

Germany

HD

Peucedanum verticillare

Italian

HD

Peucedanum zenkeri

Cameroon

a b c

Plant part(s) of use

References

Monoterpenes

Sesquiterpenes

Fl: limonene 87.53%, γ-terpinene 9.15%, St: α-pinene 50.3%, γ-terpinene 16.42, myrcene 13.54%, limonene 5.51% L: mycene (9.0%), trans-ocimene (17.8%), cis-ocimene (7.28%). R: limonene 24.8%

L: Z,E.α-farnesene (15.0%) and germacrene-D (12.69%)

L: irregular monoterpenes, β-isocyclolavandulyl acetate (6.1%), β-cyclolavandulyl acetate (16.1%) and β-cyclolavandulyl isobutyrate (17.8%), β-isocyclolavandulyl isobutyrate (5.3%). and R: β-isocyclolavandulyl acetate (15.8%) and b-cyclolavandulyl acetates (13.9%), lavandulyl acetate (9.8), β-isocyclolavandulyl isobutyrate (7.3%), β-cyclolavandulyl isobutyrate (6.2%), β-isocyclolavandulol (5.7%). R: geranyl acetate (5.7%), citronellyl acetate (5.2%) sabinene (5.2%) L: sabinene (42.5%), α-pinene (42.6%) and limonene (2.6%). Seed: α-pinene (47.3%), sabinene (45.9%). A.p: sabinene (57.8%) and δ-3-carene (36.2%). L: thymol (18.29%), ethyl-dimetyl-thiophen (8.69%), β-pinene (6.05). Fl: β-myrcene (10.68%), sabinene (8.65), β-phellandrene (6.69%), ρ-cymene (6.21), α-pinene (5.49%). Fr: 1,8-cineol (11.15%), cis carveol (6.88), camphor (5.86%) and 1-carvone (5.61%).

R: trans-sesquilavandulol 37.2% two sesquiterpene diols, 4,5-epi-cryptomeridiol

Schmaus et al. (1989)

Vellutini et al. (2005)

R: β-bisabolene (31.3%), (E)-sesquilavandulol (20.5%),

Mirza et al. (2005)

Trace L: β-bisabulene (13.29%)

Rustaiyan et al. (2001) Alavi et al. (2006b)

Fl: germacrene-B (10.06%)

Fr: caryophyllene oxide (13.65%), 8, 9dehydroisolongifolene (11.33%) and caryophylla4(12), 8(13)-dien-5-β-ol (5.19%) L: thymol (57.79%), Fl: β-myrcene (6.82%) Fl: β-bisabulene (6.10%), lanceol Alavi et al. (2006a) (5.41%), germacrene-D (45%) and germacrene-B (18.5%) and γ-lemene (9.64%) Masoudi et al. (2004) Air dried A.p: The mian components of α-Pinene Air dried A.p.: Trace (39.6%), β-pinene (23.9%) and β-phellandrene (9.5%). Bartnik et al. (2002) – Fr: RI: 1529–35.9%, RI: 1526– 27.2%, RI: 1537–7.1% were not identified. Tesso et al. (2005) tricyclene, myrcene, limonene, (Z)-β-ocimene, β-γ-gurjunene (5.6%), 2,4(8)-p-menthadiene, linalool Fr: α-ylangene, α-copaen, β-bourbonene, guaia-6,9-diene, selina-5,11-diene, valerena-4,7 (11)-diene, γ-amorphene, γ-humulene, α-bulnesene, β-elemene, (E)-β-caryophyllene, α-guaiene, α-humulene, and γ-gurjunene. guaiane type sesquiterpene hydrocarbons guaia-1(10),11-diene (1) and guaia-9,11-diene (2) were identified. Dried Fr: β-caryophyllene Fresh L and B: Sabinene (39.6%) (E)-anethole Fraternale et al. (29.5%), epicamphor (7.8%), α-pinene (6.3%) and (24.2%), (Z)-β-farnesene (12.8%) (2000) β-bisabolene (9.0%) and α-phellandrene (5.6%). β-Elemene (7.5%) Fresh Fr: Fresh Fr: sabinene (63.0%), α-phellandrene (9.3%) and β-myrcene (8.1%). β-caryophyllene Dried Fr: α-phellandrene (20.8%). Menut et al. (1995) L: limonene (23.2%), myrcene (8.9%) and myristicin (7.6%) R: dillapiole (19.1%), δ-3-carene (14.7%) and myristicin (9.0%).

Different extraction methods, including hydro-distillation (HD), steam distillation (SD), headspace solid-phase micro extraction (HS-SPME) and not reported (NR). N: Natural G: Garden.

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Table 4 Isolated compounds from different parts (aerial parts (A.p), flower (Fl), foliage (Fo), fruit (Fr), herb (H), leaf (L), root (R), seed (Se), stem (St) and whole plant (W.p)) of Peucedanum species. No.

Compounds

Simple coumarins 1 Isofraxidin 2 Isoscopoletin 3 Kallisteine A 4 Mexoticin 5 Officinalin (Peuruthenicin)

6

Officinalin isobutyrate

7

Ostruthin

8 9

Osthenol Osthole

10 11

Peucenol ( þ)-Peucedanol

12

Scopoletin

13

Stenocarpin

14

Stenocarpin isobutyrate

15

Umbelliferone

16

Umbelliferone 6-carboxylic acid

17

Umbelliprenin

18 19 20

5-Hydroxy-6-isopranyl coumarin 8-Carboxy-7-hydroxy coumarin 6-(3-Carboxybut-2-enyl)-7-hydroxy coumarin

21

7-Methoxy coumarin

Simple coumarin glycosides 22 Apiosylskimmin 23 Esculin 24 Hymexelsin 25 Peujaponiside 26 Peucedanol 7-O-beta-D-glucopyranoside 27 28 29 30 31

Rubricauloside Scopolin Skimmin Praeroside VI Praerosides VII

Linear furanocoumarins (Psoralen type) 32 Alloimperatorin 33 Alsaticocoumarin A 34 Bergapten

Part(s)a

Peucedanum species

R R R R R R, L, Fl, Fr R, L, Fl, Fr R, L, Fl, Fr R Fr A.p R Fr A.p R R Fr L L R, H R R R L R R

References

praeruptorum praeruptorum paniculatum delavayi ruthenicum ruthenicum officinale longifolium morisonii tauricum luxurians morisonii tauricum luxurians japonicum ostruthium cervaria palustre palustre ostruthium ostruthium morisonii japonicum japonicum praeruptorum harry-smithii var. subglabrum Fr cervaria R morisonii A.p luxurians R morisonii A.p luxurians R, Fr, L, Fl, St longifolium R, Fr, L, Fl oligophyllum R, Fr, L, Fl vittijagum Fr, L, Fl carvifolia R, Fr, L, Fl, St ruthenicum R, Fr, L, Fl, St officinale L palustre R praeruptorum R wulongense R delavayi W.p decursivum R morisonii W.p decursivum R praeruptorum L palustre Se zenkeri R formosanum Fr grande R praeruptorum R ostruthium R ostruthium R paniculatum Se zenkeri

Ishii et al. (2008) Kong et al. (1996b) Vellutini et al. (2007) Yan et al. (2008) Soine et al. (1973) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Shults et al. (2003) Tesso et al. (2005) Chinou et al. (2007) Shults et al. (2003) Tesso et al. (2005) Chinou et al. (2007) Chen et al. (1996) Urbain et al. (2005) Skalicka-Woźniak et al. (2009c) Ojala et al. (1999) Ojala et al. (1999) Cisowski et al. (2001) Zimecki et al. (2009) Shults et al. (2003) Ikeshiro et al. (1993) Hisamoto et al. (2003) Ishii et al. (2008) Li et al. (2009)

R L R R R L R R R R R

praeruptorum japonicum praeruptorum japonicum japonicum japonicum rubricaule praeruptorum praeruptorum praeruptorum praeruptorum

Ishii et al. (2008), Zhang et al. (2009) Hisamoto et al. (2003) Chang et al. (2008) Ikeshiro et al. (1994) Hata et al. (1968), Ikeshiro et al. (1994), Lee et al. (2004) Hisamoto et al. (2003) Rao et al. (1991) Okuyama et al. (1989) Okuyama et al. (1989) Chang et al. (2008), Ishii et al. (2008) Chang et al. (2008)

R Fr R

morisonii alsaticum oreoselinum

Shults et al. (2003) Skalicka-Woźniak et al. (2009b) Lemmich et al. (1970)

Skalicka-Woźniak et al. (2009c) Shults et al. (2003) Chinou et al. (2007) Shults et al. (2003) Chinou et al. (2007) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Ojala et al. (1999) Kong et al. (1996b), Ishii et al. (2008) Kong and Zhi (2003) Yan et al. (2008) Zhao et al. (2012) Shults et al. (2003) Zhao et al. (2012) Takata et al., (1990) Ojala et al. (1999) Ngwendson et al. (2003) Chen et al. (2008) Aslam et al. (2012c) Ishii et al. (2008) Hiermann et al. (1996) Hiermann and Schantl (1998) Vellutini et al. (2007) Ngwendson et al. (2003)

244

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

Part(s)a

A.p R R R Fr R A.p A.p A.p R

35

Bergaptol

36 37

5-Methoxybergaptol Byakangelicin

38

Cnidilin

39

Imperatorin

40

Isobyakangelicin angelate

41

Isoimperatorin

42

Isopimpinellin

43 44 45

Komalin Notoptol Osthrutol

46

Oxypeucedanin

47

Oxypeucedanin hydrate

48

Peucedanin

Peucedanum species

galbanum palustre japonicum medium var. gracile tauricum praeruptorum luxurian tauricum ruthenicum harry-smithii var. subglabrum R, Fr ruthenicum R, Fr, L, Fl officinale R, Fr, L, Fl longifolium R morisonii R morisonii R medium var. gracile Se zenkeri R japonicum A.p luxurians R morrissonii R palustre A.p galbanum R palustre R decursivum Se zenkeri R ostruthium R praeruptorum Fr alsaticum R palustre R palustre R, Fr, L, Fl longifolium R, Fr officinale R palustre A.p galbanum R japonicum R palustre Fr tauricum R morisonii A.p luxurians Fr tauricum Fr alsaticum R ostruthium A.p galbanum R palustre Se zenkeri A.p galbanum Fr alsaticum R palustre R palustre R ostruthium R, Fr, L, Fl, St officinale Fr, L, Fl longifolium R, Fr ruthenicum R palustre R palustre A.p tauricum Fr alsaticum R ostruthium Fr, L, Fl longifolium R, Fr, L, Fl, St officinale R, Fr ruthenicum R japonicum R palustre F tauricum R ostruthium A.p tauricum A.p luxurian R ruthenicum R, Fr, L, Fl longifolium R, Fr, L, Fl officinale R, Fr, L, Fl ruthenicum R morisonii Fl tauricum A.p tauricum

References

Campbell et al. (1994) Ojala et al. (1999) Huong et al. (1999) Huang et al. (2000) Głowniak et al. (2002), Tesso et al. (2005) Zhang et al. (2006) Chinou et al. (2007) Bartnik and Głowniak (2007) Alavi et al. (2008) Li et al. (2009) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Shults et al. (2003) Shults et al. (2003) Huang et al. (2000) Ngwendson et al. (2003) Chen et al. (1996) Chinou et al. (2007) Szewczyk and Bogucka-Kocka (2012) Vuorela et al. (1989) Campbell et al. (1994) Ojala et al. (1999) Xu and Kong (2001) Ngwendson et al. (2003) Urbain et al. (2005) Zhang et al. (2006) Skalicka-Woźniak et al. (2009c) Vuorela et al. (1988) Ojala et al. (1999) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Vuorela et al. (1989), Tammela et al. (2004) Campbell et al. (1994) Chen et al. (1996) Ojala et al. (1999) Głowniak et al. (2002) Shults et al. (2003) Chinou et al. (2007) Bartnik and Głowniak (2007) Skalicka-Woźniak et al. (2009c) Vogl et al. (2011) Campbell et al. (1994) Ojala et al. (1999) Ngwendson et al. (2003) Campbell et al. (1994) Skalicka-Woźniak et al. (2011) Vuorela et al. (1989) Ojala et al. (1999) Urbain et al. (2005), Vogl et al. (2011) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Vuorela et al. (1989) Ojala et al. (1999) Bartnik and Głowniak (2007) Skalicka-Woźniak et al. (2009c) Gökay et al. (2010), Vogl et al. (2011) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Chen et al. (1996) Ojala et al. (1999) Tesso et al. (2005) Urbain et al. (2005), Gökay et al. (2010) Bartnik and Głowniak (2007) Chinou et al. (2007) Soine et al. (1973) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Shults et al. (2003) Tesso et al. (2005) Bartnik and Głowniak (2007)

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

49

8-Methoxypeucedanin

50 51

30 -Acetate of oxypeucedanin hydrate Phellopterin

52

Psoralen

53 54 55 56

5-Methoxypsoralen 8-Methoxypsoralen 12-Methoxypsoralen 5-Hydroxy-8-methoxy psoralen

57 58

5,8-Dimethoxypsoralen, Xanthotoxin

59

Xanthotoxol

Linear dihydro furanocoumarins (Dihydroporalen type) 60 Deltoin

Part(s)a

Peucedanum species

References

A.p R

luxurians terebinthaceum var deltoideum ruthenicum alsaticum ruthenicum tauricum harry-smithii var. subglabrum cervaria ostruthium medium var. gracile zenkeri palustre galbanum japonica japonicum palustre formosanum ruthenicum harry-smithii var. subglabrum grande praeruptorum praeruptorum ruthenicum ruthenicum zenkeri praeruptorum galbanum praeruptorum harry-smithii var. subglabrum japonicum japonicum palustre luxurian formosanum grande palustre

Chinou et al. (2007) Ganbaatar et al. (2008)

A.p Fr R A.p R Fr R R Se L A.p R R R R A.p R Fr R R A.p A.p Se R A.p R, A.p R R R R A.p R Fr R R R

Kallisteine B (spirodihydrofurano-coumarin) Marmesin (Nodakenetin)

63

Oreoselon

Linear dihydro furanocoumarin glycoside 64 Ammijin ((  )-Marmesinin) 65 66 67 68 69 70

Decuroside Decuroside Decuroside Decuroside Decuroside Decuroside

I II III V IV VI

71 72 73 74

Isorutarin Nodakenin Praeroside I Rutarin

Skalicka-Woźniak et al. (2009c) Hiermann et al. (1996) Huang et al. (2000) Ngwendson et al. (2003) Ojala et al. (1999) Campbell et al. (1994) Chen et al. (1996) Huong et al. (1999) Ojala et al. (1999) Chen et al. (2008) Alavi et al. (2008) Li et al. (2009) Aslam et al. (2012c) Kong et al. (1993a), Chang et al. (1994) Kong et al. (1993a), Zhao et al. (1999) Alavi et al. (2008) Alavi et al. (2008) Ngwendson et al. (2003) Kong et al. (1996b) Campbell et al. (1994) Yi and Lingyi (1995) Chen et al. (1996) Chen et al. (1996) Huong et al. (1999) Ojala et al. (1999) Chinou et al. (2007) Chen et al. (2008) Aslam et al. (2012c) Ojala et al. (1999) Chen et al. (1996) Ganbaatar et al. (2008)

