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Document Type : Review Article

Authors

1 Department of Chemistry, University of Zanjan, Zanjan, Iran

2 Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

10.33945/SAMI/JCR.2019.1.7898

Abstract

Heracleum is one of the greatest genera of the Umbelliferae family that has more than 120 species. This genus is represented by 109 species in Asia. Common names for the genus or its species include hogweed and cow parsnip. This paper discusses the phytochemistry, ethnopharmacological use and pharmaceutics of Heracleum species. Many kinds of metabolites have been isolated and identified, that furanocoumarins are among the significant ones. Modern pharmacological studies demonstrated that Heracleum and its active compounds have extensive biological activity, particularly in anticonvulsant, anti-inflammatory, antifungal, anticancer, anti-psoriatric, anti-vitiligo and antioxidant activities. In clinical test, Heracleum has successfully been utilized to treat psoriasis, vitiligo, carminative, stomachs, pain killer and anticonvulsant.

Graphical Abstract

Plants of the Genus Heracleum as a Source of Coumarin and Furanocoumarin

Keywords

Main Subjects

1. Introduction

Heracleum (Apiaceae) also known as hogweed and is one of the greatest genera of the Umbelliferae family that has more than 120 species Drude (1897-1898) categorized the genus Heracleum in Umbelliferae tribe Peucedaneae subtribe Tordyliinae. Pimenov and Leonov (1993) ordered Heracleum in tribe Tordylieae W.D.J. Koch, that its arrangement in this tribe has been confirmed by the results of phylogenetic analyses of molecular data [1-4]. This genus is represented by 109 species in Asia, including 10 species in Iran. Four of the Iranian spices are indigenous, [5] and four of them are endemic [6]. In traditional medicine, some Heracleum species are used as antipyretic, analgesic, diaphoretic, [7] antiseptic, carminative, digestive and also as a flavouring agent and spice for foods for rheumatic disease, lumbago, gastralgia, and injuries from falls, fractures, contusions and strains [8]. Several compounds including coumarins, furanocoumarins, anthraquinones, stilbenes, furanocoumarin dimers, and flavonoids have been isolated and identified from various species of this genus [9-12].

Studies on the essential oils and extracts of different species of Heracleum have shown different biological properties such as cytotoxic activity for Heracleum sibiricum, [13]  antioxidant and antimicrobial activity for Heracleum nepalense [14], immunostimulant in Heracleum maximum [15] and anticonvulsant effect for H. persicum [16]. H. persicum has been known as “Golpar” in Iran and is used as flavouring agent and spice for food in many parts of Iran. In some areas of the country, Golpar is used as a flavouring agent for making pickles. The leaves and fruits of this genus are used as a flavoring agent, antiseptic, carminative, digestive and analgesic in the Iranian folk medicine [17-19].

The genus Heracleum is also a famous origin of furanocoumarins (e.g. bergapten, byakangelicol, phellopterin, xanthotoxin, isopimpinellin, and imperatorin) that show biological effects of broad spectrum [20]. They are significant drugs in vitiligo and psoriaris treatment [20, 21].

Thus, this review discusses to classify updated information on chemical constituents, biological activity and clinical studies performed on the extracts, and the main active constituents isolated from different species of plants of the genus Heracleum in the therapy of the rheumatic and in painful disorders.

2. Botanical Description and Distribution

Heracleum genus has biennial or perennial plants, tall and robust. Height is usually 100-500 cm. This genus grows from a yellow branched root system 40-60 cm deep, that reaches 15 cm in diameter at the crown when ripe. Leaves are ternately compound and on the upper surface the leaves are hairless and below slightly hairy. Lower leaves are divided into three or more segments. On the upper surface, the leaves are hairless and below slightly hairy. The hollow stem of giant hogweed is coarse and ridged with protruding white hairs that are noticeable at the node and base of the petiole. The green stem with purple blotches is often contrast easily with the white hairs. The blossoming on cow parsnip is ordered as a composite umbel with thousands of very small, white flowers or pinkish and petals 9-12 mm. fruits are egg-shaped or oval; 18 mm long by 4-10 mm, barely winged, hairless to hairy, dividing into two mericarps; each with 3–5 lengthened oil canals [22-26].

Convenient features to identify plants with purple-stemmed genus, would be the glabrous and lobed leaves shape of them. Surface glabrous and the canals oil can also be used to identify species [25].

Heracleum grows mainly in the mountain areas alongside streams, cultural landscapes, grasslands, and wetlands. They are found quite in the moderate northern hemisphere and high mountains as far south as Ethiopia. Two principal centers of Heracleum are disclosed; the Caucasus and the Sino-Himalayan regions. In agreement to the data, aggregated in the ASIUM database of Botanical Garden of Moscow State University, there are 30 species of genus Heracleum in the Causasus and Transcaucasian area; 24 species are reported from Turkey and 11 from Iran. 32 species of this genus have been recorded in the Sino-Himalayan area (25 in SW China, nine in Indian Himalaya, and eight in Nepal). The category and distribution of West Asian Heracleum plants is presented in Table1. The overwhelming majority of Heracleum species are endemic to china (out of 29 species, 21 are endemic) although some are found in western, eastern and central Caucasus and western, central, eastern and southwestern Transcaucasia. In China, 29 species are known from China, which are chiefly reported from the Hengduan Mountains of southwestern China. These species have mainly famed in the pharmaceutic uses and some are significant principle in traditional Chinese medicine. Species of this genus can lead to an intense photodermatitis as they include abundant diversity of chemical compounds and be weedy or highly invasive [27-34].

