Everlasting flowers: Phytochemistry and pharmacology of the genus Helichrysum

Industrial Crops & Products 138 (2019) 111471

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Everlasting flowers: Phytochemistry and pharmacology of the genus Helichrysum Maryam Akaberia, Amirhossein Sahebkarb,c, Narjes Azizid, Seyed Ahmad Emamia,e,

T

⁎

a

Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran c Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran d Forest and Rangeland Research Department, Khorasan Razavi Agricultural and Natural Resources Research and Education Center. AREEO, Mashhad, Iran e Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran b

ARTICLE INFO

ABSTRACT

Keywords: Helichrysum Phytochemistry Pharmacology Phloroglucinols Pyrones Anti-microbial

The plants belonging to the genus Helichrysum (Asteraceae) are known as everlasting flowers and widely used in traditional medicine worldwide. Surveys on their traditional uses as well as phytochemical and pharmacological studies have revealed the potential of these plants for drug discovery. Although there are several studies on some of the species, most of the plants need to be investigated thoroughly. The aim of this review is to present a collated and coherent overview of the documented traditional uses, pharmacological activities and particularly bioactive constituents of Helichrysum species. Scientific databases including Scifinder, ISI Web of Knowledge, PubMed and Scopus as well as several traditional texts and books were searched to collect the data. Review of studies showed that Helichrysum spp. have been used in different systems of traditional and folk medicines for the treatment of various infections, wounds, digestive problems, diabetes and colds, of which some are confirmed in modern medicine such as the antimicrobial activity. Phytochemical investigations have shown that these plants are rich in phenolic compounds such as flavonoids, pyrones, phloroglucinols and essential oils, and in some species terpenes such as sesquitepenes and diterpenes are dominant. However, among these compounds, pyrones and phloroglucinols have been reported to be the bioactive constituents in most of the studies. Overall, according to the potential of these plants, further phytochemical, ethnopharmacological and pharmacological studies are required since only a few species have been investigated so far.

1. Introduction Helichrysum genus belonging to Asteraceae family consists of about 600 species worldwide. It is originally from Africa (244 species in South Africa), Madagascar, Australasia and Eurasia. The name of the genus is derived from the Greek words “helios” and “chryos”, which mean “sun” and “gold”, respectively. This nomenclature is due to the fact that the plant species of this genus typically have inflorescences of a bright yellow color (Perrini et al., 2009). The common names of the plants are everlasting flowers and immortelles since they retain their form and color when dried and are used in dry bouquets and flower arrangements. Some species like H. arenarium are also called the golden flower referring to the golden color of the flowers.

From a systematic point of view, Helichrysum Mill. is a large genus, with a worldwide distribution (Azizi et al., 2014a, b; Azizi et al., 2019). The most well-known and studied species of this genus are H. italicum (Antunes Viegas et al., 2014), H. stoechas (Les et al., 2017), and H. arenarium (Pljevljakušić et al., 2018). Studies show that Helichrysum spp. are very rich in phenolic compounds mainly phloroglucinol derivatives and flavonoids (Bohlmann et al.,). Helichrysum spp. have been used as flavoring spices in a variety of foods and folk medicines, and for cosmetic purposes for centuries (Antunes Viegas et al., 2014). In addition, Helichrysum spp. have potential pharmacological applications for their antioxidant, antimicrobial, and anti-inflammatory activities (Taglialatela-Scafati et al., 2013; Mao et al., 2017). Considering the important role that the Helichrysum spp. play in the

Abbreviations: CRP, c-reactive protein; DPP-IV, dipeptidyl peptidase-IV; EMA, European medicines agency; HIV, human immunodeficiency virus; IL-1β, interleukin1β; IL-6, interleukin-6; IL-8, interleukin-8; JNK, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinase; MIC, minimum inhibitory concentration; mPGES1, microsomal prostaglandin E synthase-1; NO, nitric oxide; PGE2, prostaglandin E2; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; WHO, World Health Organization ⁎ Corresponding author at: Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. E-mail address: [email protected] (S.A. Emami). https://doi.org/10.1016/j.indcrop.2019.111471 Received 11 March 2019; Received in revised form 25 April 2019; Accepted 9 June 2019 0926-6690/ © 2019 Elsevier B.V. All rights reserved.

Chest problems or infection of the respiratory tract Smallpox Anthelmintic Coughs and colds and applied externally on wounds Relax body and to reduce swelling

2

foetidum (L.) Moench foetidum (L.) Moench foetidum (L.) Moench foetidum (L.) Moench fulgidum (L.f.) Willd graveolens italicum

H. H. H. H. H. H. H.

H. H. H. H. H. H. H. H. H. H.

nudifolium var. leiopodium nudifolium var. leiopodium nudifolium var. leiopodium obconicum DC odoratissimum (L.) Sweet odoratissimum (L.) Sweet odoratissimum (L.) Sweet orientale (L.) Vaill panduratum O. Hoffm. pandurifolium Schrank.