W.p R

japonicum terebinthaceum var. deltoideum harry-smithii var. subglabrum decursivum delavayi paniculatum galbanum praeruptorum japonicum decursivum delavayi harry-smithii var. subglabrum decursivum morisonii

R R R R R R R R R R W.p R R

praeruptorum delavayi decursivum decursivum decursivum decursivum decursivum decursivum decursivum praeruptorum decursivum praeruptorum praeruptorum

Okuyama et al. (1989) Yan et al. (2008) Sakakibara et al. (1984), Matano et al. (1986) Sakakibara et al. (1984), Matano et al. (1986) Sakakibara et al. (1984), Matano et al. (1986) Asahara et al. (1984), Matano et al. (1986) Asahara et al. (1984), Matano et al. (1986) Xu and Kong (2001) Yao et al. (2001) Okuyama et al. (1989) Matano et al. (1986), Zhao et al. (2012) Okuyama et al. (1989) Okuyama et al. (1989)

R

61 62

Alavi et al. (2008) Skalicka-Woźniak et al. (2009c) Kuzmanov et al. (1981) Bartnik and Głowniak (2007) Li et al. (2009)

R R R A.p R R R R R

Li et al. (2009) Xu and Kong (2001) Yan et al. (2008) Vellutini et al. (2007) Campbell et al. (1994) Kong et al. (1994) Chen et al. (1996) Liu et al. (2005) Yan et al. (2008) Li et al. (2009) Zhao et al. (2012) Shults et al. (2003)

245

246

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

Angular-type furanocoumarins (Angelicin type) 75 Angelicin 76 Oroselol 77 Pimpinellin

Angular-type furanocoumarin glycosides 78 Peucedanoside A 79 Peucedanoside B Angular-type dihydrofuranocoumarins 80 Athamantin 81 Archangelicin 82 Columbianadin

83 84 85 86 87 88 89 90 91 92 93 94 95 96

Columbianadin oxide Dihydrooroselol (8S, 9R)-9-acetoxy-O-isovaleryl-8,9-dihydrooroselol (8S, 9R)-9-acetoxy-O-senecioyl-8,9-dihydrooroselol (8R, 9S)-20 -angelyoyoxy-9-isovaleryloxy-dihydrooroselol (8S)-9-hydroxy-8,9-dihydrooroselol (8S, 9R)-9-hydroxy-O-senecioyl-8,9-dihydrooroselol (8S, 9R)-9-isovaleryloxy-8,9-dihydrooroselol (8R)-20 (methyl butyroyloxy)-8,9-dihydrooroselol (8S)-O-Senecioyl-8,9-dihydrooroselol Isopeulustrin Peucenidin Peulustrin Vaginidin

Angular-type dihydrofuranocoumarin glycosides 97 Apterin

Linear type dihydropyranocumarins (Dihdroxanthyletin type) 98 30 ,40 -Dihydroxanthyletin

Part(s)a

Peucedanum species

References

H (Fl, L, St) R R R R

oreoselinum oreoselinum palustre palustre ostruthium

Coste et al. (2011) Lemmich et al. (1970) Vuorela et al. (1989) Ojala et al. (1999) Vogl et al. (2011)

R R

praeruptorum praeruptorum

Li et al. (1994), Wu et al. (2003), Chang et al. (2007) Chang et al. (2007)

R R A.p R

oreoselinum oreoselinum luxurians palustre

R Fr R R R R R R R R R R R R R R

decursivum cervaria palustre oreoselinum oreoselinum oreoselinum oreoselinum oreoselinum oreoselinum oreoselinum oreoselinum oreoselinum palustre oreoselinum palustre oreoselinum

Lemmich et al. (1970) Lemmich et al. (1970) Chinou et al. (2007) Vuorela et al. (1989), Ojala et al. (1999), Eeva et al. (2004), Tammela et al. (2004). Xu and Kong (2001) Skalicka-Woźniak et al. (2009c) Ojala et al. (1999), Eeva et al. (2004). Lemmich and Gylle (1988) Lemmich et al. (1970) Lemmich et al. (1970) Lemmich and Gylle (1988) Lemmich et al. (1970) Lemmich et al. (1970) Lemmich et al. (1970) Lemmich and Gylle (1988) Lemmich et al. (1970) Ojala et al. (1999), Eeva et al. (2004) Lemmich et al. (1970) Ojala et al. (1999), Eeva et al. (2004) Lemmich et al. (1970), Lemmich and Gylle (1988)

R R L

praeruptorum palustre japonicum

Chang et al. (2007) Ojala et al. (1999), Eeva et al. (2004) Hisamoto et al. (2003)

R R

decursivum harry-smithii var. subglabrum terebinthaceum var. deltoideum decursivum wulongense decursivum arenarium wawrii decursivum arenarium decursivum decursivum decursivum decursivum

Yao et al. (2001) Li et al. (2009)

99

Decursin

Fr

100 101 102 103 104

Decursidin (  )-Smyrinoll; ( þ )-Decursinol ( þ)-trans-Decursidinol (  )-methyl-Decursidinol 30 (S)-Acetoxy-40 (R)-angeloyloxy-30 , 40 -dihydroxanthyletin

105

Decursitin B (xanthalin)

106

Decursitin

107

Decursitin D

R R R R R R R R R R R

108 109 110 111 112 113

Decurstin F Pd-C-III Pd-C-IV Pd-C-V Peuarenine Peuarin

R R R R R R

114 115

Peuarenarine Peuchlorin

R R

116

Peuchlorinin butyroyl isokhellactone

R

117

Peucloridin

R

decursivum decursivum decursivum decursivum arenarium arenarium var. arenarium arenarium arenarium var. arenarium arenarium var. arenarium arenarium var. arenarium

Ganbaatar et al. (2008) Liu et al. (2005) Kong and Zhi (2003) Xu and Kong (2001) Zheleva et al. (1972) Kong et al. (2003) Xu and Kong (2001) Zheleva et al. (1972) Xu and Kong (2001) Kong et al. (2000) Xu and Kong (2001), Liu et al. (2005) Yao and Kong (1999), Xu and Kong (2001), Yao et al. (2001) Yao and Kong (2001) Sakakibara et al. (1984) Yao and Kong (2001), Liu et al. (2005) Liu et al. (2005) Zheleva et al. (1972) Zheleva et al. (1976) Zheleva et al. (1972) Zheleva et al. (1976) Zheleva et al. (1976) Zheleva et al. (1976)

Linear type dihydropyranocumarin glycoside 118 30 (R)-O-β-D-Glucopyranosyl-30 ,40 -dihydroxanthyletin

R

dissolutum

Wu et al. (2004)

Angular type dihydropyranocumarin 119 (  )-cis-Khellactone

R

japonicum

Chang-yih et al. (1992)

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

247

Table 4 (continued ) Part(s)a

Peucedanum species

References

Peucedanocoumarin I

R A.p R A.p A.p R R R W.p A.p A.p R R R A.p R R R

formosanum japonicum wulongense japonicum japonicum japonicum praeruptorum delavayi japonicum japonicum japonicum praeruptorum japonoicum wulongense japonicum longshengense wawrii praeruptorum

131

Peucedanocoumarin II

R

praeruptorum

132

Peucedanocoumarin III

133

( þ/  ) Peuformosin

R R R R R R

praeruptorum japonicum medium var. gracile ostruthium harry-smithii var. subglabrum praeruptorum

Chen et al. (2008) Chang-yih et al. (1991) Kong and Zhi (2003) Chen et al. (1996) Chang-yih et al. (1991) Chen et al. (1996) Kong et al. (1993b) Yan et al. (2008) Yamada et al. (1974) Jong et al. (1992) Ikeshiro et al. (1992) Zhang et al. (2005c) Kong and Zhi (2003) Shigematsu et al. (1982) Jong et al. (1992) Huang et al. (1997) Kong et al. (2003) Takata et al. (1990), Kong et al. (1996b), Hou et al. (2009) Takata et al. (1990), Kong et al. (1993a), Zhao et al. (1999) Takata et al. (1990), Kong et al. (1993b) Chen et al. (1996) Huang et al. (2000) Vogl et al. (2011) Li et al. (2009)

R R R

japonicum japonicum praeruptorum

R R

japonicum terebinthaceum var. deltoideum dissolutum praeruptorum Japonicum japonicum praeruptorum

No.

Compounds

120

( þ)-trans-Khellactone

121 122 123 124 125 126

( 7 )-cis-30 -Acetyl-40 -tigloylkhellactone ( þ)-trans-40 -Acetyl-30 -tigloylkhellactone (  )-trans-30 -Acetyl-40 -senecioylkhellactone 30 -Angeloyloxykhellactone Coumurayin 30 (S),40 (S)-diisovaleryloxy-30 ,40 -dihydroseselin

127

30 (S),40 (S)-disenecioyloxy-30 ,40 -dihydroseselin

128 129

cis-30 -isovaleryl-40 -senecioylkhellactone Longshengensin A

130

134 135 136

137 138

Peujaponisinol A Peujaponisinol B Pteryxin

Isopteryxin ( 7 )-Praeruptorin A (Pd-Ia; Longshengensin A)

R R R R R R

139

Praeruptorin C; ( þ) praeruptorin A

A.p R

harry-smithii var. subglabrum japonicum praeruptorum

140

( 7 )-Praeruptorin B (Anomalin; Pd-II)

R R

japonicum praeruptorum

R R R R R R

wulongense formosanum delavayi harry-smithii var. subglabrum praeruptorum praeruptorum

Se R R R R R R R R R R R W.p R W.p

zenkeri japonicum praeruptorum praeruptorum praeruptorum praeruptorum praeruptorum praeruptorum formosanum japonoicum japonicum japonicum turgeniifolium praeruptorum turgeniifolium

141 142

Praeruptorin D ((þ ) Praeruptorin B) Praeruptorin E (wulongensin A)

143 144 145 146 147 148 149 150 151 152 153 154

Peujaponisin Qianhucoumarin A Qianhucoumarin B Qianhucoumarin C Qianhucoumarin D Qianhucoumarin E Qianhucoumarin I Isosamidin Samidin Selinidin ( 7 )-40 -Tigloylkhellactone Turgeniifolin A (Pd-Ib)

155

Turgeniifolin B

Ruan et al. (2011), Xiong et al. (2012a, 2012b) Ikeshiro et al. (1993) Ikeshiro et al. (1992, 1993) Takata et al. (1990), Kong et al. (1993a), Zhao et al. (1999), Wang et al. (2012) Chen et al. (1996) Ganbaatar et al. (2008) Wu et al. (2004) Chang et al. (1994a, 1994b), Fong et al. (2008) Chen et al. (1996) Huong et al. (1999) Zhao et al. (1999), Lu et al. (2001), Wu et al. (2003), Zhang et al. (2005a), Wu et al. (2009), Xu et al. (2010) Li et al. (2009) Chang-yih et al. (1991) Rao et al. (1998), Zhao et al. (1999), Rao et al. (2001), Wu et al. (2003), Zhang et al. (2003), Xu et al. (2010), Yu et al. (2012) Ikeshiro et al. (1992) Aida et al. (1995), Zhang et al. (2005c), Hou et al. (2009), Wu et al. (2009), Xu et al. (2010), Liang et al. (2012) Kong and Zhi (2003) Chen et al. (2008) Yan et al. (2008) Li et al. (2009) Yu et al. (2012) Rao et al. (1998), Zhang et al. (2006), Hou et al. (2009), Yu et al. (2012) Ngwendson et al. (2003) Ikeshiro et al. (1992) Kong et al. (1993a) Kong et al. (1993b) Kong et al. (1993b) Kong et al. (1994), Liu et al. (2004) Kong et al. (1994), Wu et al. (2009) Kong et al. (1996a) Chen et al. (2008) Ikeshiro et al. (1994) Chen et al. (1996) Chen et al. (1996) Ding (1981) Kong et al. (1994), Hou et al. (2009), Yu et al. (2011) Ding (1981)

248

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

Part(s)a

Peucedanum species

References

156 157 158

TurgeniifolinC (  )-Visnadin ( þ)-cis-30 acetoxy-40 -(2-methylbutyroyloxy)-30 ,40 -dihydroseselin

W.p R R

turgeniifolium japonicum formosanum

Ding (1981) Ikeshiro et al. (1992) Chen et al. (2008)

R L R L R L R L

praeruptorum japonicum praeruptorum japonicum praeruptorum japonicum praeruptorum japonicum

Takata et al. (1988) Hisamoto et al. (2003) Takata et al. (1988) Hisamoto et al. (2003) Takata et al. (1988) Hisamoto et al. (2003) Takata et al. (1988) Hisamoto et al. (2003)

R R

japonicum ostruthium

Chen et al. (1996) Urbain et al. (2005)

( þ)-Visamminol

Fr Fr R R R

alsaticum alsaticum japonicum medium var. gracile japonicum

Skalicka-Woźniak et al. (2012) Skalicka-Woźniak et al. (2012) Chen et al. (1996) Huang et al. (2000) Chen et al. (1996)

Dihydro furano chromones 169 Prim-O-glucosylcimifugin

R

japonicum

Chang-yih et al. (1992)

R R Fr

ostruthium decursivum alsaticum

Schinkovitz et al. (2003), Vogl et al. (2011) Liu et al. (2005) Skalicka-Woźniak et al. (2009b)

Fr, Fo Fl A.p L L L Fo Fr Fo A.p Fr, Fo Fr Fo Fr R Fr Fo Fr, Fo Fr Fr, Fo Fr Fr, Fo Fr Fr, Fo Fr W.p

tauricum alsaticum ruthenicum japonicum japonicum japonicum tauricum alsaticum tauricum ruthenicum tauricum alsaticum tauricum alsaticum delavayi alsaticum tauricum tauricum alsaticum tauricum alsaticum tauricum alsaticum tauricum alsaticum decursivum

Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Alavi et al. (2009) Hisamoto et al. (2003), Morioka et al. (2004) Hisamoto et al. (2003) Hisamoto et al. (2003) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Alavi et al. (2009) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Yan et al. (2008) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Skalicka-Woźniak and Głowniak (2008) Bartnik et al. (2003) Bartnik et al. (2003) Zhao et al. (2012)

Fr Fr L, Fl, Fr L, Fl, Fr L, Fl S, L, Fl L, Fl, Fr L, Fl L, Fl L, Fl, Fr L, Fl, Fr L, Fl, Fr Fr L A.p Fl, Fr, L

alsaticum alsaticum ruthenicum officinale longifolium carvifolia oligophyllum carvifolia longifolium officinale oligophyllum ruthenicum alsaticum sowa ruthenicum ruthenicum

Skalicka-Woźniak et al. (2011) Skalicka-Woźniak et al. (2011) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Skalicka-Woźniak et al. (2011) Lakshminarayana et al. (2005) Alavi et al. (2009) Kuzmanov et al. (1981)

Angular dihydropyrano coumarine glycoside 159 Praeroside II 160

Praeroside III

161

Praeroside IV

162

Praeroside V

Chromones 163 Eugenin 164 Peucenin Linear dihydro pyrano chromones 165 Divaricatol 166 Ledeburiellol 167 (  )-Hamaudol 168