3. Ethno-Pharmacological Use

Certain species of Heracleum have been used in traditional Asian medicine and have proven to have remarkably therapeutic activities [35]. Several Heracleum species have been used traditionally for many purposes in different countries. In traditional medicine, some Heracleum species are used as antipyretic, analgesic, diaphoretic, antiseptic, carminative, and digestive, and also as a flavoring agent and spice for foods for rheumatic disease, lumbago, gastralgia, and injuries from falls, fractures, contusions and strains. The fruits and leaves of this genus are also used as antiseptic, carminative, digestive and analgesic in the Iranian folk medicine [17, 36-41].

H. sphondylium which is known as “cow parsnip” in Europe is used against diarrhea. It is known as tavsanclotu and used against dysentery in Turkey. The roots of Heracleum candicans Wall and Heracleum yunngningense HAND.–MASS are applied in Chinese traditional medicine as an antipyretic and diaphoretic agent in local region of PR China [44-46]. In the Indian system of medicines, Heracleum candicans DC finds use as an aphrodisiac, nerve generally furanocoumarins, furanocoumarin dimer, tonic and also in the therapy of dermal illnesses.

Eastern Canadian First Nations communities use Heracleum maximum as a conventional Asian medicine and have demonstrated to have ailments that include tuberculosis [47-50]. In Thai folk medicine, the fruits of H. siamicum were used as a carminative herbal drug [51]. In Ayurveda, H. rigens has been traditionally used for urinary disorders, cough, hyperacidity, wounds, abdominal disorders, and cardiac diseases and vomiting, in addition, in Siddha, it is used for treating constipation, stomachache, diarrhoea, headache, phlegm, gastric disorders and indigestion [52]. Heracleum rapula, with the Chinese name ‘‘Baiyunhuagen’’, is commonly used in Chinese traditional medicine to dispel wind, remove dampness, expel cold, relieve pain, dredge all channels and vessels, promote blood circulation, and relax muscles and tendons [53]

Table 1. The category and distribution of West Asian Heracleum species

Distribution

Category

Russia 

H.apiifolium Boiss, H.  chorodanum (Hoffm.) DC, H. grandifloru Steven ex M.Bieb, H. leskovii Grossh, H. ponticum (Lipsky) Schischk.ex Grossh, H. roseum Steven, H.scabrum Albov, H.sibiricum L, H.sibiricum L2, H.sibiricum L3. H.transcaucasicum                                 

Turkey

H.argaeum Boiss, H.crenatifolium Boiss, H.humile Sm, H.lasiopetalum Boiss, H.marashicum Yildiz, H.pastinaca Fenzl, H.peshmenianum Ekim, H.platytaenium Boiss, H.sphondylium L. subsp. Velen, H. sphondylium ssp. ternatum, H. platytaenium, H.sphondylium.subs  .artvinense, Heracleum platytaenium               

Armenia

H.pastinacifolium K. Koch, H.schelkovnikovii Woronow, H,trachyloma Fisch, H.transcaucasicum Manden

Iran

H.anisactis Boiss, H.lasiopetalum Boiss, H.rechingeri Manden, H.persicum Desf, H. pastinacifolium C. Koch, H.transcaucasicum  Manden,  H.gorganicum, H. rawianum         

Georgia

H.antasiaticum Manden, H.asperum (Hoffm.) M.Bieb, H.yclocarpum K.Koch, H. freynianum Sommier, H.ossethicum Manden,  H.sosnowskyi Manden, H.sibiricum L, H.calcareum var. colchicum, H.chorodanum, H.dissectum, H.dulce, H.lehmannianum, H.mandenovae, H.moellendorffii, H.pastinacifolium, H.ponticum, H.pubescens, H.roseum, H.sommieri, H.sosnowskyi, H.stevenii, H.trachyloma, H.wilhelmsii,H.voroschilowii                           

Afghanistan

H.afghanicum Kitam

Chin

H.souliei, H.bivittatum Boiss, H.millefolium Diels, H.canescens Lindl, H.sibiricum, H.pyrenaicum, H.hemsleyanum, H.grandiflorum, H.cyclocarpum, H.platytaenium, H.ossethicum, H.lehmannianum, H.mantegazzianum, H.trachyloma,H.sosnowskyi,H. wolongense, H.tiliifolium, H.mollendorffii var mollendorffii, H. fargesii , H. dissectifolium, H.yungningense , H.forrestii, H.subtometellum, H.oreocharis, H.stenopterum, H.scabridum, H.rapula, ,H.franchetii, H.stenopteroides                                                            

Iraq

H. rawianum C.C.Towns 

Azarbaijan

H. pastinacifolium C. Koch, H. grandiflorum Bie

Ukraine

H. carpaticum Porc, H. ligusticifolium M.Bieb,  H. sibiricum L

4. Chemical Constituents

A great variety of species of plants belonging to the genus Heracleum have been phytochemically and pharmacologically investigated and many molecules have been isolated and identified. In this context, different classes of organic compounds of medicinal interest have been reported, including coumarins and generally furanocoumarins, furanocoumarin dimer, coumarin glycosides, anthraquinones and stilbene derivatives, and flavonoids (Table 2, Figures 1-9).

However, it should be considered that coumarins and furanocoumarins are the most plenty compounds so far verified in this genus. The genus Heracleum is a rich of furanocoumarins (such as bergapten, byakangelicol, phellopterin, xanthotoxin, isopimpinellin, and imperatorin), showing the pharmacological effects. They are used as drug for the vitiligo and psoriaris treatment [54-56].

Among the all studied species, H. candicans Wall, H. rapula, H. yunngningense and H. grandiflorum have been used more than the other species. Although a majority of these compounds are chemically identified, their complete biological activity remain totally unknown.