H. miconiifolium DC.

Intestinal parasites Chest complaints Respiratory infections Headache Colic in children Stomach and intestinal disorders Wounds and burns Headache Tonic for pregnant women Asthma and cough Malaria Respiratory conditions, back pain, heart trouble, kidney disease, and kidney stones

Antiseptic, coleretic and spasmolytic agent Chest complaints Headaches Nausea, virility Wound healing Colic Hyperfunction of the lower gastro-intestinal tract Coughs Infections of the respiratory tract Used as love charm Coughs, bronchitis, urinary tract infections and tuberculosis Colds and coughs Emetic and purgative Head cold Diarrhea in children A wound-healing and disinfectant agent, disinfectant, syphilis, diarrhea, cough and headache Infected sores Influenza Infected wounds, and herpes Eye problems Used for washing sore eyes Controlling the symptoms of diabetes mellitus, wound healing and as a diuretic Toothache, digestive disorders and catarrh, analgesic, anti-odontalgic, astringent, antiemetic and dermatologic tonic, allergy, stomach cleanser, cough, colds, tracheitis and laryngitis, skin diseases, and mouth antiseptic, liver and gall disorders, sleeplessness, headache, sniffles, helmintic infections, asthma Coughs and pulmonary tuberculosis Wounds Bronchitis, cough and pharyngitis, cardiotonic

arenarium athrixiifolium (Kuntze) Moeser caespititium (DC.) Harv caespititium (DC.) Harv caespititium (DC.) Harv callicomum Harv calophalum Klatt cochleariforme DC. cochleariforme DC. cooperi Harv crispum (L.) D. Don crispum (L.) D. Don crispum (L.) D. Don dregeanum Sond. ecklonis Sond faradifani

H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H.

H. kraussii Sch. Bip H. longifolium DC. H. melaleucum Rchb.

Intestinal problems

H. argyrophyllum DC.

Less. Less. Less. Less. Less.

H. H. H. H. H.

(L.f.) (L.f.) (L.f.) (L.f.) (L.f.)

Diarrhea and vomiting in children

H. adenocarpum DC.

appendiculatum appendiculatum appendiculatum appendiculatum appendiculatum

Traditional use

Name

Table 1 The traditional uses of Helichrysum spp. in different parts of the world.

Africa Africa Africa Africa Africa

Africa Africa Africa Africa Africa Africa

Africa Africa Africa Africa Africa

South Africa South Africa South Africa South Africa South Africa Portugal South Africa South Africa South Africa Portugal South Africa South Africa

South Africa South Africa Portugal

Europe

South South South South South

South Africa South Africa South Africa South Africa South Africa South Africa South Africa Madagascar

South South South South South South

South Africa

South South South South South

South Africa

Country/Region

Flower and seed/smoke Leaf Flower heads and leaves/ infusion Tea Whole plant/decoction Root Leaf/smoke inhalation Decoction as enema Flower and leaves/infusion Leaf/wound dressing Leaf/smoke Leaf/decoction Flowers/infusion Whole plant/sap Infusion

Aerial parts

(Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Rivera and Obón, 1995) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Rivera and Obón, 1995) (Lourens et al., 2008) (Lourens et al., 2008)

(Lourens et al., 2008) (Lourens et al., 2008) (Rivera and Obón, 1995)

(Antunes Viegas et al., 2014)

(Lourens et al., 2008) (Lourens et al., 2008)

(continued on next page)

(Grierson and Afolayan, 1999)

(Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Benelli et al., 2018)

Leaf as decoction Root/extract Leaf/smoke Root/decoction Leaves/poultice Leaf/extract Leaf/wound dressing Root/extract Decoction

(Arnold et al., 2002; Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008)

(Arnold et al., 2002; Batten and Bokelmann, 1966; Walker, 1996; Watt and Breyer-Brandwijk, 1962)

(Jacot Guillarmod, 1971; Neuwinger, 1996; Phillips, 1917) (Arnold et al., 2002; Githens, 1949)

Ref.

Leaf as smoke Whole plant/smoke Root as decoction Whole plant/ointment Enema Root Infusion Whole plant/decoction Leaf/ointment

Leaf eaten raw Whole plant/wound dressing Whole plant/wound dressing Root/wound dressing Root/ ground and burnt and smeared on the body Root as infusion

Roots/decoction

Plant part/preparation

M. Akaberi, et al.

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(Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008)

(Lourens et al., 2008) (Bigovic et al., 2010; Polat et al., 2013; Yeşilada et al., 1995) (Tetik et al., 2013) (Polat et al., 2013) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Lourens et al., 2008) (Antunes Viegas et al., 2014) (Antunes Viegas et al., 2014)

The selection of relevant data was made through a search using the keyword “Helichrysum” in scientific databases such as “SciFinder”, “Google Scholar”, “ISI Web of Knowledge”, “PubMed”, “ScienceDirect” and “Wiley Online Library”. Information obtained in local and foreign books and other sources including several traditional texts and books were used to collect the information. Table 7 shows the scientific names of Helichrysum taxa reviewed in this paper.