Dihydropyranochromone 170 Alsaticol

Phenolic acids 171 Caffeic acid

172 173 174

Neochlorogenic acid Cryptochlorogeni acid Chlorogenic acid

175 176

Cinnamic acid p-Coumaric acid

177

Ferulic acid

178 179 180

Gallic acids Gentisic acid p-Hydroxybenzoic

181

Protocatechuic acid

182

Syringic acids

183

Vanillic acid

Flavonoids 184 Astragalin 185 Hiperoside 186 Isorhamnetin

187

Kaempferol

188 189 190

Lutein Morin Quercitrin

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

Flavonoid glycoside 191 Isoquercetin 192 Isorhamnetin-3-glucoside

193

Isorhamnetin-3-rutinoside

194

Quercitrin-3-rutinoside

195

Quercitrin-3-galactoside

196

Rutin (Rutoside)

197

Rhamnetin-3-glucoside

Phenylethanoid 198 Dillapiole 199 Decursidate 200 1-(4-Hydroxyphenyl) ethan-1,2-diol 201 Elemicin 202 Myristicin 203 p-hydroxy-phenethyl ferulate 204 Salidroside Phenylpropanoid 205 Eleutheroside B (Syringing) 206 2-(4-Hydroxy-3-methoxyphenyl) propane-1,3-diol 207 3-(2-O-β-d-Glucopyranosyl-4-hydroxyphenyl) propanoic acid 208 Methyl 3-(2-O-β-d-glucopyranosyl-4-hydroxyphenyl) propanoate 209 3-O-β-d-Glucopyranosyl-2-(4-hydroxy-3-methoxyphenyl) propanol Terpenoids 210 Daucosterol

211

β-Sitosterol

Phenanthrene-quinone 212 Tanshinone I 213 Tanshinone II A Fatty acids and esters 214 Linoleic acid

Part(s)a

Peucedanum species

References

St, Fl, Fr, L L, Fl, S St, F, Fr, L L, Fl, Fr L, Fl A.p A.p Fr

longifolium carvifolia officinale oligophyllum vittijagum tauricum ruthenicum alsaticum

Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Bartnik et al. (2007) Alavi et al. (2009) Skalicka-Woźniak et al. (2011)

L Fl, Fr Fl, Fr L, Fl Fl, Fr Fl, Fr Fl, Fr A.p A.p A.p A.p St, L, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr St, L, Fl St, Fl, Fr St, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr St, L, Fl, Fr A.p L A.p A.p

japonicum officinale longifolium carvifolia vittijagum oligophyllum ruthenicum tauricum kenappii ruthenicum tauricum carvifolia longifolium officinale oligophyllum ruthenicum vittijagum carvifolia longifolium oligophyllum officinale ruthenicum vittijagum ruthenicum japonicum tauricum kenappii

Hisamoto et al. (2003) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Bartnik et al. (2007) Sarkhail et al. (2013a) Bartnik et al. (2007) Alavi et al. (2009) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Kuzmanov et al. (1981) Soine et al. (1973), Alavi et al. (2009) Hisamoto et al. (2003) Bartnik et al. (2007) Sarkhail et al. (2013a)

A.p R L A.p A.p R L

pastinacifolium decursivum japonicum pastinacifolium pastinacifolium formosanum japonicum

Sajjadi et al. (2012) Kong and Yao (2000), Yao and Kong (2001) Hisamoto et al. (2004) Sajjadi et al. (2012) Sajjadi et al. (2012) Chen et al. (2008) Hisamoto et al. (2004)

R L L L L

praeruptorum japonicum japonicum japonicum japonicum

Zhang et al. (2009) Hisamoto et al. (2004) Hisamoto et al. (2004) Hisamoto et al. (2004) Hisamoto et al. (2004)

R R R R R R R R

decursivum praeruptorum delavayi ledebourielloides praeruptorum medium var. gracile decursivum delavayi

Xu and Kong (2001) Zhang et al. (2006) Yan et al. (2008) Zheng et al. (2010) Kong et al. (1993a), Zhang et al. (2005c) Huang et al. (2000) Xu and Kong (2001) Yan et al. (2008)

R R

praeruptorum praeruptorum

Zhang et al. (2009) Zhang et al. (2009)

L, St Fl Fl Se Se Se Se Se

graveolens alsaticum cervaria chryseum obtusifolium palimbioides ruthenicum zedelmeierianum

Rao and Lakshminarayana (1988) Skalicka-Woźniak et al. (2010) Skalicka-Woźniak et al. (2010) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012)

249

250

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

Table 4 (continued ) No.

Compounds

Part(s)a

Peucedanum species

References

215

Linolenic acid

216 217

Oeanolic acid Oleic acid

218

Palmitic acid

219 220 221 222

Stearic acid Arachidic acid-2-hydroxy-glycerol ester 1,6-Dihydroxy-hexane-bis-palmitoyl ester 1,2-Dipalmitoyl-3-glucosyl glycerol

L, St R Se Se Se Se Se R Fr Fr Se Se Se Se Se L, St R Se Se Se Se Se R R R R

graveolens praeruptorum chryseum obtusifolium palimbioides ruthenicum zedelmeierianum ledebourielloides alsaticum cervaria chryseum obtusifolium palimbioides ruthenicum zedelmeierianum graveolens praeruptorum chryseum obtusifolium palimbioides ruthenicum zedelmeierianum delavayi ledebourielloides ledebourielloides ledebourielloides

Rao and Lakshminarayana (1988) Zhang et al. (2009) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Zheng et al. (2010) Skalicka-Woźniak et al. (2010) Skalicka-Woźniak et al. (2010) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Rao and Lakshminarayana (1988) Zhang et al. (2006) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Akpinar et al. (2012) Yan et al. (2008) Zheng et al. (2010) Zheng et al. (2010) Zheng et al. (2010)

Polyacetylene 223 Panaxynol 224 Acetylatractylodinol 225 Tetracosanoic

R R R

formosanum praeruptorum praeruptorum

Chen et al. (2008) Chang et al. (2007) Zhang et al. (2006)

Pyrimidines or nucleobase 226 Uracil

L

japonicum

Hisamoto et al. (2003)

Nucleosides 227 Guanosine 228 Uridine 229 Thymidine

L L L

japonicum japonicum japonicum

Hisamoto et al. (2003) Hisamoto et al. (2003) Hisamoto et al. (2003)

Amino acids 230 l-Tryptophan

L

japonicum

Hisamoto et al. (2003)

R R R L L R R R R Fr

praeruptorum praeruptorum praeruptorum sowa japonicum praeruptorum praeruptorum praeruptorum delavayi grande

Zhang et al. (2009) Kong et al. (1996b) Zhang et al. (2009) Lakshminarayana et al. (2005) Hisamoto et al. (2003) Zhang et al. (2006) Zhang et al. (2009) Miyazawa et al. (1996), Purup et al. (2009) Yan et al. (2008) Aslam et al. (2012c)

L

japonicum

Hisamoto et al. (2004)

L

japonicum

Hisamoto et al. (2004)

R R R

japonicum praeruptorum praeruptorum

Lee et al. (2004) Zhang et al. (2009) Zhang et al. (2006)

Miscellaneous 231 Adenosine 232 Anchoic acid (Azelaic acid) 233 Butyric acid 234 β-Carotene 235 Cnidioside A 236 2,6-Dimethyl quinoline 237 α-D-glucopyranose-1-hexadecanoate 238 Falcarindiol 239 240 241 242 243 244 a

Labdanyl-3-α-ol-18-(30 “-methoxy-2”-naphthyl-oate)-3-α-Larabinofuranosyl-(20 – 41″)-alpha-L-arabinofuranoside (3S)-O-β-d-Glucopyranosyl-6-[3-oxo-(2S/R)-butenylidenyl]-1,1,5trimethylcyclohexan-(5R)-ol (a norisoprenoid glucoside( (3S)-O-β-d-Glucopyranosyl-6-[3-oxo-(2R)-butenylidenyl]-1,1,5trimethylcyclohexan-(5R)-ol (a norisoprenoid glucoside) Myo-inositol D-Mannitol monohexadecanoate Sclerodin

The plant parts have been reported by the authors in their original works.

composition of some species, such as Peucedanum knappii (Sarkhail et al., 2013a) and Peucedanum formosanum (Chen et al., 2008), is inadequately known, although few flavonoids or coumarins have been detected in these plants. A total of 158 coumarins, 13 phenolic acids, 13 flavonoids, 11 phenylpropanoids, 8 chromones, 9 fatty acids, 2 steroids, and a number of volatile oils (monoterpenoids, sesquiterpenoids) have been identified from Peucedanum species. Phytochemical analysis of the essential oils from

Peucedanum species summarized in Table 3, and coumarins, flavonoids, phenolics and other components are reviewed in Table 4. 4.1. Terpenoids Terpenoids are classified according to the number of isoprene units. For example, monoterpenoids (C10) are made from

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

two isoprene units, sesquiterpenoids (C15) from three units, diterpenoids (C20) from four units, and triterpenoids (C30) from six units (Huang et al., 2012). Monoterpenoids and sesquiterpenoids are the primary compounds of the essential oils that are mainly extracted by hydrodistillation (HD), steam-distillation (SD), headspace solid-phase microextraction techniques (HS-SPME) and supercritical methods, and then identified by gas chromatography (GC)-based techniques (Sides et al., 2000; Skalicka-Woźniak et al., 2009a). The genus Peucedanum is rich in aromatic plants, but taxonomically many of its species are still unresolved. Because characterization of each Peucedanum species by anatomical and morphological features is difficult, chemical analysis of essential oils has played an important role in identifying chemotaxonomic markers. Analysis of essential oils indicated that the main components of Peucedanum species oils are monoterpene hydrocarbons (Kapetanos et al., 2008; Figuérédo et al., 2009) and in many Peucedanum species, including Peucedanum officinale, Peucedanum alsaticum, Peucedanum austriacum, Peucedanum oreoselinum, Peucedanum longifolium and Peucedanum cervaria, (7)α-pinene (4.0–38.7%) (Kapetanos et al., 2008; Skalicka-Woźniak et al., 2008, 2009a) is the major component of essential oils. However some species, such as Peucedanum ruthenicum (Alavi et al., 2006a) and Peucedanum paniculatum (Vellutini et al., 2005), are dominated by other monoterpenes or sesquiterpenes (Tepe et al., 2011). Climatic factors variations, extraction techniques and different plant parts could influence the quality and quantity of essential oil compounds. For example, in the essential oil of Peucedanum oreoselinum fruit, the amounts of the two main components γ-terpinene (12.2–17.5%) and β-pinene (8.5–14.5%) increase in the presence of sunlight. Limonene is the major compound (44.1–82.4%), and α-pinene is found in all studied Peucedanum oreoselinum samples at concentrations of approximately 4.0–11% (Motskute and Nivinskene, 1999). Skalicka-Woźniak et al. (2009a) studied the effects of different extraction methods on the essential oils from Peucedanum cervaria fruits. In both HD and HS-SPME extracts α-pinene and sabinene were the dominant compounds (31.3–38.6%), but the amounts of these monoterpenes were larger than those isolated by HD. In contrast, α-terpinene, β-linalool, trans-verbenol, β-bourbonene and α-humulene were detected only by HD. In that study, more than 80% of oil from Peucedanum cervaria included α-pinene, sabinene, and β-pinene, confirming the close botanical relationship of Peucedanum cervaria with Peucedanum alsaticum, Peucedanum schotti, Peucedanum scoparium, Peucedanum oreoselinum and Peucedanum petiolare. Analysis of the essential oil of Peucedanum officinale showed that the flower oil differs from the other parts of plant by its significant quantity of α-phellandrene (Figuérédo et al., 2009). In Peucedanum ruthenicum the dominant compounds from leaf, flower and fruit oils are not similar. In leaf oil, thymol (18.3%) and β-bisabolene (13.3%) are the major components while these compounds are not found in flowers and fruits of Peucedanum ruthenicum (Alavi et al., 2006b). In another study, higher humidity changed the amounts of thymol and β-bisabolene of leaf oil from Peucedanum ruthenicum to 57.8% and 6.0%, respectively (Alavi et al., 2006a). The volatile oils of different parts of Peucedanum petiolare were analyzed by Mirza et al. (2005). They showed that α-pinene (42.6–47.3%) and sabinene (42.3–45.9%) are the major components of leaf and seed oil whereas in the rhizome oil, sesquiterpenes (51%), β-bisabolene (31.3%), and (E)-sesquilavandulol (20.5%) are the main components. β-Bisabolene and (E)-sesquilavandulol are found in large amounts only in the rhizome of Peucedanum petiolare (Mirza et al., 2005), and β-bisabolene is detected in a high quantity (13.29%) in the leaf oil of Peucedanum ruthenicum (Alavi et al., 2006b). Peucedanum alsaticum, Peucedanum cervaria (Skalicka-Woźniak et al., 2008; Chizzola, 2012), Peucedanum verticillare, Peucedanum ostruthium,

251

Peucedanum petiolare (Mirza et al., 2005) and Peucedanum ruthenicum (Alavi et al., 2006b) contain a large quantity of sabinene. Cisowski et al. (2001) reported that the major components of essential oil from rhizome of Peucedanum ostruthium are monoterpenes, sabinene (35.2%) and 4-terpineol (26.6%), while sesquiterpenes, β-caryophyllene (16.1%) and α-humulene (15.8%) are found in significant quantities in herb volatile oil. Peucedanum galbanum (Campbell et al., 1994), Peucedanum cervaria (Kapetanos et al., 2008) and Peucedanum ruthenicum (Alavi et al., 2006b) oils contain significant amounts of p-cymene (38.7%, 7.7% and 6.21%, respectively), which is present only at small amounts in other Peucedanum species such as Peucedanum petiolare and Peucedanum oreoselinum, Peucedanum alsaticum and Peucedanum officinale. In addition, three ρ-menthatrienes, unique compounds belonging to Apium graveolens and Petroselinum crispum as well as coumarins, xanthotoxin and psoralen, are found in Peucedanum galbanum oil (Campbell et al., 1994). Schmaus et al. (1989) analyzed the volatile oils of fruits, stalks, leaves, and roots of Peucedanum palustre. Monoterpene hydrocarbons are the main compounds in the fruit and stalk oils, while in the root oil monoterpene hydrocarbons (33%) and oxygenated sesquiterpenes (41%) are significant. Only in the oil of root has trans-sesquilavandulol been found in large amounts (37.2%). Because of the presence of similar primary sesquiterpenes, alcohols, trans-cyclobutyl sesquilavandulol and lancifolol (Fig. 1), there is a close chemotaxonomic relationship between Peucedanum palustre and Peucedanum lancifolium oils (Schmaus et al., 1989). Fraternale et al. (2000) confirmed that α-phellandrene (5.6– 20.8%) is the one of the major compounds in Peucedanum verticillare oil. Limonene is not detected in this oil, whereas Peucedanum oreoselinum, Peucedanum grande, Peucedanum cachrydifolia, Peucedanum officinale, Peucedanum cervaria, Peucedanum alsaticum, Peucedanum longifolium, Peucedanum austriacum and Peucedanum zenkeri have a significant amount of (7)-limonene. Moreover, the presence of some compounds distinguished Peucedanum verticillare oil from other Peucedanum species' oil: (E)-anethole, which reaches approximately 30% in the oil, and epicamphor, which reaches approximately 7.8%, are not found in the essential oils from Peucedanum oreoselinum, Peucedanum officinale, Peucedanum grande, Peucedanum cachrydifolia and Peucedanum zenkeri (Fraternale et al., 2000). Approximately 3.5% of the oil extracted from the fresh fruit of Peucedanum verticillare is nerol, which is detected only at trace amounts in Peucedanum cachrydifolia oil. The essential oils of Peucedanum verticillare, Peucedanum palustre (Vuorela et al., 1989), Peucedanum zenkeri (Menut et al., 1995), Peucedanum officinale and Peucedanum cervaria (Kapetanos et al., 2008) are rich in myrcene, a compound that occurs in small amounts in Peucedanum alsaticum, Peucedanum austriacum, Peucedanum oreoselinum, Peucedanum longifolium and Peucedanum cachrydifolia (Kapetanos et al., 2008). In conclusion, Peucedanum verticillare oil chemotaxonomically is characterized by the presence of anethole and epicamphor and the absence of limonene (Fraternale et al., 2000). Bornyl acetate, the main compound (81%) in the essential oil of Peucedanum officinale (Evergetis et al., 2012), is found only in Peucedanum scoparium (Masoudi et al., 2004) but not reported in other previous studies on Peucedanum officinale oils (Jaimand et al., 2006; Figuérédo et al., 2009). Cisowski et al. (2001) analyzed the essential oil from Peucedanum ostruthium herb and rhizome. β-Caryophyllene (16.1%) and α-humulene (15.8%) are the dominant compounds in the herb oil, while sabinene (35.2%) and 4terpineol (26.6%) are the major compounds in the rhizome oil. Moreover, a coumarin (osthole) is in both essential oils (5.5% in herb oil and 5.1% in rhizome oil). In a few species of Peucedanum, such as the fruit oil of Peucedanum tauricum (Bartnik et al., 2002), there are high levels of sesquiterpenoids. Additionally, rhizome oil of Peucedanum petiolare,