Table 2. Chemical components isolated from plants of the genus Heracleum

 

 

 

 

           

Figure 1. Monoterpenoids isolated from the seeds of Heracleum candolleanum.

Figure 2. Spirotrifuranocoumarin isolated from H. candicans.

Figure 3. Furanocoumarins isolated from H. candicans.

Figure 4. Furanocoumarins isolated from H. candicans.

Figure 5. Furanocoumarins isolated from H. candicans.

Figure 6. Furanocoumarin glucosides isolated from H. candicans.

Figure 7. Furanocoumarin isolated from Heracleum species.

Figure 8. Furanocoumarin isolated from Heracleum species.

Figure 9. Furanocoumarins isolated from Heracleum yunngningense.

Clearly, the complication of the admixture and the existence of the multiple compounds in low concentrations cause to be the isolation and identification of these substances very arduous. Some studies have specified the existence of multiple furanocoumarins in H.yunngningense (Table 1), the authors of this review cannot recognize any of these compounds from the same species but gathered in China. So, different environmental conditions affect the chemical compounds [101].

Concerning the part of the plant most investigated, we have observed that in general the whole plant material is used, since these species are commonly small herbs and are employed in this manner in folk medicine. Our research team has carried out phytochemical studies of this genus via bioassay-guided isolation, allowing the identification of different compounds with pharmaceutical effects existing in the active fractions or extracts. In this way, we have isolated the principal furanocoumarin existing in H. platytaenium, reffering to sphondin that exhibits antioxidant and anticholinesterase activity [82]. It is worth noting that this furanocoumarin has been utilized as a pattern to prepare novel active molecules, especially 4'-Aminomethyl-4,5',8-trimethylpsoralen and 4,5,8 trimethylpsoralen (trioxalen) derivatives [102]. Besides angelicin, we also have isolated 8 furanocoumarin, steroid compound and a dihydrofurocoumarin glycoside that will be conversed in more detail in the biological section (Table 3).

However, it is also important to demonstrate that the genus Heracleum is a main origin of furanocoumarins (e.g. bergapten, byakangelicol, phellopterin, xanthotoxin, isopimpinellin, and imperatorin), that demonstrate pharmaceutical properties of broad spectrum [53-55]. They are typical phototoxic compounds leading to photodermatitis upon exposure to UV light [103]. In humans and experimental animals, chronic furanocoumarin treatment, in combination with UV light, is used in the therapy of psoriasis and vitiligo [21,57].

5. Chemical Constitiuents

Up to now, it still abides a worldwide health preference to extend new remedial methods for therapeutic a countless of diseases, and to establish those discoveries in an surrounding of stability [104]. Owing to the variety, wide metabolic span, and provided. Accessibility, plants demonstrate a potentially worth origin of biologically important constituents that should be probed for their capability pharmaceutical utilize. About 6.5 billion patients are applying medicinal plants in some formation on a relatively orderly foundation, and the use of plant-based traditional pharmaceuticals in the world is ongoing to increase as the population extends [105]. Heracleum pharmacological effects have enticed wide consideration. Orally, Heracleum has traditionally been utilized to therapy impotency, treatment of skin diseases, epilepsy, urinary disorders, gastric disorders, stomachache, phlegm, cough, hyperacidity, wounds, abdominal disorders, and cardiac diseases, vomiting, antipyretic, diaphoretic, analgesic, dysentery, diarrhea laryngitis, and bronchitis [36-40]. A general overview on the present situation of modern biological assay is reported in supplemental (Table 3)

Table 3. Biological Activity of the Isolated Constituents of Some Species of Heracleum.

Species

Compound

Pharmacological Activity

Ref.

H. candicans

heraclenin

anti-inflammatory

[21]

 

 

anti-coagulant

[106]

 

 

skin photosensitizing

[107]

 

bergapten

melanogenesis stimulation activity

[108]

H. lanatum

psoralen

anti-psoriatric

 

H.canescens

 

anti-vitiligo

 

H.moellendorffii Hance

 

antifungal

[106, 109]

H. platytaenium

 

anticancer

[110]

H. candicans Wall

xanthotoxin

treat leucoderma

[62]

 

 

suntan lotions

 

H. crenatifolium

bergapten

anticonvulsant

[101]

H. persicum

aconitine

anticonvulsant

[110]

 

sphondin

anti-inflammatory, analgesic

[58, 111]

 

 

folli­culogenesis

[111]

 

ergosterol

antifungal

[112]

 

 

anti-AF

 

H. nepalense

bergapten

anti-inflammatory

[113]

H. souliei

heraclemycin C

antitubercular

[92]

H. mantegazzianum

xanthotoxin

antimicrobial

[114]

 

pimpinellin

 

 

 

phellopterin

 

 

H. moellendorffii

psoralen

antiarrhythmic

[115]

H. platytaenium

xanthotoxin

Anti  AChE

[82]

 

isopimpinellin

Anti  BChE

 

 

pimpinellin

 

 

 

psoralen

antioxidant

 

 

pimpinellin

 

 

H.laciniatum

sphondin

anti-inflammatory

[111]

H rapula

Rapulasides A,B

Inhibitor platelet aggregatio

[69]

H. maximum

falcarindiol

antimycobacterial

[15]

 

6-isopentenyloxyisobergapten

 

 

H. moellendorffii

panaxynol

 

[90]

 

falcarindiol

 

 