Turkey Turkey South Africa South Africa South Africa South Africa Spain Spain

Wounds Diabetes Dysmenorrhea Colic Epilepsy Rheumatism Toothache, urologic conditions and digestive disorders Conjunctivitis and ocular infections, pharyngitis and tonsillitis, wounds, hemorrhoids, intestinal parasitic infections, toothache, kidney disorders Headaches Sore eyes Bladder problems

3. Traditional uses All over the world, the plants of genus Helichrysum has been used in traditional medicine for at least 2000 years. These plants have traditionally been used for ornamental, medicinal and food purposes (Antunes Viegas et al., 2014). For instance, H. italicum subsp. picardii is an aromatic halophyte common in southern Europe frequently used as a spice and traditional medicine. Generally, everlasting flowers have been used mainly in different traditional medicines as an infusion or decoction; for example, H. stoechas Moench infusion has been used traditionally to treat diverse disorders such as influenza and cold, fever, nervousness, as well as gallbladder, urinary bladder, digestive and pancreas problems (Benítez et al., 2010). The preparation of H. arenarium in the form of an infusion or decoction that is based on its traditional use for treating digestive problems (e.g. fullness and bloating) has been approved by the World Health Organization (WHO) and the European Medicines Agency (EMA). Table 1 shows the application of different Helichrysum spp. in various traditional medicine. These data show that the most frequently reported traditional uses of Helichrysum spp. are related to its antimicrobial properties. However, it has been also used as an analgesic agent and for the treatment of diabetes and digestive problems.

South Africa South Africa South Africa

South Africa South Africa Turkey Coughs, colds, catarrh, headache, fever, menstrual disorders, and urinary tract infections Renew virility in men Gastric and hepatic disorders, jaundice, dysuria and kidney stones

Leaf/tea Root/decoction Flowers as infusion, and decoction Ointment as infusion Flowers as infusion Root/decoction enema Leaf/decoction Roots Flowers as infusion Flowers and stems as decoction and ointment Aerial parts/smoke inhalation Decoction Root/decoction

Leaf and root/infusion Leaves South Africa South Africa

4. Phytochemistry Lloyd et al. was the first group who investigated the phytochemical composition of the plants belonging to the genus Helichrysum in 1967 by working on the species H. dendroideum (Bohlmann and Zdero, 1973), of which some terpene alcohols were isolated. Other studies on this genus confirmed the presence of terpenoids and essential oils as one of the main classes of secondary metabolites. However, further studies by other research groups on the genus showed that phenolic and oxygenated compounds contributed the major components. The reported secondary metabolites from the genus can be categorized into six structural types: flavonoids and chalcones, phenolic acids, terpenes and essential oils, pyrones (both homo- and heterodimeric), benzofurans (bitalin esters) and phloroglucinols (Taglialatela-Scafati et al., 2013) consisting mainly of two types of substituents: a prenyl/geranyl group and an acyl group. The most common acyl substituents are methyl, isopropyl, and 2-methylbutanoyl.

The isolated pyrones from Helichrysum spp. can be either monomers such as the compound micropyroe 1 and glycosylated forms of yangonin 2-3 (acylated styrylpyrones) (D’ Abrosca et al., 2013) or they can be hetero- and homo-dimers (Fig. 1 and Table 6); helipyrone A 4 (Opitz and Hänsel, 1970), B 5, and C 6 (Vrkcoč et al., 1975) are examples of

H. stoechas H. stoechas

H. plicatum H. plicatum

4.1. Pyrones H. plicatum

H. pedunculatum Hilliard and Burtt H. pedunculatum Hilliard & B.L.Burtt H. petiolare Hilliard and Burtt

Infusion South Africa H. patulum (L.). Don.

Heart trouble, backache, kidney disease, coronary thrombosis, bladder conditions/ infections, asthma, and influenza Antiseptic Inflammation and wounds

(Lourens et al., 2008) (Bhat and Jacobs, 1995)

2. Search strategy

Country/Region

(Lourens et al., 2008)

traditional medicinal practices of many countries around the world, reviewing the studies and investigations about these valuable plants could be helpful for future drug discovery investigations. The present review deals with the traditional uses and pharmacological studies of Helichrysum spp. In addition, this review introduces the bioactive compounds isolated from the genus.

Traditional use Name

Table 1 (continued)

Plant part/preparation

Ref.