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P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

H

H

H

Guaia-9,11-diene

Guaia-1(10),11-diene O

O

O OH

OH

cis-Sesquilavandulol

trans-Sesquilavadulol acetate

trans-cyclobutyl-sesquilavadulol

OH OH

Lancifolo

trans-Sesquilavandulol

OR

OR

R H

B-Cyclolavandulol B-Cyclolavandulyl acetate

B-iso-Cyclolavandulol

11CO-12CH 3

B-iso-Cyclolavandulyl acetate

B-Cyclolavandulyl propionate

11CO-12CH -13CH 2 3

B-Cyclolavandulyl isobutyrate

11CO-12CH-13,14(CH ) 3 2

B-Cyclolavandulyl valerate

B-iso-Cyclolavandulyl propionate

11CO-12CH -13CH-14, 15(CH ) 2 3 2

B-iso-Cyclolavandulyl isobutyrate B-iso-Cyclolavandulyl valerate

Fig. 1. Some essential oils compounds from Peucedanum species.

Peucedanum longifolium, Peucedanum cervariifolium and Peucedanum ruthenicum has a high level of sesquiterpenes. Several sesquiterpenes were isolated for the first time from the genus Peucedanum. For example two new guaiane-type sesquiterpene hydrocarbons, guaia-1 (10),11-diene and guaia-9,11-diene (Fig. 1), were isolated from the fruit oil of Peucedanum tauricum (Tesso et al., 2005). From the leaves and roots of Peucedanum paniculatum, essential oils were obtained by Vellutini et al. (2005). Eight novel, natural andirregular monoterpene esters were identified, and they had lavandulyl or cyclolavandulyl skeletons (see Fig. 1). β-Cyclolavandulyl acetate and isobutyrate (16.1% and 17.8%, respectively) are the major compounds in the leaf oil, whereas β-isocyclolavandulyl and β-cyclolavandulyl acetates (15.8% and 13.9%, respectively) are the main components of the root oil. For the first time the β-cyclolavandulyl ester compounds, including β-cyclolavandulyl acetate, β-cyclolavandulyl isobutyrate, β-cyclolavandulyl isovalerate and β-isocyclolavandulyl acetate, and β-isocyclolavandulyl esters, such as β-isocyclolavandulyl acetate, β-isocyclolavandulyl propionate, β-isocyclolavandulyl isobutyrate and β-isocyclolavandulyl isovalerate, were isolated from Peucedanum paniculatum leaf and root oils (Vellutini et al., 2005) (see Fig. 1). The presence of trans-sesquilvanadulol is a characteristic of Peucedanum

lancifolium and Peucedanum palustre oil and shows the close botanical relationship of the two species because it is not detected in other Peucedanum plants (Kubeczka et al., 1989). A new acyclic diterpenoid, peucelinendiol (Fig. 1), was identified for the first time in the ether extract of Peucedanum oreoselinum root by Lemmich (1979). Trace amounts (0.2%) of neophytadiene (linear diterpene) and abietatriene (cyclic diterpene) are found in essential oils of Peucedanum austriacum and Peucedanum longifolium, respectively (Kapetanos et al., 2008) (Fig. 1). Tanshinone I (212) and tanshinone IIA (213) (see Fig. 12) are two diterpene quinones in Peucedanum praeruptorum root extract (Zhang et al., 2005c). The most prevalent triterpenes in Peucedanum species are β-sitosterol (Kong et al., 1993a, 1993b; Huang et al., 2000; Xu and Kong, 2001; Yan et al., 2008) and daucosterol (Xu and Kong, 2001; Yan et al., 2008; Zheng et al., 2010). 4.2. Coumarins Coumarins are a large class of plant secondary compounds found in the highest levels in the fruits, followed by the roots, stems and leaves. This group of natural compounds has received great attention because of their biological activities. Coumarins

P. Sarkhail / Journal of Ethnopharmacology 156 (2014) 235–270

have a benzopyrone skeleton. They include four major sub-types: simple coumarins; furanocoumarins; pyranocoumarins; and pyrone-substituted coumarins. Furanocoumarins consist of a five-membered furan ring fused with the coumarin nucleus and are divided into linear (psoralen type) or angular (angelicin type) forms with substituents at one or both of the remaining benzoic positions. Pyranocoumarin compounds, containing a sixmembered ring, are analogous to the furanocoumarins. Pyronesubstituted coumarins include an unsaturated six membered ring containing one oxygen atom and a ketone group that are substituted in the pyrone (Lacy and O’Kennedy, 2004)). The main chemical groups that are widely distributed in the genus Peucedanum are furanocoumarins, followed by angular-type pyranocoumarins (Takata et al., 1990; Chang et al., 2008; Ishii et al., 2008). Some of the isolated angular-type pyranocoumarins (seselins) from this genus are named praeruptorins, which comprise a free sugar khellactone skeleton (dihydroseselin) with different substituents at the two stereogenic centers (C-30 and C-40 ). According to their chemical structures, cis-khellactones are generally divided into 2 groups: the 30 R,40 R and 30 S,40 S configurations. The 30 S,40 S configuration is found mostly in Peucedanum praeruptorum and

253

R4 R3 R 2O

O

O

R1 (22) R1= H, R2= Api(1"-6")Glc, R3= H, R4= H (23) R1= H, R2= H, R3= Glc, R4= H (24)

R1= H, R2= Api(1"-6")Glc, R3= OCH3, R4= H

(25) R1= H, R2= Api(1"-6")Glc, R3= CH2CHOHCOH(CH3)2, R4= H (26) R1= H, R2= Glc, R3= CH2CHOHC(CH3)2OH, R4= H (27)

R1= CH2CHOHC(CH3)2O-Api(1"-6")Glc, R2= OCH3, R3= H, R4= OCH3

(28)

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

(29)

R1= H, R2= Glc, R3= H, R4= H

Fig. 3. Simple coumarins glycosides isolated from the species of genus Peucedanum.

R4 4

5

R3

6

R2

7

3 R1

2 O 1

8

R2

O R3

R1

O

(1) R1= OCH3, R2= OH, R3= OCH3, R4= H

CH3 R = H 4 CH3 H3C

(4) R1= CH2CHOHCOH(CH3)2,

R2= OCH3, R3= H, R4= OCH3

(32) R1= CH2CHC(CH3)2, R 2= H, R3= H, R4= OH (33) R1= OCH2COCCH3CH2CHCHC(CH3)2OH, R2=R3=R4= H (34) R1= OCH3, R2=R3=R4= H

(5) R1= H, R2= OH, R3= COOCH3, R4= H

(35) R1= OH, R2=R3=R4= H

(7) R1= H, R2= OH, R3= CH=C(CH2)CH2-CH2CH=C(CH3)2, R4= H

(37) R1=OCH3 , R4= OCH2CHOHCOH(CH3)2

(8) R1= CH2CH=C(CH3)2, R2= OH, R3= H, R4= H

(38) R1= OCH2CH=C(CH3)2 R2=R3= H, R4=OCH3

(9) R1= CH=C(CH3)2, R2= OCH3, R3= H, R4= H

(39) R1=R2=R3=H, R4=3,3 dimethylallyloxy

(10) R1= H, R2= OH, R3=

H3C

CH3 CH3

R 4= H

(11) R1= H, R2= OH, R3= CH2CHOHC(CH3)2OH, R4= H

(42) R1=R4= OCH3

R2=R3= H

(45) R1= OCH2CH(C(CH3)2OH)OC=OCCH3=CHCH3,

(13) R1= OCH3, R2= OH, R3= COOCH3, R4= H

R2=R3=R4= H

(46) R1= OCH2CH-O-CH(CH3)2, Epoxyisopentenyl , R2=R3=R4= H

(15) R1= H, R2= OH, R3=R4= H O

(41) R1= OCH2CH=C(CH3)2, R2=R3=R4= H

(44) R1=R2=R3= H, R4=OCH2CHOHCOH(CH3)2

(12) R1= H, R2= OH, R3= OCH3, R4= H, R4= H

(17) R1= H, R2=

O

R4

(2) R1= H, R2= OCH3, R3= OH, R4=H (3) R1= H, R2= OH, R3=

O

(47) R1= OCH2CH(OH)C(CH3)2OH, R2=R3=R4= H

R3=R4= H

(18) R1= H, R2= H, R3= OH, R4= OCH=C(CH3)2

(48) R1=R4=H, R2=OCH3 R3=CH(CH3)2 (51) R1=OCH3, R2=R3=H, R4= OCH2CH=C(CH3)2

(19) R1= COOH, R2= OH, R3=R4= H

(52) R1=R2=R3=R4= H

(20) R1=R2= OH, R3= C=CCH3COOH, R4= H

(58) R1=R2=R3=H, R4=OCH3

(21) R1= H, R2= OCH3, R3=R4= H

(59) R1=R2=R3=H, R4=OH

Fig. 2. Simple coumarins isolated from the species of genus Peucedanum.

Fig. 4. Psoralen type coumarins isolated from the species of genus Peucedanum.

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ability (Shen et al., 2012) and anti-HIV effects (Lee et al., 1994). (7)-Praeruptorin A (PA) (138) or dl-praeruptorin A (Pd-la) and (7)-praeruptorin B (PB) (140) or dl-praeruptorin B (Pd-II, anomalin) are the most famous praeruptorins. They were found for the first time in Peucedanum praeruptorum. Because of a chiral preference in the herb, dextrorotatory isomers of praeruptorin A and praeruptorin B are naturally more abundant than their levorotatory enantiomers (Chen et al., 1979). To date, more than 50 coumarins have been isolated from Peucedanum praeruptorum (Chen et al., 1979; Song et al., 2011). The structures of coumarins from various species of Peucedanum (from 1 to 162) are displayed in Figs. 2–9.

Peucedanum japonicum plants (Ren et al., 2013; Sarkhail et al., 2013b). The coumarin contents in several species are extremely similar, consisting largely of simple coumarins and linear and angular-type furanocoumarins. Peucedanum officinale, Peucedanum longifolium, Peucedanum ruthenicum, Peucedanum tauricum, Peucedanum morisonii and Peucedanum alsaticum are characterized by the presence of linear furanocoumarins, e.g., bergaptol, peucedanin and isoimperatorin. Peucedanum praeruptorum, Peucedanum japonicum, Peucedanum formosanum and Peucedanum harry-smithii var. subglabrum are most likely closely related because of the presence the angular-type dihydropyranocoumarins, e.g., praeruptorins A and B. A number of Peucedanum species, e.g., decursivum, japonicum and praeruptorum, are unique in their high coumarin glycoside contents. Praeruptorins are considered the main components responsible for several pharmacological properties (Sarkhail et al., 2013b), such as calcium antagonist activity (Chang et al., 1994b), antiplatelet aggregation (Aida et al., 1995), P-glycoprotein inhibitory

4.3. Other compounds Based on phytochemical studies, besides essential oils and coumarins, a range of flavonoids, phenols, phenylpropanoids, polyynes, glycosides, chromones, fatty acids, steroids, amino acids and

HO O O

O

O

O O

O

(60)

O

(61) O

H

Me HO

O

Me

O

O

O

O

O

(63)

(62) HO

Glc

OH

H

Me O

O O

OH

O

Me

O

OH

HO

O

O O

O

O

O

OH HO

(64)

(65)

O O OH

O

O O

O

Glc

O

O O

O

OH

(70)

OH

OCH3

(71)

HO Glc

OH

O

O O

O

O

O OH

(72)

O

O O

OH HO

(73)

HO O

O

OH

O

O

OGlc

(74) Fig. 5. Dihydropsoralen type coumarin isolated from the species of genus Peucedanum.

O

O

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255

OCH3 H3CO O

O

O

O

O

O

O

O (75)

(76)

OH

O

O

O

O

(77)

O

O

O

O

O

O

OR2 O

R1O O

(80) R1=R2= Isovaleryl

O O (83)

O

(82)

(81) R1=R2= Angeloyl (85) R1= Isovalery, R2= Acetyl (86) R1= Sencioyl, R2= Acetyl

O

O

(88) R1=R2= H

O

R1

(89) R1= Sencioyl, R2= H (90) R1= H, R2= Isovaleryl

R2

HO

(94) R1= Acetyl, R2= Senecioyl (96) R1= H, R2= Isovaleryl

(87) R1= OCOCH2CH(CH3)2, R2= OCOCCH3CHCH3 (91) R1= H, R2= OCOCHCH3CH2CH3

O

O O

O

O

O

O

O OH O

O

O

O HO

HO (92) R=Sencioyl

O

O O

RO

O

O

O

(93)

O-B-d-glucosyl

(95)

(97)

Fig. 6. Angelicin and Dihydroangelicin type coumarins isolated from the species of genus Peucedanum.

nucleosides have been discovered in the Peucedanum species (Table 4). A few Peucedanum species contain fewer than 20 flavonoids, such as Peucedanum alsaticum (Skalicka-Woźniak et al., 2011), Peucedanum tauricum, Peucedanum officinale (Kuzmanov et al., 1981), Peucedanum ruthenicum (Kuzmanov et al., 1981; Alavi et al., 2009) and Peucedanum kenappi (Sarkhail et al., 2013a). The flavonoids in Peucedanum are mostly flavonols, including isorhamnetin, quercetin and kaempferol along with their glycosides. Caffeic (171), chlorogenic (174), coumaric (176), ferulic (177) and vanillic acids (183) are the most prevalent phenolic acids in this genus (Manach et al., 2004; Macheix et al., 2005).