6. Conclusions

In a clinical test, Heracleum has successfully been utilized to treat the psoriasis, vitiligo, carminative, stomachs, pain killer, and anticonvulsant. Modern in vitro and in vivo pharmacological studies have increasingly confirmed the traditional use of the Heracleum plants. The raw extracts and constituents from the aerial parts or roots have plenty sorts of  pharmacological effects, particularly in the betterment of carminative, digestive, stomachs, antiproliferative, antimycobacterial, inhibitor platelet aggregation, anti-inflammatory, antioxidant, anticholinesterase, antimicrobial, antitubercular, analgesic, anticancer, anti-vitiligo, anti-psoriatric, anti-coagulant,  anti-inflammatory, and antifungal effects. Most of the pharmacological activity of Heracleum plants can be illustrated by a more content of furanocoumarins present in the genus, particularly psoralen and xanthotoxin. Recently phytochemical and pharmaceutical investigation of the constituents isolated from the genus Heracleum have attracted much attention, but the pharmaceutical researches so far have mainly been performed in vitro and in vivo with animals. Thus, pharmaceutical investigation in humans are crucially necessary to verify this conventional phytotherapy. The compounds of the genus Heracleum, their pharmaceutical and cytotoxicity properties should be more studied with both in vitro and in vivo studies. Also, due to profile, their remedial performance and economical attentions, the total furanocoumarins and/or active constituents may be developed into novel drugs for the therapy of different diseases, particularly psoriasis and vitiligo.

Acknowledgment

The authors would like appreciate the University of Zanjan, Iran for its support.

 