M. Akaberi, et al.

3

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Fig. 1. Pyrones from Helichrysum spp.

homo-dimer pyrones. Hetero-dimer pyrones are reported to consist of one phloroglucinol ring attached to an α-pyrone moiety via a methylene bridge. Bohlmann et al. (1980) isolated 23-methylauricepyrone 7 as a mixture with norauricepyrone 8 from H. auriceps (Bohlmann and Zdero, 1980b). Appendino et al. (2001) isolated and identified arzanol 9 and arenol 10 as novel prenylated phloroglucinol α-pyrones from H. italicum (Roth) Don spp. Microphyllum (Appendino et al., 2007a; Lavault and Richomme, 2004). Although the presence of a prenyl side chain is typical to these heterodimers like 9-14 (Appendino et al., 2007a;

Akaberi et al., 2019), 7, 16 (Bohlmann and Zdero, 1980b), and 24 (Rosa et al., 2007), in some reported structures it can be absent (norauricepyrone 8) (Jakupovic et al., 1986), rearranged (heliarzanol, 15) (Taglialatela-Scafati et al., 2013), or doubled as a geranyl group (17-23 isolated from H. decumbens) (Tomás-Barberán et al., 1990; TomásLorente et al., 1989; Akaberi et al., 2019). Not only hetero-dimers but also hetero-trimers with two α-pyrone rings have been found from the genus, for instance, 23-methylitalidipyrone 25 and italidipyrone 26 from H. italicum (Hänsel et al., 1980).

4

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Fig. 2. Phloroglucinols from Helichrysum spp.

As abovementioned, in some derivatives, the prenyl or geranyl groups are rearranged and create new scaffolds. They may undergo cyclization leading to the formation of chromane and benzofuran derivatives such as compounds italipyrone 27, 20-prenylitalipyrone 28, plicatipyrone 29, isobutyrylhelichromenopyrone 30, 2-methylbutyrylhelichromenopyrone 31, helicerastripyrone 32 (Bohlmann et al., 1984; Hänsel et al., 1980; Rios et al., 1991), helicepyrone 33, cycloarzanol 34, and helicyclol 35 (Akaberi et al., 2019). Lepidissipyrone 36 and 8-prenyllepidissipyrone 37 are examples of a chromanone moiety in the molecules isolated from H. lepidissimum (Jakupovic et al., 1989b). In a recent study, two new pyrone derivatives Helitalone A 38 and B 39 have been isolated and identified from H. italicum (Werner et al., 2019). Interestingly, these compounds are the first examples of

pyrones reported from Helichrysum genus bearing an isopropyl and 1butyl substitutes in the pyrone ring moieties. It is noteworthy that in arzanol 9 or other α-pyrone phloroglucinols, the presence of several hydrogen bond donor or acceptor sites makes intramolecular hydrogen bonding patterns the dominant stabilizing factor. The lowest energy conformers have the highest number of stronger intramolecular hydrogen bonds (Mammino, 2017). In this case, thanks to the presence of an acyl group (COR group) whose sp2 O can form an intramolecular hydrogen bond with one of the two ortho OHs, and the presence of an α-pyrone ring which is attached to one position meta to the COR group, arzanol can form up to three OeH···O bonds simultaneously (Mammino, 2017).

5

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Fig. 3. Benzofurans and phtalides from Helichrysum spp.

4.2. Phloroglucinols

et al., 1986; Popoola et al., 2015b). Some reported phloroglucinols from this genus include helinudifolin 40, 41 (Jakupovic et al., 1986), helinivene A 42 and B 43, 1-(butanone)-3-prenyl-phloroglucinol 44, 1-(2methylbutanone)-3-prenyl-phloroglucinol 45, 1-butanone-3-(3-

Phloroglucinols as homo-dimers and monomers are another class of secondary metabolites present in most of the studied species (Jakupovic

Table 2 Flavonoids and phenolic acids reported from Helichrysum spp. Helichrysum spp.

Compound (s)

Activity

Ref.

H. arenarium subsp. arenarium

Caffeic acid conjugates (chlorogenic acid and dicaffeoylquinic acids) and flavonoids (apigenin, naringenin, apigenin-7-O-glucoside and naringenin-Ohexosides) Naringenin-7-O-β-d-glycoside, isoquercitrin, and astragalin Galangin

Antibacterial

(Gradinaru et al., 2014)

_ Antibacterial and antioxidant Antifungal

(Yang et al., 2009) (Cushnie and Lamb, 2006; De La Puerta et al., 1999) (Tomás-Lorente et al., 1989)

_

(Gouveia and Castilho, 2009)

Atimicrobial

(Malolo et al., 2015)

Anti-biofilm _

(D’Abrosca et al., 2013) (Karasartov et al., 1992)

Anticarcinogenic Antimicrobial _

(Yagura et al., 2008) (Malolo et al., 2015) (Gouveia and Castilho, 2011)

_

(Mutanyatta-Comar et al., 2006)

Antioxidant Antioxidant

(Aiyegoro and Okoh, 2009) (Carini et al., 2001)

Antioxidant

(Popoola et al., 2015a)

H. arenarium (L.) Moench H. aureonitens H. decumbens H. devium H. foetidum (L.) Moench H. italicum H. italicum H. maracandicum H. mechowianum Klatt. H. obconicum H. paronychioides H. pedunculatum H. stoechas H. teretifolium