Phenylpropanoid compounds have also been identified (Kong and Yao, 2000; Yao et al., 2001; Hisamoto et al., 2004; Sajjadi et al., 2012). Two new phenylpropanoid glucosides, 3-(2-O-β-Dglucopyranosyl-4-hydroxyphenyl) propanoic acid (207) and methyl-3-(2-O-β-D-glucopyranosyl-4-hydroxyphenyl) propanoate (208), have been identified in the n-butanol soluble fraction of Peucedanum japonicum leaves (Hisamoto et al., 2004). To date, only a few investigations have analyzed the fatty acid profiles of Peucedanum species. For instance the fatty acid compositions of seeds from five species of Peucedanum, including ruthenicum, chryseum, palimbioides, obtusifolium, and zedelmeierianum,

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O

O O

O

O

O

O

O

O

O

O O

O

O

O

O

O

O

(99)

O

O

O

O

O

O

O

O

Me

O

O

O

O

Me O

O

O

O

O

O

(103)

(102)

(101)

Me

O

HO

HO

(110)

(109)

OMe

OH

O

O

O

O (100)

HO

O

O

O

O

O O

O

O

(111)

O

(112)

O

O OMe

O

OR2

H

O

O

R1O O

O

O

O

O

O

O

O

O

O

O

(113)

O

senecioyloxy

O

O

O OH

O O

O

O O

O

OH

O

O

(115)

O

O

O

O

O

O

Cl

Cl

R2 angeloyloxy angeloyloxy angeloyloxy H H

O

O (114)

(104) R1 (105) angeloyloxy (106) senecioyloxy (107) H (108) Ac

O

O

O O

O

(116) Cl

angeloyloxy

O

HO Cl

O

OH

O

O

Glc-O

O O

O

O

O

O (118)

(117)

Fig. 7. Dihydroxanthylen type coumarins isolated from the species of genus Peucedanum.

were determined by Akpinar et al. (2012). Oleic acid (C 18:1 ω-9, 31.28–68.06%) (217), linoleic acid (C 18:2 ω-6, 15.99–33.74%) (214) and palmitic acid (C 16:0, 5.78–14.68%) (218) are the major fatty acids in the seed oils of these species. In Peucedanum palimbioides oil, oleic acid (23.57%) is a major compound. The polyyne compound falcarindiol (238) (see Fig. 12), a potential anticancer component of some vegetables such as carrots, parsley, celery, parsnip and fennel (Purup et al., 2009), has been found in Peucedanum praeruptorum (Miyazawa et al., 1996). The isolated components from different Peucedanum species are listed in Table 4. A number of isolated compounds, including chromones, phenolic acids, phenylpropanoids and miscellaneous compounds are displayed in Figs. 10–12.

confirmed by biological and pharmacological studies. Several extracts of Peucedanum spp. and isolated compounds have been evaluated for their anti-inflammatory, antipyretic, cardiopulmonary, neuroprotection, anti-cancer, antioxidant, antityrosinase, antimicrobial, amoebicidal, antihelmintic, antiplatelet aggregation, anti-diabetic and phototoxic effects. Peucedanum praeruptorum and Peucedanum japonicum extracts and their major compounds, e.g., praeruptorins, have been well studied. (7 )-PA and (7)-PB are effective in several cellular and animal models of inflammatory mediator release and tumor cell lines, and the molecular mechanisms that drive these effects have been discerned in some detail. Therefore, these compounds are attractive for the discovery and development of anticancer and immunosuppressant drugs. An overview of the modern pharmacological investigations performed on these species is described in detail below.

5. Pharmacological and toxicological aspects In the Peucedanum genus, 12 species of Peucedanum (accepted or unresolved), including Peucedanum alsaticum, Peucedanum cervaria, Peucedanum decursivum, Peucedanum formosanum, Peucedanum galbanum, Peucedanum grande, Peucedanum graveolens, Peucedanum japonicum, Peucedanum officinale, Peucedanum ostruthium, Peucedanum praeruptorum and Peucedanum pastinacifolium are used in traditional medicine. The validity of traditional applications of some Peucedanum species appears to be

5.1. Anti-inflammatory and antipyretic activities Airway hyperreactivity that causes periodic bronchoconstriction and obstruction is one of the significant characteristics of allergic asthma (Crimi et al., 1998). Ethanol extract of Peucedanum ostruthium roots showed significant dose-dependent inhibition activity in carrageenan-induced edema test in rats; at the dose of 120 mg/kg orally, it reduced edema up to 57%. In another

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257

Fig. 8. Dihydroseselin type coumarins isolated from Peucedanum species.

Fig. 9. Dihydroseselin glycoside coumarins isolated from Peucedanum species.

investigation the main isolated compound, 6-(3-carboxybut-2enyl)-7-hydroxycoumarin (20), showed approximately 50% and 61.8% inhibition of edema at concentrations 30 and 300 μg/kg, respectively. Both the extract and isolated coumarin strongly decreased prostaglandin E2 (PGE2), PGI2, and PGD2 in stimulated rabbit ears. The IC50 value of the extract and isolated coumarin in

5-lipoxygenase assay, respectively, were 66 μg/mL and 0.25 μM. The extract and coumarin have been characterized as dual inhibitors of cyclooxygenase and 5-lipoxygenase activity. On the other hand, both of them showed antipyretic effects on yeast-induced fever in rat. However 6-(3-carboxybut-2-enyl)-7-hydroxycoumarin was more potent than acetylsalicylic acid (ASA) and indomethacin, as 400 μg/kg of this compound (i.p.) reduced the average of temperature by 2.1 1C after three hours, while ASA at dose of 160 mg/kg decreased the hyperthermia by 2.9 1C after two hours (Hiermann and Schant, 1998). The Peucedanum praeruptorum coumarin fraction (CPPD) significantly suppressed airway hyperreactivity in a dose-dependent manner in the presence of lung resistance induced by acetylcholine chloride in experimental mice. In addition the effect of a high dosage of CPPD is comparable with that of dexamethasone, which is consistent with a previous report of the attenuation of acetylcholine-induced bronchoconstriction in rabbits by CPPD in vitro (Zhao et al., 1999). Zhang et al. (2005b) explained the significant anti-tussive and anti-inflammatory effects of the major components of Peucedanum praeruptorum. Yu et al. (2012) reported that the anti-inflammatory effect of (7)-PA-(138) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells may be due to inhibition of NF-κB signaling. (7)-PA inhibited nitric oxide (NO), TNF-α and IL-1b production in a dose-dependent

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Me O

O

Me

O Me OH

HO

O

Me

O (164)

(163)

OH

OH

O

R2O

Me HO

Me Me

O

R1

O

Me

O (168)

Me Me

O

O

O

O

O

OH

O

H Me

HO Me

Me

O

(165) R1=OH R2= acetyl (166) R1=OH R2=angeloyl (167) R1=R2=H

Me

O

O

O

O

Me Me

O

HO

O

O OH

OH (169)

HO OH

(170)

Fig. 10. Chromons isolated from the species of genus Peucedanum.

manner. (7 )-PA treatment at 25 mg/mL inhibited LPS-stimulated NO production up to 54%. Moreover, (7)-PA treatment at the same dose had a 42% and 54% inhibitory effect on TNF-α and IL-1b production, respectively. ( 7)-PA also inhibited iNOS expression at the levels of protein and mRNA. Treatment with ( 7)-PA showed inhibitory effects on TNF-α and IL-1b mRNA expression in LPSstimulated RAW264.7 cells. Therefore, (7)-PA can decrease the pro-inflammatory mediator release and display anti-inflammatory effects. In another study Xiong et al. (2012c) reported the inhibitory effect of CPPD, containing praeruptorins, on allergic airway inflammation and T helper cell type 2 predominant responses in BALB/c mice. ( 7)-PA has also shown potent anti-inflammatory effects in a murine model of chronic asthma. (7)-PA significantly reduced airway inflammation and airway hyperresponsiveness by reducing IL-4 IL-5, IL-13 and leukotriene C4 (LTC4) in bronchoalveolar lavage fluid (BALF) and immunoglobulin (Ig) E in serum. Moreover this compound suppressed the expression of some factors involved in inflammatory responses, such as transforming growth factor β (TGF-β1). It inhibited eotaxin protein and mRNA expression, IκBα degradation, NF-κB nuclear translocation, NF-κB DNA-binding activity, and RelA/p65 phosphorylation, as well as up-regulating Smad7 in lung tissue and INF-γ in BALF (Xiong et al., 2012a, 2012b). Praeruptorins (þ )-PA (PC) (139), (þ )-PB (PD) (141), and PE (142) showed anti-inflammatory activity in LPS-stimulated RAW264.7 murine macrophage cells by inhibiting STAT3/NF-κB signaling. All of those compounds significantly decreased lipopolysaccharide (LPS)-induced production of NO, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and mRNA and protein

expressions of inducible NO synthase. Both PD and PE had higher anti-inflammatory activity than PC (Yu et al., 2012). Recently, two studies evaluated the effects of praeruptorins C (139), D (141), E (142) and ( 7)-PA (138) on LPS-induced pulmonary inflammation. Pretreatment with 80 mg/kg/orally of both PD and PE significantly decreased the total cell and PMN counts and decreased TNF-α and IL-6 (pro-inflammatory cytokines) in bronchoalveolar lavage fluid, while the effective doses of ( 7)-PA and PC were 320 mg/kg. PD and PE at doses of 80 mg/kg decreased TNF-α up to 51% and 56%, respectively, and thereby suppressed the release of IL-6 up to 51% and 59%, respectively. In addition, PD and PE improved pathologic changes in the lung and inhibited the NFκB activation in acute lung injury induced by LPS and HCl (Yu et al., 2012; Xiong et al., 2012b). 5.2. Antioxidant activity Free radicals play a major role in various chronic pathologies, such as cancer and cardiovascular diseases. Hisamoto et al. (2003) evaluated the antioxidant activity of the extracts and fractions obtained from Peucedanum japonicum leaves by two methods, DPPH radical scavenging followed by lipid peroxidation of the egg yolk phosphatidylcholine liposomes induced by 2,20 -azobis (2-amidinopropane) dihydrochloride (AAPH). As the n-butanol soluble fraction showed the highest activity, it was chromatographed for isolation of potent compounds. Isoquercitrin, rutin, neochlorogenic acid (172), cryptochlorogenic acid (173) and chlorogenic acid (174) were the main potent constituents of this fraction, which showed DPPH radical-scavenging activity

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259

Fig. 11. Some phenolic compounds from Peucedanum species.

(80.1–94.3%) after 5 h of reaction. Additionally, these compounds had a higher inhibitory activity in lipid peroxidation of the phosphatidylcholine liposome induced by AAPH than those of αtocopherol and L-ascorbic acid. Afterward two compounds isolated from Peucedanum japonicum leaves, 2-(4-hydroxy-3-methoxyphenyl) propane-1,3-diol (206) and 3-O-β-D-glucopyranosyl-2-(4hydroxy-3-methoxyphenyl) propanol (209), exhibited an appreciable DPPH radical-scavenging activity after 24 h of reaction (73.9–87.9%), while α-tocopherol and L-ascorbic acid reacted with DPPH radical rapidly (Hisamoto et al., 2004). These results confirmed that the analysis of the kinetics of compounds' free radical scavenging is important for understanding their antiradical actions. Morioka et al.

(2004) explained that the DPPH radical-scavenging effect of Peucedanum japonicum is one of the defense mechanisms against colon cancer cells. Peucedanum japonicum showed antioxidant activity in dose-dependent manner with IC50 ¼8777 μg/mL. The EtOAc fraction of Peucedanum knappii, which showed the highest radical-scavenging activity (SC50 ¼36.4 mg/mL), was selected for the isolation and identification of major active compounds. Two known flavonol glycosides, rhamnetin-3-О-β-D-glucopyranoside (197) and isorhamnetin-3-О-β-D-glucopyranoside (193), showed SC50 values of 0.29 mg/mL and 0.89 mg/mL, respectively, in a DPPH assay. The inhibitory effect of isorhamnetin-3-О-ß-D-glucopyranoside on DPPH radical was lower than that of quercetin (Sarkhail et al., 2013a).

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O

O O

O

O

O

(212)

HO

(223)

(213)

COOH HOOC

COOH O

O-Glc

(232)

(235)

HO

HO

R1 R2 Glc

(238) OH O

O

O

OH

(240) R1= H, R2= COCH3 (241) R2= COCH3, R2= H

O OH

O

(244) Fig. 12. Some miscellaneous compounds from Peucedanum species.

The methanol extract of Peucedanum graveolens (dill) showed a dosedependent antioxidant effect in the DPPH assay. Three hundred microliters of it at 100 1C inhibited DPPH free radicals by approximately 77%, and heating increased the antioxidant activity of dill extract significantly (Po0.05) (Roy and Urooj, 2013). The antioxidant capacities of the essential oils of Peucedanum longifolium and Peucedanum palimbioides were assayed by four different methods: a ß-carotene/linoleic acid assay, a DPPH free radical scavenging, a method to measure their reducing power and a method to measure their chelating effect. Peucedanum palimbioides and Peucedanum longifolium oils showed strong antioxidant capacity (90.58% and 70.73%, respectively) in the β-carotene/ linoleic acid assay at 2.0 mg/mL. At the same dose, Peucedanum palimbioides oil had a stronger chelating effect (90.39%) than Peucedanum longifolium (24.12%). At 1 mg/mL the concentrationreducing power of Peucedanum palimbioides oil (0.248%) was greater than that of Peucedanum longifolium (0.104%), but neither of them exhibited activity as strong as those of the synthetic antioxidants. Both oils showed moderate activity (41.87–47.26%) in DPPH free radical scavenging in comparison with the synthetic antioxidants (Tepe et al., 2011). 5.3. Antityrosinase activity Hisamoto et al. (2004) investigated the tyrosinase inhibitory activity of some isolated phenolic compounds from Peucedanum japonicum leaves. All compounds, including 2-(4-hydroxy-3-methoxyphenyl) propane-1,3-diol (206) and 3-O-β-D-glucopyranosyl-2-(4hydroxy-3-methoxyphenyl) propanol (209) were weaker than kojic

acid. Sarkhail et al. (2013a) showed that the most potent mushroom tyrosinase inhibition of the aerial parts of Peucedanum knappii extracts was achieved with the ethyl acetate fraction (IC50 ¼517 mg/mL) in a dose-dependent manner. Rhamnetin-3-О-β-D-glucopyranoside (197) and isorhamnetin-3-О-β-D-glucopyranoside (193), the main flavonoids isolated from EtOAc, showed anti-tyrosinase activity with IC50 values of 27.95 mg/mL and 82.03 mg/mL, respectively. The inhibitory effect of rhamnetin-3-О-β-D-glucopyranoside on tyrosinase was higher than that of kojic acid. 5.4. Anti-microbial, amoebicidal and antihelmintic activities The agar disc diffusion method was employed to determine the antimicrobial activities of Peucedanum paniculatum leaf and root oils against 11 bacterial strains (Vellutini et al., 2005). The results confirmed the antibacterial activity of oils on Staphylococcus aureus, Serratia marcescens, Micrococcus luteus, Bacillus subtilis, Enterobacter cloacae and Escherichia coli. However, the minimum inhibitory concentration (MIC) of leaf and root oils against Staphylococcus aureus was 0.3% (3 mg/mL). Skalicka-Woźniak et al. (2007, 2009a) measured the antibacterial activity of essential oils from fruits of Peucedanum alsaticum and Peucedanum cervaria against 10 reference microorganisms by the agar dilution method using Mueller-Hinton agar. Among the Gram-positive bacteria, only Bacillus subtilis and Micrococcus luteus were sensitive to these oils (MIC ¼2000 mg/L). Neither essential oil inhibited the growth of the Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, nor Proteus mirabilis, even at the highest concentration tested (2000 mg/L).