[1] Yu, Y.; Downie, S. R.; He, X.; Deng, X.; Yan, L. (2011). Phylogeny and biogeography of Chinese Heracleum (Apiaceae tribe Tordylieae) with comments on their fruit morphology. Plant systematics and evolution, 296(3-4), 179-203.
[2] Pimenov, M. G.; Leonov, M., The genera of    the Umbelliferae: a nomenclator. Royal Botanic Gardens, Kew: 1993.
[3] Downie, S.; Plunkett, G.; Watson, M.; Spalik, K.; KATZ, D.; VALIEJO, C.; Terentieva, E.; Troitsky, A.; Lahham, J.; EL, A. (2001). Tribes and clades within Apiaceae subfamily Apioideae: the contribution of molecular data. Edinburgh Journal of Botany, 58(02), 301-330.
[4] Ajani, Y.; Ajani, A.; Cordes, J. M.; Watson, M. F.; Downie, S. R. (2008). Phylogenetic analysis of nrDNA ITS sequences reveals relationships within five groups of Iranian Apiaceae subfamily Apioideae. Taxon, 57(2), 383-401.
[5] Pimenov, M.; Leonov, M. (2004). The Asian Umbelliferae biodiversity database (ASIUM) with particular reference to South-West Asian taxa. Turkish Journal of Botany, 28(1-2), 139-145.
[6] Mozaffarian, V., A dictionary of Iranian plant names: Latin, English, Persian. Farhang Mo'aser: 1996.
[7] Grover, J.; Yadav, S.; Vats, V. (2002). Medicinal plants of India with anti-diabetic potential. Journal of ethnopharmacology, 81(1), 81-100.
[8] Brusotti, G.; Cesari, I.; Frassà, G.; Grisoli, P.; Dacarro, C.; Caccialanza, G. (2011). Antimicrobial properties of stem bark extracts from Phyllanthus muellerianus (Kuntze) Excell. Journal of ethnopharmacology, 135(3), 797-800.
[9] Khalid, H.; Abdalla, W. E.; Abdelgadir, H.; Opatz, T.; Efferth, T. (2012). Gems from traditional north-African medicine: medicinal and aromatic plants from Sudan. Natural products and bioprospecting, 2(3), 92-103.
[10] Bolzani, V. d. S.; Valli, M.; Pivatto, M.; Viegas, C. (2012). Natural products from Brazilian biodiversity as a source of new models for medicinal chemistry. Pure and Applied Chemistry, 84(9), 1837-1846.
[11] Li, J. W.-H.; Vederas, J. C. (2009). Drug discovery and natural products: end of an era or an endless frontier? Science, 325(5937), 161-165.
[12] Newman, D. J.; Cragg, G. M. (2012). Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of natural products, 75(3), 311-335.
[13] Bogucka-Kocka, A.; Smolarz, H.; Kocki, J. (2008). Apoptotic activities of ethanol extracts from some Apiaceae on human leukaemia cell lines. Fitoterapia, 79(7), 487-497.
[14] Dash, S.; Nath, L. K.; Bhise, S. (2005). Antioxidant and antimicrobial activities of Heracleum nepalense D Don root. Tropical Journal of Pharmaceutical Research, 4(1), 341-347.
[15] Webster, D.; Taschereau, P.; Lee, T. D.; Jurgens, T. (2006). Immunostimulant properties of Heracleum maximum Bartr. Journal of ethnopharmacology, 106(3), 360-363.
[16] Sayyah, M.; Moaied, S.; Kamalinejad, M. (2005). Anticonvulsant activity of Heracleum persicum seed. Journal of ethnopharmacology, 98(1), 209-211.
[17] Amin, G. R., Popular medicinal plants of Iran. Iranian Research Institute of Medicinal Plants Tehran: 1991; Vol. 1.
[18] Newman, D. J.; Cragg, G. M. (2007). Natural Products as Sources of New Drugs over the Last 25 Years⊥. Journal of natural products, 70(3), 461-477.
[19] Zhang, H.; Chen, F.; Wang, X.; Yao, H.-Y. (2006). Evaluation of antioxidant activity of parsley (Petroselinum crispum) essential oil and identification of its antioxidant constituents. Food Research International, 39(8), 833-839.
[20] Trott, J.; Gerber, W.; Hammes, S.; Ockenfels, H.-M. (2008). The effectiveness of PUVA treatment in severe psoriasis is significantly increased by additional UV 308-nm excimer laser sessions. European Journal of Dermatology, 18(1), 55-60.
[21] Bhatnagar, A.; Kanwar, A.; Parsad, D.; De, D. (2007). Psoralen and ultraviolet A and narrow‐band ultraviolet B in inducing stability in vitiligo, assessed by vitiligo disease activity score: an open prospective comparative study. Journal of the European Academy of Dermatology and Venereology, 21(10), 1381-1385.
[22] Rechinger, K. H. (1974). Linaceae. Flora iranica(106).
[23] Nielsen, C.; Ravn, H. P.; Nentwig, W.; Wade, M. (2005). The Giant Hogweed Best Practice Manual. Guidelines for the management and control of an invasive weed in Europe. Forest and Landscape Denmark, Hoersholm.
[24] Moravcova, L.; Pyšek, P.; Krinke, L.; Pergl, J.; Perglova, I.; Thompson, K. (2007). Seed germination, dispersal and seed bank in Heracleum mantegazzianum. Ecology and management of giant hogweed, 74-91.
[25] Fan, L.; Zhang, Y.; Huang, R.; Qin, S.; Yi, T.; Xu, F.; Tang, Y.; Qu, X.; Chen, H.; Miao, J. (2013). Determination of five flavonoids in different parts of Fordia cauliflora by ultra performance liquid chromatography/triple-quadrupole mass spectrometry and chemical comparison with the root of Millettia pulchra var. laxior. Chemistry Central Journal, 7(1), 1.
[26] Logacheva, M.; Valiejo-Roman, C.; Pimenov, M. (2008). ITS phylogeny of West Asian Heracleum species and related taxa of Umbelliferae–Tordylieae WDJ Koch, with notes on evolution of their psbA-trnH sequences. Plant Systematics and Evolution, 270(3-4), 139-157.
[27] Camm, E.; Buck, H.; Mitchell, J. (1976). Phytophotodermatitis fromHeracleum mantegazzianum. Contact Dermatitis, 2(2), 68-72.
[28] Kavli, G.; Volden, G.; Raa, J. (1982). Accidental induction of photocontact allergy to Heracleum laciniatum. Acta dermato-venereologica, 62(5), 435.