3,5-dihydroxy-6,7,8-trimethoxyflavone, 5,7-dihydroxy-3,6,8-trimethoxy-flavone and 3,5-dihydroxy-6,7-dimethoxyflavone Quinic acid derivatives, O-glycosylated flavonoids, caffeic acid derivatives and a protocatechuic acid derivative 7, 4′-dihydroxy-5-methoxy-flavanone, 6′-methoxy-2′,4, 4′-trihydroxychalcone, 6′methoxy-2′,4-dihydroxychalcone -4′-O-β-D-glucoside, apigenin (4), apigenin-7-Oβ-D-glucoside, kaur-16-en-18-oic acid Lignans, and quinic acid derivatives Kaempferol, 3,5,7-trihydroxy-8-methoxyflavone and 3,5-dihydroxy-6,7,8trimethoxyflavone Naringenin chalcone, and isosalipurposide 3,5,7-trihydroxy-8-methoxyflavone, and 4,5-dicaffeoyl quinic acid Quinic acid deriavtives, caffeoylquinic acid, malonylcaffeoylquinic acid, coumaroylquinic acid, and caffeoylshikimic acids 3-methylquercetin, 3,3´-dimethylquercetin, 3,7-dimethylkaempferol, penduletin, eupalitin, 2-(2-methylpropanoyl)-4-prenylphloroglucinol, and 2-(2methylbutanoyl)-4-prenylphloroglucinol Flavonoids, proanthocyanidin and phenolic contents Neo-chlorogenic acid, chlorogenic acid and crypto-chlorogenic acid, isomeric dicaffeoyl quinic acids, isomeric naringenin glucosides, quercetin, kaempferol and apigenin glucosides and a tetrahydroxychalcone-glucoside Isoxanthohumol, 2',4',6'-trihydroxy-3'-prenylchalcone, isoglabranin, glabranin, quercetin and compounds 44-48

6

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Fig. 4. Flavonoids and chalcones from Helichrysum spp.

methylbut-2-enylacetate)-phloroglucinol 46, 1-(2-methylpropanone)-3prenylphloroglucinol 47, caespitate 48 (Popoola et al., 2015b), 2-butanoyl-4-prenylphloroglucinol 49 (Mutanyatta-Comar et al., 2006), 2(2-methylpropanoyl)-4-prenylphloroglucinol 50 (Jakupovic et al., 1986), 2-(2-methylbutanoyl)-4-prenylphloroglucinol 51 (Bohlmann and Mahanta, 1979), caespitin 52 (Dekker et al., 1984), 53 (Drawert and Beier, 1976), 54 (Bohlmann and Mahanta, 1979), 55 (Bohlmann et al., 1984), 56 (Randriaminahy et al., 1992), and 57 (Jakupovic et al.,

1989b) (Fig. 2 and Table 6). Recently, helispiroketals A–H 58-65, phloroglucinol derivatives bearing an α,β-unsaturated spiroketal unit with five-membered rings, have been isolated from the endemic Iranian H. oocephalum (Akaberi et al., 2019). 4.3. Benzofurans and phtalides Benzofuran derivatives are another class of heterocyclic compounds

7

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Table 3 The major constituents and pharmacological activities of the essential oils from Helichrysum spp. Helichrysum spp.

Major compounds

Activity

Ref.

H. arenarium (L.) Moench.

Spathulenol (36.6%) and β-pinene (12.5%) _ Beta-caryophyllene, δ-cadinene, octadecane, heneicosane

Antimicrobial Antibacterial _

Linalool (1.7%), anethole (3.2%), carvacrol (3.6%) and α-muurolol (1.3%) Hexadecanoic acid (14.7%), β-caryophyllene (10.6%), α-humulene (7.7%) Alpha-pinene (38.5%), β-caryophyllene (23.0%), 1,8 cineole (12.0%), Isoborneol (28.2%), β-caryophyllene (12.9%), δ-cadinene (6.3%), bornyl acetate (6.0%), carvacrol (37.7%), α-pinene (19.7%) and β-caryophyllene (8.5%) Beta-pinene (10.3%), 1,8-cineole (24.8%) and α-humulene (10.1%) 1,8-cineole (27.3%) 1, 8-cineole (18%), α-humulene (11.6%) and β-caryophyllene (9.6%)

_ _ _

(Chinou et al., 2004) (Moghadam et al., 2014) (Judzentiene and Butkiene, 2006) (Czinner et al., 2000) (Javidnia et al., 2009) (Azar et al., 2011)