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Moreover, they tested the essential oil and some of its components of Peucedanum alsaticum fruits against six Gram-positive and Gram-negative bacteria. The Gram-positive strains Staphylococcus epidermidis ATCC 12228, Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 6538, Bacillus cereus ATCC 10876, Bacillus subtilis ATCC 6633, Micrococcus luteus ATCC 10240 and the Gram-negative strains Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 13883, Peucedanum aeruginosa ATCC9027, and Proteus mirabilis ATCC 12453 were used. The MICs were determined by the agar dilution method. The essential oil had an effect against two Gram-positive bacteria, Bacillus subtilis and Micrococcus luteus with MIC¼ 2000 mg/L, while the oil and its components limonene, bornyl acetate, and α-phellandrene had no effect on the growth of any Gram-negative bacteria tested. On the other hand, 4-terpineol and linalool inhibited the growth of Gram-negative bacteria, with an MIC of 2000 mg/L, and showed similar activity against all the Gram-positive strains tested except Staphylococcus epidermidis, against which 4-terpineol had no effect. At a concentration of 1000 mg/L, linalool, 4-terpineol and bornyl acetate inhibited the growth of Bacillus subtilis, Bacillus cereus, and Micrococcus luteus but were inactive against the other strains tested. Limonene and α-phellandrene had no effect on the growth of any of the strains tested (Skalicka-Woźniak et al., 2008). Fatty acid fractions isolated from the fruits of Peucedanum cervaria and Peucedanum alsaticum displayed moderate antibacterial activity that covered only Gram-positive bacteria, including staphylococci. The growth of Gram-negative bacteria and Candida species was not altered even at the highest extract concentrations applied (MIC44 mg/mL). Peucedanum alsaticum showed stronger antibacterial properties against Gram-positive bacteria, with MIC values between 0.125 and 0.5 mg/mL, while Peucedanum cervaria extract inhibited the growth of Gram-positive strains, with MIC values between 0.25 and 2 mg/mL. At the same concentration (MIC¼0.25 mg/mL), both extracts were active only against Micrococcus luteus. Moreover, the minimal bactericidal concentration (MBC) for Peucedanum alsaticum and Peucedanum cervaria hexane extracts varied from 0.25 to 2 mg/mL and from 0.5 to 4 mg/mL, respectively. Oleic (217) and linoleic acids (214), the main compounds of both extracts, were responsible for the antibacterial activity against Gram-positive bacteria and indicated a synergistic antimicrobial effect (Skalicka-Woźniak et al., 2010). The methanol extract of Peucedanum graveolens (seed) exhibited moderate antimicrobial activity against Salmonella typhi (size of zone of inhibition Z5– 9 mm) by the disc diffusion method (Rani and Khullar, 2004). The ethyl acetate fraction and praeruptorin A (138) from Peucedanum praeruptorum root had antimicrobial activity on Streptococcus agalactiae, with MIC values 250 and 100 μg/mL, respectively (Lu et al., 2001). Schinkovitz et al. (2003) screened Peucedanum ostruthium root for in vitro anti-mycobacterial activity against Mycobacterium fortuitum, a pathogen responsible for some infections in the lung and cutaneous soft tissue. The highest activity was found in the dichloromethane extract from Peucedanum ostruthium (MIC¼16 μg/mL). In the second step two known compounds, named ostruthin (7) and imperatorin (39), were isolated from the active fraction. Ostruthin exhibited significant inhibitory activities against different strains of rapidly growing Mycobacteria, such as Mycobacterium aurum, Mycobacterium fortuitum, Mycobacterium phlei and Mycobacterium smegmatis, with MIC values between 3.4 and 6.7 μM, which were similar to those of ethambutol and isoniazid, but imperatorin showed no activity at concentrations up to 1.9 mM. The geranyl side chain of ostruthin increased lipophilicity in comparison with simple hydroxycoumarins such as umbelliferone (15), which may be an important factor for increasing activity. Umbelliferone showed weakly inhibitory activity (MIC¼0.79 mM). Twenty fractions from the ethyl acetate extract of Peucedanum ostruthium rhizome were applied to three pathogenic bacteria

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(Bacillus cereus, Escherichia coli, and Staphylococcus aureus) to determine its antimicrobial activity using the disc diffusion method. The potent fraction had a large inhibition halo of 9.0 mm in diameter on Bacillus cereus at a concentration of 16.2 mg/mL. Escherichia coli and Staphylococcus showed no sensitivity to the ethyl acetate extract. Oxypeucedanin (46) and oxypeucedanin hydrate (47) were detected as the major compounds from this fraction and while oxypeucedanin hydrate showed a significant antimicrobial activity against Bacillus cereus at 220 μg, oxypeucedanin had no effect (Gökay et al., 2010). The acetone extract of the aerial parts and roots of Peucedanum nebrodense showed no antimicrobial activity in vitro at the concentration of 100 g/mL against the following Gram-positive and Gram-negative human-pathogenic bacteria: Staphylococcus aureus, Streptococcus agalactiae, Bacillus subtilis, Escherichia coli, Peucedanum aeruginosa. It also had no effect against the antifungal bacteria Candida albicans and Candida tropicalis (Schillaci et al., 2003). The methanol extract and n-hexane fraction of Peucedanum zenkeri seeds showed antimicrobial activity. Imperatorin (39), bergapten (34) and isopimpinellin (42) were responsible for the antimicrobial action (Ngwendson et al., 2003). The methanol and MeOH/H2O (1: 1 v/v) extracts of Peucedanum salinum were screened for the antiviral and virucidal effects on human adenovirus type 5. The methanol extract of Peucedanum salinum at the concentrations of 0.5 and 1 mg/mL exhibited antiviral activity, with a decrease in virus titer of 2 log and 1.33 log, respectively. The MeOH/H2O extract (1:1 v/v) at concentrations of 1 and 2 mg/mL reduced the titer of the virus by 1.33 log and 1.5 log, respectively. On the other hand, the examined extracts showed no virucidal activity against adenovirus type 5 (Rajtar et al., 2012). The essential oil of Peucedanum ruthenicum fruits showed antimicrobial activity against various Gram-positive bacteria, such as Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus cereus, with MIC values of 0.03–0.29 mg/mL, determined using the agar dilution method. This oil showed no activity against the Gram-negative bacteria Escherichia coli, Peucedanum aeruginosa, and Salmonella typhi (Alavi et al., 2005). The antibacterial activity of polar and nonpolar extracts from the roots of Peucedanum ruthenicum was studied using the cup plate technique to determine the growth inhibition of Staphylococcus aureus, Staphylococcus epidermidis, Peucedanum aeruginosa and Escherichia coli. The polar phase of the roots exhibited no significant antibacterial effect on the tested bacteria. On the other hand the nonpolar phase showed inhibitory effect against Staphylococcus aureus and Escherichia coli, with MICs of 156.2 and 312.5 μg/mL, respectively, whereas it was inactive against Staphylococcus epidermidis and Peucedanum aeruginosa, with MICs 41000 μg/mL (Sabri et al., 2009). The antibacterial activities of the essential oil of whole parts of Peucedanum japonicum were studied against drug-susceptible and -resistant skin pathogens using the disc diffusion method (Yang et al., 2009). The MIC of Peucedanum japonicum against antibiotic-susceptible Staphylococcus epidermidis CCARM 3709 was 0.13 mL/mL, while tetracycline-resistant Staphylococcus epidermidis CCARM 3711 and Malassezia furfur KCCM 12679 had minimum susceptibility to Peucedanum japonicum essential oil (MIC¼ 5 mL/mL). These results confirm that it is a good candidate for treatment of acne. All of the MeOH extracts of Peucedanum caucasicum, Peucedanum palimbioides, Peucedanum chryseum, and Peucedanum longibracteolatum at 32.0 mg/mL showed a time- and dose-dependent amoebicidal action on trophozoites and cysts, but the extract of Peucedanum longibracteolatum exhibited the most amoebicidal activity at 4.0 mg/mL or higher (Malatyali et al., 2012). The effects of different extracts (petroleum ether, chloroform, ethyl acetate, methanol, water extract) of Peucedanum praeruptorum roots against Dactylogyrus intermedius were assayed by Wu et al. (2011) and the chloroform extract was the most effective after 48 h of exposure, with EC50 ¼240.4 mg/L.

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5.5. Cardiopulmonary protection Vascular smooth muscle relaxation occurs through multiple mechanisms. Intracellular Ca2 þ plays an important role in the endothelium-independent relaxation of vascular smooth muscle. Blockade of either extracellular Ca2 þ influx or internal Ca2 þ release efficiently relaxes vascular smooth muscle. On the other hand, endothelium-dependent relaxation is caused by various vasodilators present in endothelium and the secretion of NO, prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) (Xu et al., 2010). Based on traditional uses of Peucedanum ostruthium, Joa et al. (2011) evaluated the dichloromethane extract of Peucedanum ostruthium rhizomes for any antiproliferative activity in rat aortic vascular smooth muscle cells (VSMCs). This extract inhibited serum (10%)-induced VSMC proliferation in a concentrationdependent manner. Additional identification and biological testing of its main components showed that the coumarin ostruthin (7) was the major antiproliferative substance; the IC50 for CH2Cl2 extract and ostruthin were, respectively 24 and 26 μg/mL. In an earlier study, the Ca2 þ -antagonistic activity of Peucedanum ostruthium rhizome extract was confirmed in depolarized aortic strips by Rauwald et al. (1994). Aida et al. (1998) found that some isolated compounds from Peucedanum japonicum had non-competitive antagonistic effects on acetylcholine (Ach)- and histamine-induced contraction in the isolated guinea pig ileum. Moreover these compounds showed noncompetitive antagonist action on serotonin-induced contraction of the rat uterus after injection of estradiol, while none of them inhibited the rabbit thoracic aorta contractions induced by epinephrine. These findings confirm that Peucedanum japonicum has spasmolytic and antiallergic effects. Hao et al. (1996) reported that ( 7)-PA strongly relaxed ileum and tracheal smooth muscles. Afterward, Zhao et al. (1999) established the relaxant effect of the isolated pyranocoumarins from Peucedanum praeruptorum and Peucedanum decursivum roots on isolated rabbit tracheas and pulmonary arteries. PC (139), (7)-PA (138) and pteryxin (136) showed noticeable relaxant activities in tracheal preparations constricted with 40 mM KCl or 10 μM acetylcholine. The relaxant effects of PC, (7)-PA and pteryxin in KCl-constricted tracheas are more effective than that in acetylcholine- or phenylephrineconstricted tracheas. These compounds at a dose of 30 μM completely relaxed tracheas constricted with 40 mM KCl, while P-II (peucedanocoumarin II) (131) at the same concentration created partial relaxation. These results confirmed that PC, (7)-PA and pteryxin are responsible for calcium antagonistic action and that the presence of acetoxy groups on C30 and C40 of dihydroseselin is critical for relaxing smooth muscles. Additionally 8-methoxypsoralen (8-MOP) (54) showed a noticeable relaxant effect in the presence of 10 μM phenylephrine, without any effect in the presence of 40 mM KCl. This action may be partially caused by the inhibitory activity of 8-MOP on cytochrome P-450, known as the link between the store and plasma membrane Ca2 þ pathways. Recently, Xu et al. (2010) demonstrated the bioactive compounds from Peucedanum praeruptorum roots; (7 )PA (138) are the main agents responsible for VSMC relaxation. Both (þ)-PA (PC) (139) and (  )-PA showed a concentration-dependent relaxation activity in isolated rat aortic rings contracted by KCl. (þ )-PA is more effective than ( )-PA because (þ)-PA but not (  )-PA, in the molecular docking studies, can bind to the pharmacophores of eNOS, thus stimulating NO/cGMP signaling. All these data strongly suggest that the relaxation of VSMCs by (þ )-PA can be related to both endothelium-dependent and -independent mechanisms, while (  )-PA exerts only an endothelium-independent effect. Additionally, (þ)-PA improved the vascular hypertrophy by decreasing the area of smooth muscle cells (SMCs), collagen

content and [Ca2 þ ] in SMCs, and by increasing nitric oxide (NO) in reno-vascular hypertensive rats (Rao et al., 2002). Rao et al. (1998) showed the effect of PC (139) and PE (142) in relaxing swine coronary arteries and decreasing contractility in guinea-pig left atria due to their calcium antagonist activity, but the calcium antagonistic activity of nifedipine was more potent than those of both PC and PE. In contrast, PC at doses of 2 mg/kg p.o. decreased the blood pressure in conscious normotensive and renal hypertensive rats and created significant drops in vertebral, left circumflex coronary and femoral vascular resistance in anesthetized dogs at doses of 20 and 100/μg/kg i.v. A preliminary clinical trial confirmed that PC was useful in the treatment of exertional angina pectoris. A dosage of 100 mg daily of PC decreased chest pain, the rate of angina attacks, the ST-segment changes, and the dose of nitroglycerine consumption. Chang et al. (1994b) reported that (7)-PA (138) was a cardiohemodynamic compound because of its Ca2 þ channel blocker activity. The effect of (7)-PA on mean aortic pressure and rate– pressure product was about one-tenth as strong as that of diltiazem. In a further study, ( 7)-PA showed calcium channel blockage and vasodilatory activity in cardio-hemodynamic modulation. Additionally it regulated the expression of several immediate-early genes, including IL-6, Fas, Bax, and Bcl-2, and decreased neutrophil infiltration. These factors have significant effects on ischemic-reperfused myocardium, so ( 7)-PA has the effect of lowering the rate of cardiomyocyte apoptosis (Chang et al., 2002). ( 7)-PA had a dose-dependent Ca2 þ channelblocking effect in single ventricular cells of guinea pig. Inhibitory rates of (7 )-PA at doses of 1, 10, and 100 μM were 21%, 33.5%, and 45%, respectively (Li et al., 1994; Chang et al., 2007). ( 7)-PA at 1.0 mmol/L during 30-min preventive perfusion reduced NF-κB activity from 0.98 70.13 to 0.65 70.17 (P o0.05 vs. solvent) and decreased tumor necrosis factor-α (TNF-α) from 13.7 76.1 mg/L to 9.4 72.7 mg/L (Po 0.01 vs. solvent) in ischemic-reperfused (I/R) myocardium. This could be one of the molecular mechanisms of (7)-PA in cardioprotection (Wang et al., 2004). Injection of (7)PA (0.1–3.0 mg/kg i.v.) on ischemic myocardial dysfunction in anesthetized dogs significantly and dose-dependently enhanced coronary blood flow and reduced mean aortic pressure, maximal rate of rise in left ventricular pressure, rate–pressure product and systemic vascular resistance, with a slight rise in heart rate. In addition infusion of 0.15 mg/kg/min (7 )-PA for 30 min enhanced myocardial function in anesthetized open-chest dogs with regional myocardial dysfunction (Chang et al., 1994a). In another study, Wang et al. (1995) showed that (±)-PA could open potassium channel in single isolated myocardiocytes of guinea pig, with an EC50 of 0.2 µmol/L. The CHCl3 fraction of Peucedanum japonicum root extract inhibited phenylephrine (PE)-induced vasoconstriction at 100 μg/mL. The active isolated compound, (þ )-PA (139), in the concentration range of 1–100 μM, dose-dependently relaxed PE pre-contracted aortic ring concentration, and this effect was partially endothelium dependent and mediated by the nitric oxide and cyclic GMP pathway. However indomethacin, a cyclooxygenase inhibitor, had no effects on the action of (þ)-PA. Atropine, a muscarinic receptor antagonist; triprolidine, an H1 histaminergic receptor antagonist; and propranolol, a β-adrenoceptor antagonist, have no significant effects on the actions of this compound, so its vasorelaxant effect apparently is not mediated by any of these receptors. In addition, (þ)-PA (PC) suppressed the high K þ (80 mM)-induced and Ca2 þ -dependent contractions in a dose-dependent manner. Based on these results (þ)-PC seems to be a voltage-operated Ca2 þ channel blocker rather than a receptor-operated Ca2 þ channel blocker, but it weakly relaxed PE (142) pre-contracted aortic rings in the presence of nifedipine, a blocker of voltage-operated calcium channels. On the other hand, tetraethylammonium (TEA, a non-specific K þ channel blocker) did