[29] Derraik, J. G. (2007). Heracleum mantegazzianum and Toxicodendron succedaneum: plants of human health significance in New Zealand and the National Pest Plant Accord. The New Zealand Medical Journal (Online), 120(1259).
[30] Liu, Y.; Zhang, C.; Li, L.; Xiao, Y. (2006). [Studies on chemical constituents in roots of Heracleum rapula]. Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China journal of Chinese materia medica, 31(4), 309-311.
[31] Walker, N.; Hulme, P.; Hoelzel, A. (2003). Population genetics of an invasive species, Heracleum mantegazzianum: implications for the role of life history, demographics and independent introductions. Molecular Ecology, 12(7), 1747-1756.
[32] Jahodová, Š.; Trybush, S.; Pyšek, P.; Wade, M.; Karp, A. (2007). Invasive species of Heracleum in Europe: an insight into genetic relationships and invasion history. Diversity and Distributions, 13(1), 99-114.
[33] Nielsen, C.; Hartvig, P.; Kollmann, J. (2008). Predicting the distribution of the invasive alien Heracleum mantegazzianum at two different spatial scales. Diversity and Distributions, 14(2), 307-317.
[34] Taniguchi, M.; Yokota, O.; Shibano, M.; Wang, N.-H.; Baba, K. (2005). Four coumarins from Heracleum yunngningense. Chemical and pharmaceutical bulletin, 53(6), 701-704.
[35] Pu, F.; Watson, M. (2005). Heracleum L. Flora of China, 14, 195-202.
[36] Sonboli, A.; Azizian, D.; Yousefzadi, M.; Kanani, M.; Mehrabian, A. (2007). Volatile constituents and antimicrobial activity of the essential oil of Tetrataenium lasiopetalum (Apiaceae) from Iran. Flavour and fragrance journal, 22(2), 119-122.
[37] Souri, E.; Farsam, H.; Sarkheil, P.; Ebadi, F. (2008). Antioxidant activity of some furanocoumarins isolated from Heracleum persicum. Pharmaceutical Biology.
[38] Niu, X.-M.; Li, S.-H.; Wu, L.-X.; Li, L.; Gao, L.-H.; Sun, H.-D. (2004). Two new coumarin derivatives from the roots of Heracleum rapula. Planta medica, 70(06), 578-581.
[39] Naraghi, M., Medicinal flowers and plants. Tehran. Amir Kabir publications: 1972.
[40] Zargari, A. (1997). Iranian medicinal plants. Tehran: Tehran University Publications.
[41] Evans, W., Trease and Evan‟ s Pharmacognosy; WB Saunders Comp. Ltd. Elsevier): 1996.
[42] Baytop, T. (1999). Turkiye′ de Bitkiler ile Tedavi Gecmisten Bugune (Therapy with Medicinal Plants in Turkey. Past and Present), 2nd Ed., Nobel Tip Basimevi, Istanbul, 373.
[43] Song, L. (1999). Chinese Materia Medica (Zhonghua BenCao). Shanghai Science and Technology Press, Shanghai, 8, 711-712.
[44] Sinicae, D. F. R. A. A., Edita, Flora Reipublicae Popularis Sinicae. Science Press, Beijing: 1979.
[45] Bentley, K. (1993). β-Phenylethylamines and the isoquinoline alkaloids. Natural Product Reports, 10(5), 449-470.
[46] Nath, Y.; Nazir, B.; Handa, K. (1961). Bergapten from the fruits of Heracleum candicans. Indian J Pharm, 23, 303-304.
[47] Hinds, H. R.; Young, C. M.; Clayden, S. R., Flora of New Brunswick: A manual for the identification of the vascular plants of New Brunswick. Dept. of Biology, University of New Brunswick: 2000.
[48] Lacey, L., Micmac Medicines: Remedies and Recollections. Halifax, NS: Nimbus Pub.: 1993.
[49] Kuljanabhagavad, T.; Sriubolmas, N.; Ruangrungsi, N. (2010). Chemical composition and antimicrobial activity of the essential oil from Heracleum siamicum. J Health Res, 24(2), 55-60.
[50] Walker, M., Identifying, Harvesting and Using Wild Plants of Eastern Canada.Nimbus Publishing: 2008.
[51] Tavares, A. C.; Gonçalves, M. J.; Cruz, M. T.; Cavaleiro, C.; Lopes, M. C.; Canhoto, J.; Salgueiro, L. R. (2010). Essential oils from Distichoselinum tenuifolium: chemical composition, cytotoxicity, antifungal and anti-inflammatory properties. Journal of ethnopharmacology, 130(3), 593-598.
[52] Sun, H.; Lin, C.; Niu, F. (1978). study of the Chinese drugs of Umbelliferae. I. The chemical constituents of the roots of Angelica apaensis Shan et Yuan., Heracleum rapula Fr., and Heracleum scabridum Fr. Chih wu Hsueh pao. Acta botanica sinica.
[53] Hoult, J.; Paya, M. (1996). Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. General Pharmacology: The Vascular System, 27(4), 713-722.
[54] Hadaček, F.; Müller, C.; Werner, A.; Greger, H.; Proksch, P. (1994). Analysis, isolation and insecticidal activity of linear furanocoumarins and other coumarin derivatives fromPeucedanum (Apiaceae: Apioideae). Journal of chemical ecology, 20(8), 2035-2054.
[55] Glowniak, K. (1988). Investigation and isolation of coumarin derivatives from Polish plant material. Dissertation, Medical University, Lublin.
[56] Sajjadi, S. (2008). Isolation and identification of xanthotoxin (8-methoxypsoralen) from the fruits of Heracleum persicum Desf. ex Fischer. Research in Pharmaceutical Sciences, 2(1), 13-16.
[57] Aynehchi, Y.; Aliabadi, Z.; Salehi Sormaghi, M. In FURANOCOUMARINS IN THE ROOTS OF HERACLEUM PERSICUM DESF, I International Symposium on Spices and Medicinal plants 73, 1977; pp 103-108.
[58] Ghodsi, B. (1976). Flavonoids of three Heracleum species: H. Persicum L., H. sphondylium L. and H. montanum Schl.
[59] Johnson, J. A.; Webster, D.; Gray, C. A. (2013). The Canadian medicinal plant Heracleum maximum contains antimycobacterial diynes and furanocoumarins. Journal of ethnopharmacology, 147(1), 232-237.