Bera-caryophyllene (46.4%) and α-humulene (10.9%) (E)-caryophyllene (55.6%) Alpha-fenchene (35.6%), γ-curcumene (17.7%) Alpha-fenchene (32.3%), γ-curcumene (19.4%), (E)-β-caryophyllene (14.2%), αcurcumene (2.9%), limonene (2.8%), lavandulyl acetate (2.1%) and α-fenchene hydrate (1.7%) (E)-caryophyllene (34.6%) Selina-5,11-diene (45.3%), δ-3-carene (7.8%), 1,8-cineole (4.2%) and βcaryophyllene (4.9%) Alpha-cubebene (10.5%), β-caryophyllene (9.4%), azulene-octahydro (7.5%), caryophyllene oxide (8.2%) 1,8-cineole (47.4%) 1,8-cineole (47.4%), bicyclosesquiphellandrene (5.6%), γ-curcumene (5.6%), αamorphene (5.1%) and bicyclogermacrene (5%) 1,8-cineole (59.7%) 1,8-cineole (51.5%) (E)-caryophyllene (34.0%) Gamma-curcumene, α-pinene, β-selinene, α-selinene, and limonene Neryl acetate (32.65%), γ‐Curcumene (11.64%), Italidione I (7.42%), Limonene (5.54%), Neryl propionate (4.80%), Italidione II (2.65%), Italidione III (1.92%) Alpha-trans-bergamotene (10.2%) and β-acoradiene (10.1%) Neryl acetate (8.1%), β-acoradiene Nerol (2.8-12.8%) and neryl acetate (5.6-45.9%) Iso-italicene epoxide (16.8%), β-costol (7.5%) and (Z)-α-trans-bergamotol (4.7%) Alpha-Cedrene (13.61%), α-curcumene (11.41%), geranyl acetate (10.05%), limonene (6.07%), nerol (5.04%), neryl acetate (4.91%) and α-pinene (3.78%) Alpha-cedrene (13.61%), α-curcumene (11.41%), geranyl acetate (10.05%), limonene (6.07%), nerol (5.04%), neryl acetate (4.91%) and α-pinene (3.78%) Alpha-pinene (10.2%), α-cedrene (9.6%) aromadendrene (4.4%), β-caryophyllene (4.2%), and limonene (3.8%), neryl acetate (11.5%), 2-methylcyclohexyl pentanoate (8.3%), 2-methylcyclohexyl octanoate (4.8%), and geranyl acetate (4.7%) Neryl acetate (26.0%), nerol (9.1%), neryl propionate (6.7%), γ-curcumene (10.8%) and cis-dihydro-occidentalol (4.3%) Nerol and its esters (acetate and propionate), limonene, and linalool Neryl acetate (17.6–35.6%), nerol (3.7–14.4%) and eudesmen-5-en-11-ol (6.4–23.5%) Nerol (10.7%), neryl acetate (28.9%), neryl propionate (11.4%) and γ-curcumene (11.4%) Guaiol (8.9%), nerol (7.0%) and β-caryophyllene (6.0%) Beta-caryophyllene (30.7%), α-pinene (12.1%), α-humulene (9.8%) and βsesquiphellandrene (6.9%) Rosifoliol (22.3%), β-caryophyllene (10.1%) and α-humulene (9.0%) Limonene (74.6%) and α-pinene (12.9%) Beta-caryophyllene (35.4%) and γ-curcumene (22.3%) Neryl acetate (18.2%), rosifoliol (5-eudesmen-11-ol, 11.3%) Delta-cadinene (8.4%) and γ-cadinene (6.7%) Gamma-gurjunene (11.06%), spathulenol (9.90%), alloaromadendrene (7.53%), β-caryophyllene (7.10%) β-pinene (51.6%), limonene (16.9%), α-humulene (5.6 %), β-caryophyllene (4.7 %) Alpha-pinene (47% and 41%), β-caryophyllene (14% and 5%) and α-curcumene (4% and 20%) Alpha-pinene (43.4%), (E, E)-farnesol (16.8%) and α-humulene (14.6%) Beta-caryophyllene (13.5%), menthone (10.8%), dodecane (9.1%) and menthol (8.9%) Fenchene (88.3%) Cis-α-bisabolene (22.7%), β-caryophyllene (12.6%), β-caryophyllene oxide (8.8%), β-bisabolene (4.7%) and viridiflorol (3.7%) Beta-elemene, beta-caryophyllene, geraniol, and camphene 1,8-cineole (11.7%) and β-caryophyllene (29.5%)

_ _ Insecticidal _

(Baser et al., 2002) (Cavalli et al., 2001) (Ramanoelina et al., 1992) (Baser et al., 2002) (Cavalli et al., 2001) (Benelli et al., 2018) (Cavalli et al., 2006)

_ _

(Cavalli et al., 2001) (El-Olemy et al., 2005)

_

(Bagci et al., 2013)

Insecticidal Cytotoxic, antimalarial, and antioxidant _ _ _ _ Antibacterial

(Kasmi et al., 2017) (Afoulous et al., 2011)

_

(Zeljkovic et al., 2015)

_ Phytotoxic Antimicrobial

(Leonardi et al., 2013) (Mancini et al., 2011) (Djihane et al., 2017)

Antimicrobial

(Djihane et al., 2017)

Anti-bacterial and antifungal

(Mastelic et al., 2005)

_

(Marongiu et al., 2003)

Antifungal _

(Angioni et al., 2003) (Usai et al., 2010)

_

(Satta et al., 1999)

_ Antimicrobial

(Tsoukatou et al., 1999) (Bougatsos et al., 2003)

_ _ Anticancer

(Javidnia et al., 2009) (Ruberto et al., 2002) (Pino et al., 2004) (Ornano et al., 2015)

_

(Elkiran et al., 2013)