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not affect the vasodilatory activity of compound against PE-induced contraction. Endothelium dependence and Ca2 þ channel blockade are two of the multiple mechanisms involved in the vasorelaxant effect of this compound (Lee et al., 2002). Tammela et al. (2004) found that Peucedanum palustre root extract and isolate coumarins have calcium channel blocking activity, and the Ca2 þ uptake inhibition of columbianadin was approximately 10-fold greater than that of verapamil. 5.6. Neuroprotection Four isolated coumarin compounds, praeruptorin A (138), xanthotoxin (58), psoralen (52), and bergapten (34), from chloroform extract of the root of Peucedanum japonicum showed inhibitory activities on monoamine oxidase in mouse brain with IC50 values of 27.4 μM, 40.7 μM, 35.8 μM, and 13.8 μM, respectively (Huong et al., 1999). A bioautographic anti-acetylcholine esterase (ACE)-inhibited TLC assay performed with CH2Cl2 root extract of Peucedanum ostruthium confirmed the presence of several ACE compounds. Among these isolated compounds the coumarins were more active than peucenin (164), a chromone derivative. Ostruthol (45), a potent ACE coumarin, showed a white inhibition spot on TLC at concentration 0.001 μg, indicating that it was approximately 10-fold more active than ACE inhibitor galanthamine (Urbain et al., 2005). Zhang et al. (2001) investigated the effect of (7 )-PA (138) on ATP-sensitive potassium channels (KATP channel) in human cortical neurons. KATP channels are widely present in the CNS, and activation of KATP channels is one of the endogenous mechanisms of protection against ischemia or hypoxia. ( 7)-PA was a potassium channel opener (KCO) that increased the extracellular K þ and caused cellular membrane hyperpolarization (Zhang et al., 2001). Yang et al. (2013) showed that (þ )-PA (PC) (139) at dose of 10 μM had a protective effect (92.5 77.5%, Po 0.05 vs. NMDA alone) against loss of cellular viability in excitatory neurotoxicity mediated by NMDA in primary cortical neurons. In addition, PC increased the ratio of Bcl-2/Bax in NMDA-injured neurons and inhibited neuronal apoptosis by reversing intracellular Ca2 þ overload. PC inhibited GluN2B-containing NMDA receptors by exposure to NMDA but did not change the expression of GluN2A-containing NMDA receptors. These results suggest that the neuroprotective activity of PC is partly related to the downregulation of the expression of GluN2B-containing NMDA receptors and regulation of the Bcl-2 family (Yang et al., 2013). Administration of osthole (9) at doses of 50, 100 and 150 mg/kg intraperitoneally (i.p.) had no significant effect on the anticonvulsant activity of two classical antiepileptic drugs (AEDs: phenytoin [PHT] and valproate [VPA]) in the mouse maximal electroshock seizure (MES) model. Thus, osthole shows a neutral pharmacodynamic interaction with two classical AEDs drug (Łuszczki et al., 2011). 5.7. Antidiabetic effect Diabetic rats treated with hydro-alcoholic extract of the aerial parts of Peucedanum pastinacifolium at 500 mg/kg body weight for 30 days had significantly reduced serum total cholesterol, triglyceride and LDL-C, whereas HDL-C significantly increased, as with treatment glibenclamide treatment (Movahedian et al., 2010). The antidiabetic effect of the 80% EtOH extract from Peucedanum japonicum led to the isolation of one coumarin and one cyclitol compound. Peucedanol 7-O-β-D-glucopyranoside (26) showed 39% inhibition of postprandial hyperglycemia at the dose of 5.8 mg/kg, and myo-inositol significantly reduced postprandial hyperglycemia by 34% (Lee et al., 2004). Okabe et al. (2011) reported that Peucedanum japonicum (PJ) was a safe and useful natural agent to reduce obesity or body weight. They fed a 10% and

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20% of PJ (leaves and stems) diet to obese mice. This diet inhibited the body weight gain and fat accumulation in the abdominal and subcutaneous deposits after 4 weeks. PJ reduced serum and liver triglycerides and serum leptin in a dose-dependent manner without any harmful effects on the liver. Additionally, PJ increased fecal excretion of triglycerides, reduced the amount of saturated fatty acids, and improved the level of polyunsaturated and n-3 fatty acids in the liver. In another study, mice fed with 10% dried powder of leaves and stems from PJ for 4 weeks had significantly decreased serum triglycerides (TG), leptin, abdominal fat, and adipocyte size. In addition, PJ significantly increased fecal excretion of TG, reduced the fecal excretion of bile acid, and tended to increase the fecal excretion of total cholesterol. On the other hand, enhancement of adipocyte differentiation and normalization of adipose tissue functionality were caused by upregulation of the PPARγ, FXRα, DGAT1, and ATGL genes in the PJT-fed mice (Nukitrangsan et al., 2011). Nukitrangsan et al. (2012) explained the anti-obesity effect of PJ leaves and stem in high-fat diet-induced obese mice. Animals were fed PJ powder or extracts of PJ in water, 50% ethanol or 100% ethanol. The 100% ethanol extract of PJ decreased serum and liver triglycerides and reduced fat accumulation, adipocyte size and lipase activity in vitro. Preliminary phytochemical analysis confirmed the presence of some anti-obesity phenolic compounds, including neochlorogenic acid (172), chlorogenic acid (174) and rutin (196), in PJ extract. These compounds may be responsible for decreasing the absorption of fat and modulating obesity-related gene expression in the liver, adipose tissue, and muscle. 5.8. Antiplatelet aggregation Jong et al. (1992) observed the significant antiplatelet aggregation activity of cis-30 ,40 -diisovalerylkhellactone (126) (at 50 μg/mL) from PJ. Additionally some compounds isolated from the root of Peucedanum japonicum, including eugenin (163), (  )-selinidin (152), ( þ)-pteryxin (136), imperatorin (39), bergapten (34), cnidilin (38) and (þ)-visamminol (168), showed strong antiplatelet aggregation activity in vitro (Chen et al., 1996). 30 ,40 -Diisovalerylkhellactone diester (PJ-1) from the medicinal herb Peucedanum japonicum inhibited the aggregation and ATP release of rabbit platelets induced by PAF (platelet-activating factor) (2 ng/mL) and collagen (10 μg/mL), with IC50 values of approximately 56.3 μM and 89.4 μM, respectively. PJ-1 also inhibited the thromboxane B2 formation and the phosphoinositide breakdown caused by collagen and PAF, respectively. Briefly, the main antiplatelet effect of PJ-1 may be due to its dual activities of blocking PAF receptorinduced activation and inhibiting phospholipase A2 (Hsiao et al., 1998). Polyacetylene (panaxynol) (223), seselin-type dihydropyranocoumarins ((–)-cis-khellactone (119), (þ )-anomalin (141)) and psoralen-type furanocoumarins (psoralen (52), xanthotoxin (58)) from the root extract of Peucedanum formosanum showed strong anti-platelet aggregation activities. (–)-Isosamidin (150), (þ)-peuformosin (133), (þ )-cis-30 acetoxy-40 -(2-methylbutyroyloxy)-30 ,40 dihydroseselin (158), and p-hydroxy-phenethyl ferulate (203) at 100 mg/mL completely or nearly completely inhibited platelet aggregation induced by collagen. (–)-cis-30 -Isovaleryl-40 -senecioylkhellactone (128), (þ )-cis-30 -acetoxy-40 -(2-methylbutyroyloxy)30 ,40 -dihydroseselin and p-hydroxyphenethyl ferulate (203) at 100 mg/mL reduced platelet-activating factor (PAF)-induced platelet aggregation. Of these isolated compounds, p-hydroxyphenethyl ferulate showed the strongest anti-platelet aggregation effect. This benzenoid compound at 5 mg/mL completely inhibited the platelet aggregation activity, with IC50 values of 5.1, 10.5 and 99.4 mM for platelet aggregation induced by arachidonic acid (AA), collagen and PAF, respectively (Chen et al., 2008).

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The pyranocoumarins ( 7)-PA and (7)-PB antagonize platelet aggregation, particularly that induced by platelet-activating factor (PAF) (Aida et al., 1995). Praeruptorin C at dose of 20 mg/kg/day for 9 weeks increased the vascular hypertrophy by decreasing SMC size, collagen content, and SMC Ca2 þ influx and increasing NO production in the thoracic aorta of renovascular and spontaneously hypertensive rats (Rao et al., 2001). 5.9. Anti-cancer activity Nishino et al. (1990) considered the effect of ( 7)-PB on the in vivo tumor-promoting action of 12-O-tetradecanoylphorbol-13acetate (TPA) in 7,12-dimethylbenz[a]anthracene-initiated mouse skin. Administration of 10 mmol/painting of (7)-PB before the TPA treatment inhibited tumor formation for up to 20 weeks of tumor promotion. The CHCl3 extract of the PJ roots showed cytotoxic activity against the P-388 lymphocytic leukemia system, with an ED50 of 7.6 pg/mL. Furthermore (þ)-PA has cytotoxicity activity on P-388 lymphocytic leukemia system in culture, with an ED50 of 2.6 pg/mL (Chang-yih et al., 1991, 1992). Cytotoxic pyranocoumarins, including (þ )-trans-khellactone (120), (þ )-trans-40 -acetyl-30 tigloylkhellactone (122) and ( þ)-PA, isolated from the chloroform extract of the aerial parts of PJ showed inhibitory activity against P-388 lymphocytic leukemia cells, with EDSDs of 2.8, 1.7 and 2.6 pg/mL, respectively (Chang-yih et al., 1991). In another investigation the CHCl3 extract of the PJ roots exhibited cytotoxic activity against the P-388 lymphocytic leukemia system, with an ED50 of 7.6 pg/mL. Moreover two isolated pyranocoumarins, (  )-cis-khellactone and ( þ)-PA, had a cytotoxic effect on the P-388 lymphocytic leukemia in cell cultures, with an ED50 of 2.8 and 2.6 pg/mL, respectively (Chang-Yih et al., 1992). Morioka et al. (2004) investigated the chemopreventive effects of PJ by counting both aberrant crypt foci (ACF) and β-cateninaccumulated crypts (BCACs) as biomarkers of rat colon carcinogenesis. They studied the effect of PJ on the cell proliferation stimulated by azoxymethane (AOM). The number of ACF in the groups with 0.2% and 1% PJ (approximately 3 ACF) was significantly lower than in control (10.8 74.9, P o0.05), and the mean number of BCACs in both treated groups (median 0.8/cm2/rat) was lower than that in the control group (2.138 70.54/cm2/rat; P o0.0001). Moreover, proliferating cell nuclear antigen (PCNA) labeling considerably decreased in both treated groups in comparison to control. These results confirmed the chemopreventive activity of PJ on the initial stage of colon carcinogenesis through inhibition of both ACF formation and accumulation of β-catenin by decreasing the cell proliferation and antioxidant activity. Kong et al. (2003b) studied the cytotoxic activity of ( 7)-PA both on RAW264.7 cells and starch-elicited primary mouse peritoneal macrophages. RAW264.7 and primary mouse macrophages treated with (7 )-PA in doses ranging from 1 to 100 mg/mL had no effect on cell viability. In addition, (7 )-PA had no cytotoxic activity in doses ranging from 1 to 60 mg/mL. These findings confirmed the good safety profile of (7 )-PA in vitro (Kong et al., 2003b). Zhang et al. (2003) found that (þ )-PA and (  )-PA significantly induced HL-60 (human promyelocytic leukemia) cell differentiation toward both the myelocytic and monocytic lineages, making both enantiomers potential components of leukemia treatments. The effect of (7)-PA on induction of differentiation in HL-60 cells was time- and dose-dependent. Stimulation with 20 mg/mL (7)-PA for 72 h decreased cell growth by 90%, and cell cycle analysis showed a higher proportion of G1-phase cells compared to control. In another study (þ)-PA triggered mitochondria-mediated apoptosis in HL-60 cells and exhibited a dose-dependent apoptotic effect at 10–30 pg/mL on DNA fragmentation, with involvement of the extracellular signalregulated kinase (ERK), c-Jun n-terminal kinase (JNK) and p38 MAPK