[60] Kavli, G.; Raa, J.; Johnson, B.; Volden, G.; Haugsbø, S. (1983). Furocoumarins of Heracleum laciniatum: isolation, phototoxicity, absorption and action spectra studies. Contact dermatitis, 9(4), 257-262.
[61] Kaul, M.; Bhat, B.; Atal, C. (1982). Heracleum candicans Wall.—a potential source of xanthotoxin. Cultivation and utilization of medicinal plants. Jammu, India: Council of Scientific and Industrial Research (CSIR), Publications and Information Directorate, 317-320.
[62] Nakamori, T.; Taniguchi, M.; Shibano, M.; Wang, N.-H.; Baba, K. (2008). Chemical studies on the root of Heracleum candicans WALL. Journal of natural medicines, 62(4), 403-412.
[63] Taniguchi, M.; Inoue, A.; Shibano, M.; Wang, N.-H.; Baba, K. (2011). Five condensed furanocoumarins from the root of Heracleum candicans Wall. Journal of natural medicines, 65(2), 268-274.
[64] Inoue, A.; Shibano, M.; Taniguchi, M.; Baba, K.; Wang, N.-H. (2011). Four novel furanocoumarin glucosides, candinosides A, B, C and D, from Heracleum candicans Wall. Journal of natural medicines, 65(1), 116-121.
[65] Inoue, A.; Taniguchi, M.; Shibano, M.; Wang, N.-H.; Baba, K. (2010). Chemical studies on the root of Heracleum candicans Wall.(Part 3). Journal of natural medicines, 64(2), 175-181.
[66] Sharma, Y.; Zaman, A.; Kidwai, A.; Bates, R.; Thalacker, V. (1966). Coumarin constituents of Heracleum candicans—III. Tetrahedron, 22(9), 3221-3225.
[67] Bandopadhyay, M.; Malik, S.; Seshadri, T. (1973). Coumarins from the roots and seeds of Heracleum candicans. Indian journal of chemistry.
[68] Walasek, M.; Grzegorczyk, A.; Malm, A.; Skalicka-Woźniak, K. (2015). Bioactivity-guided isolation of antimicrobial coumarins from Heracleum mantegazzianum Sommier & Levier (Apiaceae) fruits by high-performance counter-current chromatography. Food chemistry, 186, 133-138.
[69] Xiao, W.; Li, S.; Niu, X.; Zhao, Y.; Sun, H. (2005). Rapulasides A and B: two novel intermolecular rearranged biiridoid glucosides from the roots of Heracleum
[70] rapula. Tetrahedron letters, 46(34), 5743-5746.
[71] Zhang, C.; Liu, Y.; Xiao, Y. Q.; Li, L. (2009). A new trimeric furanocoumarin from Heracleum rapula. Chinese Chemical Letters, 20(9), 1088-1090.
[72] Niu, X.-M.; Li, S.-H.; Jiang, B.; Zhao, Q.-S.; Sun, H.-D. (2002). Constituents from the roots of Heracleum rapula Franch. Journal of Asian natural products research, 4(1), 33-41.
[73] Lee, D.; Bhat, K. P.; Fong, H. H.; Farnsworth, N. R.; Pezzuto, J. M.; Kinghorn, A. D. (2001). Aromatase Inhibitors from Broussonetia p apyrifera. Journal of natural products, 64(10), 1286-1293.
[74] Mahmoodi, K.; Valizadeh, H.; Hosseinzadeh, Z.; Bahadori, M. (2015). Furanocoumarins from Heracleum rawianum in Iran. Iran Chem Commun, 3, 1-6.
[75]  Bogucka-Kocka, A.; Krzaczek, T. (2003). The furanocoumarins in the roots of Heracleum sibiricum L. Acta Polon Pharm-Drug Res, 60(5), 401-403.
[76] Rajtar, G.; Zolkowska, D.; Kleinrok, Z.; Marona, H. (1999). Antiplatelets activity of some xanthone derivatives. Acta poloniae pharmaceutica, 56, 319-324.
[77] Saraswathy, A.; Sasikala, E.; Purushothaman, K. (1990). Chemical investigation on Heracleum rigens Wall. Indian Drugs, 27, 316-319.
[78] Mishyna, M.; Laman, N.; Prokhorov, V.; Fujii, Y. (2015). Angelicin as the principal allelochemical in Heracleum sosnowskyi fruit. Natural product communications, 10(5), 767-770.
[79] Shakhmatov, E. G.; Toukach, P. V.; Kuznetsov, S. P.; Makarova, E. N. (2014). Structural characteristics of water-soluble polysaccharides from Heracleum sosnowskyi Manden. Carbohydrate polymers, 102, 521-528.
[80] Skalicka-Woźniak, K.; Głowniak, K. (2012). Pressurized liquid extraction of coumarins from fruits of Heracleum leskowii with application of solvents with different polarity under increasing temperature. Molecules, 17(4), 4133-4141.
[81] Sun, H.; Lin, Z.; Niu, F., 224-227 (1980) Ch (En) Chemotaxonomy. Geog: 1980.
[82] Dincel, D.; HATIPOĞLU, S. D.; GÖREN, A. C.; TOPÇU, G. (2013). Anticholinesterase furocoumarins from Heracleum platytaenium, a species endemic to the Ida Mountains. Turkish Journal of Chemistry, 37(4), 675-683.
[83] Kasumova, G.; Serkerov, S. (2011). A new natural methoxyfurocoumarin from Heracleum pastinacifolium. Chemistry of Natural Compounds, 47(3), 358-359.
[84] Ibadullaeva, S.; Serkerov, S. (2000). Coumarins of Heracleum pastinacifolium. Chemistry of Natural Compounds, 36(5), 534-534.
[85] Akhmedov, D.; Serkerov, S. (1998). Coumarin derivatives from the epigeal part ofHeracleum grandiflorum. Chemistry of natural compounds, 34(1), 101-101.
[86] Komissarenko, N.; Derkach, A.; Kovalev, I.; Satsyperova, I. (1978). Coumarins from roots of Heracleum leskovii. Khimiia prirodnykh soedinenii.
[87] Chacko, S.; Sethuraman, M.; George, V. (2000). Monoterpenoids from the seeds of Heracleum candolleanum. Fitoterapia, 71(5), 616-617.
[88] Kurbanova, F.; Serkerov, S. (2012). A new psoralenic methoxyfurocoumarin from fruit of Heracleum transcaucasicum. Chemistry of Natural Compounds, 1-2.
[89] Nakano, Y.; Matsunaga, H.; Saita, T.; MORI, M.; KATANO, M.; OKABE, H. (1998). Antiproliferative constituents in Umbelliferae plants II. Screening for polyacetylenes in some Umbelliferae plants, and isolation of panaxynol and falcarindiol from the root of Heracleum moellendorffii. Biological and Pharmaceutical Bulletin, 21(3), 257-261.