Antibacterial and cytotoxic _

(Lawal et al., 2015)

_ _

(Lwande et al., 1993) (Firouznia et al., 2007)

_ Antimicrobial

(Öztürk et al., 2014) (Bougatsos et al., 2003)

_

(Baser et al., 2002)

H. artemisioides Boiss. et Hausskn. H. aucheri H. bracteiferum

H. cordifolium H. faradifani

H. forsskahlii (Gmel) Hilliard et Burt H. graveolens H. gymnocephalum

H. hypnoides H. italicum

H. italicum G. Don ssp. microphyllum (Willd) Nym

H. italicum ssp. serotinum H. kraussii H. H. H. H.

leucocephalum Boiss. litoreum Guss. melaleucum Rchb. ex Holl. microphyllum Cambess. ssp. tyrrhenicum Bacch. H. noeanum Boiss. H. odoratissimum (L.) Less.

H. oocephalum Boiss. H. plicatum subsp. isauricum H. rugulosum H. rupestre H. rusillonii

_ _ _

(Cavalli et al., 2001) (Baser et al., 2002) (Cavalli et al., 2001) (Jerković et al., 2016) (Cui et al., 2015)

(Kuiate et al., 1999)

(continued on next page) 8

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Table 3 (continued) Helichrysum spp.

Major compounds

Activity

Ref.

H. selaginifolium H. splendidum

Beta-pinene (38.2%) Germacrene D-4-ol (17.08%), germacrene D (9.04%), bicyclogermacrene (8.79%) and δ-cadinene (8.43%) Alpha-terpinene (14.9%), β-pinene (10.2%) and 1,8-cineole (8.6%) Beta-caryophyllene, α-humulene, α-pinene and limonene Alpha-pinene (28.3%), epi-α-bisabolol (21.9%) and β-caryophyllene (5.5%) Alpha-pinene (28.3%), epi-α-bisabolol (21.9%) and β-caryophyllene (5.5%)

_ _

(Cavalli et al., 2001) (Marongiu et al., 2006)

_ Antibacterial _ _

(Chagonda et al., 1999) (Roussis et al., 2002) (Tsoukatou et al., 1999) (Tsoukatou et al., 1999)

H. stoechas (L.) H. stoechas ssp. stoechas

69 (Rosa et al., 2007), 70 (Jerković et al., 2016), 71 (Proksch and Rodriguez, 1983), isocaproylbitalin A 72 (Bohlmann and Zdero, 1970) and bitalin A β-D-glucopyranoside derivative 73 (D’ Abrosca et al., 2013), nonanoylbitalin A 74 (Bohlmann and Zdero, 1970), oleoylbitalin A 75 (Bohlmann and Zdero, 1970), propanoylbitalin A 76 (Bohlmann and Zdero, 1970), 2,3-dihydro-5,7-dihydroxy-2-isopropenyl-6-(2-methylpropenoyl)benzofuran 77 (Bohlmann et al., 1984), 78, 79 (D’ Abrosca et al., 2013), 80 (Opitz and Hansel, 1971), and 81 (Hänsel et al., 1980) have been identified in different Helichrysum species. In a study in 2016, supercritical CO2 extraction of dried immortelle flowers (H. italicum) yielded tremetone derivatives 12-acetoxytremetone, gnaphaliol 70 as well as bitalin A 66 and 9-acetylgnaphadiol (Jerković et al., 2016). These compounds can be found as glucosides like β-D-OGlcs of gnaphadiol (Bohlmann et al., 1984; Mari et al., 2014; Rigano et al., 2014; Rosa et al., 2007; Taglialatela-Scafati et al., 2013). Phtalide derivatives have also been reported from Helichrysum spp. Platypterophtalide 82 (Jakupovic et al., 1987b) has been identified from the roots of H. platypterum (Jakupovic et al., 1987b). The compound 5,7-dihydroxyphtalide 83 (Vrkoč et al., 1973), 5,7-dimethoxyphtalide 84 (Opitz and Hansel, 1971), 7-hydroxy-5-methoxyphthalide 85 (Opitz and Hansel, 1971) and its glucosides 7-O-β-D-glucopyranoside, 7-O-(6-O-malonyl-β-D-glucopyranoside), and 7-O-[β-D-glucopyranosyl -β-D-glucopyranoside] have been reported from H. italicum, H. arenarium and H. polyphyllum. 4.4. Flavonoids, chalcones, and phenolic acids These compounds play an important role in the antioxidant and anti-inflammatory activities reported for this genus and contribute the major components of the polar fractions from various species (Facino et al., 1990). Table 2 shows the phenolic compounds isolated so far from the polar extracts of Helichrysum spp. Flavonoids have been found as both glycosides and free aglycones as well as dimers, trimers, or more complex aggregates (Fig. 4). For instance, free aglycones of apigenin, naringenin and kaempferol as well as their glycosides have been reported from the flower heads of H. plicatum (Bigović et al., 2017). Some other known flavonoids reported from Helichrysum spp. are prunin, isosalipurposide, narirutin, naringin, eriodictyol, luteolin, galuteolin, astragalin and quercetin (Bohlmann et al., 1984; Grinev et al., 2016; Mao et al., 2017). Since Helichrysum spp. are rich in flavonoids, many new structures have also been reported. Flavonoid-related structures 86-89 (Popoola et al., 2015a) have been isolated and identified from H. teretifolium (Popoola et al., 2015a). Compounds 90-93 (Morikawa et al., 2009) including four new flavanone and chalcone glycosides named arenariumosides I, II, III, and IV have been reported from the methanolic extract from the flowers of H. arenarium (Wang