pathways. (þ)-PA elevated Bax protein level and mitochondrialbound Bax and increased the Bax:Bcl-2 ratio, causing the loss of mitochondrial membrane potential and cytochrome c release (Fong et al., 2004). Wu et al. (2003) reported that pyranocoumarins, PA, in two conformational forms induced cell death through apoptotic mechanisms, with an IC50 of 41.9 72.8 and 17.3 78.2 μM for drug-sensitive KB-3-1 and multidrug resistant (MDR) KB-V1, respectively. Administration of pyranocoumarins with anti-tumor drugs, such as doxorubicin, paclitaxel, puromycin or vincristine, to the MDR KB-V1 cell line exhibited a synergistic effect, but not in drug-sensitive KB-3-1 cells. After 6 h of pyranocoumarin treatment, doxorubicin accumulation improved in KB-V1 cells by 25%. However KB-V1 cells treated with different doses of pyranocoumarins for 24 h had suppressed expression of P-glycoprotein at both the protein and mRNA levels. Moreover, pyranocoumarins rapidly reduced the cellular ATP content in a dose-dependent manner in KB-V1 cells. Lately, the synthesis of new derivatives of (30 S,40 S)-cis-khellactone coumarins has received much attention in the search for more potent compounds against tumor cells and HIV (Ren et al., 2013). Shen et al. (2006) have reported that a new semi-synthetic compound, (7)-30 -O,40 -O-dicinnamoyl-cis-khellactone (DCK), is more effective than ( 7)-PA or verapamil in reversing Pgp-MDR. Interestingly unlike ( 7)-PA, which suppresses Pgp expression, DCK does not suppress but instead binds directly to Pgp. The structure–activity relationship of two new semi-synthetic methoxylated compounds, (7)-30 -O,40 -O-bis(3,4-dimethoxycinnamoyl)-cis-khellactone (DMDCK) and (7)-3-O-bis(4-methoxycinnamoyl)-cis-khellactone (MMDCK), was studied by Fong et al. (2008). Unlike PA, which downregulated Pgp expression, neither DMDCK nor DCK suppressed Pgp expression but instead bound directly to Pgp. Methoxy substitution of the aromatic rings significantly enhanced the interaction between Pgp and pyranocoumarins and affected the Pgp-MDR reversing action, while 4methoxy substitution only slightly decreased the activity. DMDCK was a good Pgp modulator because of its higher Pgp-MDR reversing activity and lower cytotoxicity (Fong et al., 2008). The 30 ,40 -cis-configuration of aromatic acyls was more effective than their trans-isomers in the MDR-reversing capability of pyranocoumarins (Shen et al., 2012). Furthermore, the rigid stereochemistry of 30 R- and 40 R-configured khellactone derivatives is necessary for their anti-HIV effect (Xie et al., 1999). The methanol extract of Peucedanum praeruptorum at 300 mg/mL decreased the growth of SGC7901 human gastric cancer cells by 51.2% (Po0.01). This effect was due to the high concentrations of PA and PB in the extract. Both PA and PB had cytotoxic and antiproliferative activities on the SGC7901 cells. In addition the combination of PA at 100 mM and doxorubicin (DOX) at 0.25 or 0.5 mM inhibited SGC7901 cell growth by 55.4% or 62.8% (Po0.01 vs. DOX alone), respectively, and decreased the dose of DOX necessary for the desired effects in chemotherapy (Liang et al., 2010). In vitro the acetone extract of the aerial parts and roots of Peucedanum nebrodense had antiproliferative effects against K562 (human chronic myelogenous leukemia) and L1210 (murine leukemia) cell lines, with IC50 values of 0.27 g/mL, compared to only a moderate activity on HL-60 (human leukemia) cells, with an IC50 value of 14.0 g/mL (Schillaci et al., 2003). Two aliphatic esters, 1,2-dipalmitoyl-3glucosyl glycerol (222) and 1,6-dihydroxy-hexane-bis-palmitoyl ester (221), were isolated from the roots of Peucedanum ledebourielloides and showed potential effects against the human gastric carcinoma SGC-7901, human colon cancer HT-29, and human promyelocytic leukemia HL-60 cancer cell lines. 1,2-Dipalmitoyl-3-glucosyl glycerol displayed more activity against HT-29 (IC50 ¼0.21 μg/mL) than 1,6-dihydroxy-hexane-bis-palmitoyl ester and 5-fluorouracil (standard), while 1,6-dihydroxy-hexane-bis-palmitoyl ester was more

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potent in inhibiting HL-60 (IC50 ¼0.49 μg/mL) in comparison to other tested compounds (Zheng et al., 2010). In a sulforhodamine B cytotoxicity assay, the IC50 values of (7 )-PA on drug-sensitive KB-3-1 (human oral epidermoid carcinoma) cells and KB-V1 (its multidrug resistant (MDR) subline) cells were 17.26 78.24 μM and 41.91 72.80 μM, respectively. However, the IC50 of doxorubicin was 3.057 0.28 μM for KB-V1 and 0.06 70.01 μM for KB-3-1. DNA fragmentation analysis established that pyranocoumarins induced cell death through apoptotic mechanisms (Wu et al., 2003). A number of natural and synthesized components have been screened for their P-glycoprotein (Pgp)-inhibiting property. Though Pgp has a significant role in protecting living tissues from damage by extruding xenotoxics out of cells, its overexpression can reduce the cellular levels of anticancer drugs and cause multidrug resistance (MDR) in tumor cells (Krishna and Mayer, 2000). Furanocoumarin peucedanin from Peucedanum tauricum fruits at a dose of 15 μg/mL inhibited heat-shock protein (Hsp) 72 and Hsp 27 expression by 77.5% and 74.0%, respectively, in HeLa B human carcinoma cells. The incubation time and concentration of peucedanin affected the processes of apoptosis and necrosis and the morphology of HeLa cells (Bartnik et al., 2006). 5.10. Phototoxicity Many studies, both in vitro and in vivo, have been performed on the photoreactivity of coumarins. Some of these compounds can be applied for hyperproliferation skin diseases such as psoriasis. Furanocoumarins, including xanthotoxin (58), psoralen (52), bergapten (34), isopimpinellin (42) and imperatorin (39), have photosensitization, phototoxic, mutagenic and photocarcinogenic properties (Campbell et al., 1994). Ojala et al. (1999) detected the phototoxicity of lyophilized extract of Peucedanum palustre leaf and a number of coumarins in a bioassay of Artemia salina. Umbelliferone (15) and athamantin (80) had neither toxic nor phototoxic properties, while the LC50 values (μg/mL) of bergapten, psoralen, peucedanin (48), xanthotoxin and isopimpinellin were 0.05, 0.09, 5, 14 and 103, respectively. In addition, the LC50 of plant extract after flowering was more than before flowering because of the increased coumarin content in the flowering stage. The phototoxic activity of bergapten, psoralen and xanthotoxin increased with irradiation time, while they were not toxic to Artemia salina without radiation. In contrast, peucedanin was toxic to Artemia salina irrespective of the irradiation time. 5.11. Toxicity No behavioral effects or acute toxicity has been detected after oral administration of fractions or praeruptorins A and B from Peucedanum praeruptorum root in mice. Moreover, after intraperitoneal administration of high doses (1 g/kg) of the EtOAc fraction and (7)-PA, only delayed mortality was observed. In the cytotoxic assay against Artemia salina, the EtOAc fraction and praeruptorins A and B showed 40.2, 121.2 and 34.5 μg/mL IC50 values, respectively (Lu et al., 2001). Nishino et al. (1990) pretreated mice with (7 )-PB at the dose of 10 mmol/painting for 20 weeks, which had no toxicity. The median lethal dose (LD50) of the extraction of Peucedanum praeruptorum was over 5 g/kg in an acute toxicity test in mice (Xiong et al., 2012a, 2012b). The general pharmacological evaluation of praeruptorins showed that oral administration of (7 )-PA or (7)-PB did not irritate behavioral effects in mice, and no acute toxicity or mortality occurred at the dose of 1 g/kg (Lu et al., 2001). The methanol extract of the fruits of Peucedanum grande and a naphthyl labdanoate diarabinoside isolated from that extract had nephroprotective activity against gentamicin-induced nephrotoxicity in Wistar rats (Aslam et al., 2012a, 2012b, 2012c).

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6. Conclusion The present review summarized the traditional medicine uses (TMUs) and phytochemical and pharmacological aspects of the genus Peucedanum. To date over 300 molecules, including terpenoids, coumarins, flavonoids, phenolic acids, phenylpropanoids, glycosides, amino acids and essential oils, have been identified from Peucedanum plants. Because the botanical classification of Peucedanum species by anatomical and morphological features is difficult and some species are confused with other species, chemical constituents of essential oils and coumarins have been valuable as chemotaxonomic markers. In this review I mentioned 58 Peucedanum species, of which only 37 species are accepted in this genus (The Plant List, 2013). Non-polar fractions, essential oils and coumarins are mainly responsible for antimicrobial activities. For example Peucedanum alsaticum and Peucedanum cervaria fruits, which are consumed as antimicrobial agents in European local medicine, have shown antibacterial activity against Grampositive bacteria (Skalicka-Woźniak et al., 2010). However other traditional uses of Peucedanum alsaticum and Peucedanum cervaria, e.g., diaphoretic, diuretic, stomachic and sedative actions, have not been investigated. The anti-bacterial activity of the essential oil from Peucedanum japonicum against the drug-resistant skin pathogen Staphylococcus epidermidis confirmed its potential use as an alternative remedy for the treatment of acne and other skin infections (Yang et al., 2009). The doses between 1000 and 3000 mg/L of various oils or isolated compounds from Peucedanum plants had potential activity against some bacteria (Vellutini et al., 2005; Skalicka-Woźniak et al., 2007, 2009a) even though a few had MIC o1000 (Lu et al., 2001; Alavi et al., 2005; Gökay et al., 2010). For example ostruthin, a coumarin isolated from Peucedanum ostruthium rhizome, showed significant inhibitory activities against different strains of Mycobacteria, with MIC values between 3.4 and 6.7 μM. Furthermore, oxypeucedanin hydrate from the ethyl acetate extract of Peucedanum ostruthium rhizome showed significant antimicrobial activity against Bacillus cereus (Gökay et al., 2010). Some Peucedanum species usually associated with the presence of phenolic compounds, including phenolic acids, flavonoids and phenylpropanoids, have shown antioxidant and anti-tyrosinase properties. Rhamnetin-3-О-β-D-glucopyranoside (197) and isorhamnetin-3-О-β-D-glucopyranoside (193), the main flavonoids isolated from Peucedanum knappii, showed DPPH radicalscavenging and anti-tyrosinase activity (Sarkhail et al., 2013a). In addition isoquercitrin, rutin, neochlorogenic acid (172), cryptochlorogenic acid (173) and chlorogenic acid (174), the main potent constituents of the n-butanol fraction of Peucedanum japonicum leaves, exhibited a significant DPPH radical-scavenging activity (Hisamoto et al., 2003). Throughout the present review I found that some traditional medicinal uses of Peucedanum species have been validated and supported by pharmacological investigations, and most studies have focused on the roots of Peucedanum plants, which are rich in bioactive coumarins. In vitro and in vivo pharmacological studies have revealed that coumarins or nonpolar extract/fractions are responsible for a range of activities, including anti-inflammatory, antidiabetic, anti-platelet aggregation, and antiproliferative activities, cardiopulmonary protection, neuroprotection and phototoxicity. For example the roots of Peucedanum praeruptorum and Peucedanum decursivum, which are traditionally used for some respiratory diseases and pulmonary hypertension, were validated to possess vasorelaxant and antiallergic activity by pharmacological tests (Zhao et al., 1999). Moreover, the Peucedanum praeruptorum coumarin fraction suppressed airway hyperreactivity and had anti-inflammatory and anti-microbial effects (Zhao et al., 1999; Lu et al., 2001). The root of Peucedanum japonicum, which is prescribed against coughs, colds and

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antifebrile in Japanese local medicine, showed antiallergic and vasorelaxant activity in vivo (Aida et al., 1998; Lee et al., 2002). The anti-inflammatory and anti-pyretic effects of Peucedanum ostruthium root validated its use in traditional medicine for inflammatory diseases such as ulcers and cancer (Hiermann and Schant, 1998). The effectiveness of Peucedanum praeruptorum in TCM in decreasing chest pain, presumably in angina pectoris and ischemic heart (Rao et al., 1988), is due to the presence of some active pyranocoumarins (( 7)-PA and PE), which have a significant vasodilating effect. The cardioprotective effects of (7 )-PA and PE were mediated by their calcium antagonist activity and suppression of TNF-α, IL-6, Fas, Bax, Bcl-2 and NF-κB (Hao et al., 1996; Rao et al., 1988; Chang et al., 2002). In addition, the praeruptorins (7)-PA (138), D (141) and E (142) had potent anti-inflammatory effects in vitro and in vivo in pharmacological studies (Yu et al., 2012; Xiong et al., 2012a, 2012b). Based on the results of in vitro pharmacological research on (7 )-PA, it is effective in the concentration range of 1–100 μM. The beneficial action of the extracts and coumarins in some chronic inflammatory diseases, such as cardiovascular disease, asthma and cancer, may be related to their suppression of cyclooxygenase (COX) or/and lipoxygenase (LOX) activity, mediated by decreased the production of NO, LT, TNF-α and reactive oxygen species (ROS). Columbianadin (82) from Peucedanum palustre root extract had calcium channel blocking activity (Tammela et al., 2004), and 6-(3carboxybut-2-enyl)-7-hydroxycoumarin (20) from Peucedanum ostruthium root had significant anti-edema and antipyretic effects (Hiermann and Schantl, 1998). A number of coumarins from Peucedanum, such as eugenin (163), (  )-selinidin (152), (þ)-pteryxin (136), imperatorin (39), bergapten (34), cnidilin (38), (þ )-visamminol (168) (Chen et al., 1996), cis-30 ,40 -diisovalerylkhellactone (126) (Jong et al., 1992), (–)-isosamidin (150), (þ )-peuformosin (133), (þ)-cis-30 acetoxy-40 -(2-methylbutyroyloxy)-30 ,40 -dihydroseselin (158), and p-hydroxy-phenethyl ferulate (203) (Chen et al., 2008), showed anti-platelet aggregation activity. The cytotoxic effects of some coumarins, such as PA (138) and PB (140) (Chang-yih et al., 1991, 1992; Zhang et al., 2003; Liang et al., 2010), have prompted a noticeable increase in the number of structure–activity relationship studies (SARs). Thus far, a few semisynthetic pyranocoumarins for improving the efficacy of these compounds have been prepared (Fong et al., 2008; Shen et al., 2012). In addition these findings suggest that some pyranocoumarins, e.g., PA, have the remarkable potential to be developed into new chemotherapeutic agents to treat cardiopulmonary diseases and cancers. Unfortunately, clinical studies are lacking. Just one clinical trial has been performed on (þ )-PA (PC) (139), which demonstrated its efficacy in the treatment of exertional angina pectoris. Although the pharmacokinetic profiles of praeruptorins in human and rat liver microsomes have been summarized, future studies in humans should be performed to establish their safety and efficacy. Toxicological studies of Peucedanum species and their isolated compounds are limited. Most reports showed no toxicity or mortality at the effective doses (Nishino et al., 1990; Lu et al., 2001; Xiong et al., 2012a, 2012b). However furanocoumarins, including xanthotoxin (58), psoralen (52), bergapten (34), isopimpinellin (42) and imperatorin (39), caused photosensitization and showed phototoxic, mutagenic and photocarcinogenic properties under irradiation conditions (Campbell et al., 1994; Ojala et al., 1999). As hepatotoxicity associated with coumarins related to the formation of a coumarin 3,4-epoxide intermediate has been reported (Lake et al., 2002), additional studies are required to quantify the acute and chronic toxicity in animals before clinical trials. As mentioned above TMUs of Peucedanum species have been investigated by some pharmacological and biological studies, but

further studies are required to identify the individual compounds responsible for these activities, their mechanisms of action and their toxicity. In conclusion, throughout my literature review, I observed that the research on Peucedanum has focused on a few species and their active components. Therefore, the phytochemical and pharmacological profiles of other species should be analyzed to find new bioactive substances.

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