[90] Zhang, H. (1981). [Studies on the coumarin of root of Heracleum moellendorffii Hance (author's transl)]. Zhong yao tong bao (Beijing, China: 1981), 6(5), 27-29.
[91] Wu, S.-J.; Li, D.-Y.; Zhang, L.; Du, X.-D.; Zhang, Y.-K. (1986). Studies on the coumarins from the zou-ma-qin (Heracleum moellendorffii Hance var. Paucivitatum). Yao Xue Xue Bao, 21, 599-604.
[92] Liu, M.; Abdel-Mageed, W. M.; Ren, B.; He, W.; Huang, P.; Li, X.; Bolla, K.; Guo, H.; Chen, C.; Song, F. (2014). Endophytic Streptomyces sp. Y3111 from traditional Chinese medicine produced antitubercular pluramycins. Applied microbiology and biotechnology, 98(3), 1077-1085.
[93] Lawrie, W.; McLean, J.; Younes, M. E. G. (1968). Constituents of the seeds of Heracleum sphondylium. Phytochemistry, 7(11), 2065-2066.
[94] Heinrich, M.; Barnes, J.; Gibbons, S.; Williamson, E., Fundamentals of Pharmacognosy. Phytotherapy: 2004.
[95] Komissarenko, N.; Fedorin, G. (1984). Coumarins of the roots ofHeracleum aconitofolium andH. grandiflorum. Chemistry of Natural Compounds, 20(5), 618-619.
[96] Tolibaev, I.; Glushenkova, A. (1996). Lipids ofHeracleum lehmannianum seeds. Chemistry of natural compounds, 32(1), 7-10.
[97] Razdan, T.; Kachroo, V.; Harkar, S.; Koul, G. (1982). Furanocoumarins from Heracleum canescens. Phytochemistry, 21(4), 923-927.
[98] Rosenthal, G. A.; Berenbaum, M. R., Herbivores: Their interactions with secondary plant metabolites: Ecological and Evolutionary Processes. Academic Press: 2012; Vol. 2.
[99] Zobel, A. M.; Brown, S. A. (1990). Seasonal changes of furanocoumarin concentrations in leaves ofHeracleum lanatum. Journal of chemical ecology, 16(5), 1623-1634.
[100] Tosun, F.; Kızılay, Ç. A.; Erol, K.; Kılıç, F. S.; Kürkçüoğlu, M.; Başer, K. H. C. (2008). Anticonvulsant activity of furanocoumarins and the essential oil obtained from the fruits of Heracleum crenatifolium. Food chemistry, 107(3), 990-993.
[101] Gupta, B. D.; Banerjee, S. K.; Handa, K.; Atal, C. (1976). Heratomin and heratomol, new coumarins from Heracleum thomsoni. Phytochemistry, 15(8), 1319-1320.
[102] Calixto, J. B.; Santos, A. R.; Filho, V. C.; Yunes, R. A. (1998). A review of the plants of the genus Phyllanthus: their chemistry, pharmacology, and therapeutic potential. Medicinal research reviews, 18(4), 225-258.
[103] Isaacs, S. T.; Shen, C.-K. J.; Hearst, J. E.; Rapoport, H. (1977). Synthesis and characterization of new psoralen derivatives with superior photoreactivity with DNA and RNA. Biochemistry, 16(6), 1058-1064.
[104] Battersby, A. R.; Fookes, C. J.; Matcham, G. W.; McDonald, E. (1980). Biosynthesis of the pigments of life: formation of the macrocycle. Nature, 285, 17-21.
[105] Cordell, G. A.; Colvard, M. D. (2012). Natural products and traditional medicine: turning on a paradigm. Journal of natural products, 75(3), 514-525.
[106] Cordell, G. A. (2015). Ecopharmacognosy and the responsibilities of natural product research to sustainability. Phytochemistry Letters, 11, 332-346.
[107] Govindarajan, R.; Singh, D. P.; Singh, A. P.; Pandey, M. M.; Rawat, A. K. S. (2007). A validated HPLC method for quantification and optimization of furocoumarins in different extracts of fruits of Heracleum candicans. Chromatographia, 66(5-6), 401-405.
[108] Mukherjee, P. K. (2002). Quality control of herbal drugs: an approach ro evaluation of botanicals.
[109] Sharma, Y.; Zaman, A.; Kidwai, A. (1964). Chemical examination of Heracleum candicans—I: Isolation and structure of a new furocoumarin—heraclenin. Tetrahedron, 20(1), 87-90.
[110] Smith, M. L.; Gregory, P.; Bafi‐Yeboa, N. F.; Arnason, J. T. (2004). Inhibition of DNA polymerization and antifungal specificity of furanocoumarins present in traditional medicines. Photochemistry and photobiology, 79(6), 506-510.
[111]  Mariano, T. M.; Vetrano, A. M.; Gentile, S. L.; Heck, D. E.; Whittemore, M. S.; Guillon, C. D.; Jabin, I.; Rapp, R. D.; Heindel, N. D.; Laskin, J. D. (2002). Cell-impermeant pyridinium derivatives of psoralens as inhibitors of keratinocyte growth. Biochemical pharmacology, 63(1), 31-39.
[112] Yang, L.-L.; Liang, Y.-C.; Chang, C.-W.; Lee, W.-S.; Kuo, C.-T.; Wang, C.-C.; Lee, H.-M.; Lin, C.-H. (2002). Effects of sphondin, isolated from Heracleum laciniatum, on IL–1β-induced cyclooxygenase-2 expression in human pulmonary epithelial cells. Life sciences, 72(2), 199-213.
[113] Hemati, A.; Azarnia, M.; Nabiuni, M.; Mirabolghasemi, G.; Irian, S. (2012). Effect of the Hydroalcoholic Extract of Heracleum persicum (Golpar) on Folliculogenesis in Female Wistar Rats. Int J Food Sci, 14, 47-52.
[114] Razzaghi-Abyaneh, M.; Saberi, R.; Sharifan, A.; Rezaee, M.-B.; Seifili, R.; Hosseini, S.-I.; Shams-Ghahfarokhi, M.; Nikkhah, M.; Saberi, I.; Amani, A. (2013). Effects of Heracleum persicum ethyl acetate extract on the growth, hyphal ultrastructure and aflatoxin biosynthesis in Aspergillus parasiticus. Mycotoxin research, 29(4), 261-269. 
[115] Bose, S. K.; Dewanjee, S.; Sahu, R.; Dey, S. P. (2011). Effect of bergapten from Heracleum nepalense root on production of proinflammatory cytokines. Natural product research, 25(15), 1444-1449.
[116] Eun, J. S.; Choi, B. H.; Park, J. A.; Im Lee, G.; Lee, T. Y.; Kim, D. K.; Jung, Y. H.; Yoo, D. J.; Kwak, Y. G. (2005). Open channel block of hKv1. 5 by psoralen fromHeracleum moellendorffii hance. Archives of pharmacal research, 28(3), 269-273.