Fig. 5. Sesquiterpenes from Helichrysum spp.

and possible active constituents present in Helichrysum spp. (Fig. 3). Tremetone derivatives such as bitalin A 66 (Bohlmann and Zdero, 1970; Rosa et al., 2007), acetoxytremetone 67, 68, acetoxyhydroxytremetone

9

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Fig. 6. Diterpenes from Helichrysum spp.

et al., 2009). Moreover, the precursors of flavonoids have been detected as monomers and dimers; chemical profiling of infusions and decoctions of H. italicum subsp. picardii by UHPLC-PDA-MS showed chlorogenic and quinic acids, dicaffeoylquinic-acid isomers and gnaphaliin-A as the major constituents (Pereira et al., 2017). Cameroonenoside A 94, a new cinnamic acid glycoside ester has been isolated for the first time from H. cameroonense (Antoine et al., 2011). Among various flavonoid constituents of Helichrysum, chalcones are considered to be one of the most important bioactive compounds (95 and 96) (do Nascimento and Mors, 1972d; Popoola et al., 2015a). For example, Aljancic et al. (2014) could identify two structurally distinct chalcone dimers namely tomoroside A 97 and tomoroside B 98 from H. zivojinii with anti-cancer activities. Similar to these chalcone dimers, Morikawa et al. (2015) identified three new dimeric dihydrochalcone glycosides named arenariumosides V-VII 99-101 from a methanol extract of everlasting flowers of H. arenarium L. Moench.

4.5. Terpens and essential oil Studies on the essential oil profile of plants belonging to Helichrysum genus constitute the major investigations established on these plants and revealed that these species produce a complex bouquet of vegetative and floral volatiles. Several essential oil products from Helichrysum spp. are being sold in the markets for medicinal and non-medicinal purposes. Table 3 summarizes the main compounds in the essential oil of different species and their biological activities. The studies have shown that the essential oil mainly includes monoterpenes and sesquiterpenes and the most reported activity for the oil is antibacterial and antifungal properties; however, there are a few reports about their insecticidal and cytotoxic activities. Helichrysum spp. is a rich source of sesquiterpenes like other members of the plants belonging to Compositae family. The chemical structures of sesquiterpenes that have been reported to date are depicted in Fig. 5 (102-119). Eudesman sesquiterpenes like eudesm-5-en11-ol 116 from the oil of H. italicum (Bianchini et al., 2004), drimane

10

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Fig. 7. Miscellaneous compounds from Helichrysum spp.

sesquiterpenes, and guaiane sesquiterpenes are found to be the most reported ones (Mari et al., 2014). A large number of diverse diterpenes have been reported from Helichrysum genus. Most of them belong to abietan, pimaran, and kaurane diterpenes (120-139) (Fig. 6and Table 6). For example, a diterpene acid related to erythroxydiol A 124 has been isolated from H. refluxum (Bohlmann et al., 1985). Triterpenes have also been isolated from some species. A few examples are 3β-hydroxy-28,13-ursanolide, ursololactone (Lloyd and Fales, 1967), and 3-acetyl-28-oleananoic acid (Bohlmann et al., 1979b).

derivatives like helinudichromene quinone 140 (Jakupovic et al., 1986), 6-acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran 141 (Bohlmann and Stöhr, 1980; de Quesada et al., 1972), 6-benzoyl-5,7dihydroxy-2-methyl-2-(4-methyl-3-pentenyl)chroman 142 (Bohlmann and Zdero, 1980a), 5,7-dihydroxy-6-isobutyryl-2,2-dimethylchroman 143, 5-hydroxy-6-isobutyryl-7-methoxy-2,2-dimethylchroman 144, 2,2dimethyl-8-(2-methyl-1-oxopropyl)-5,7-dimethylchroman 145, 146 (Jakupovic et al., 1986), 5,7-dihydroxy-2,3-dimethyl-4-chromanone 147 (Mutanyatta-Comar et al., 2006), acetophenones like 4-hydroxy-3-(3methyl-2-butenyl)acetophenone 148 (Appendino et al., 2007a; Sala et al., 2001), some phenolic derivatives 149 (Bohlmann and Misra, 1984), 150 (Bohlmann and Hoffmann, 1979), 151 (Bohlmann and Hoffmann, 1979), 152 (Sala et al., 2001), 153 (Jakupovic et al., 1987a), 154 (Bohlmann and Ziesche, 1979), glycosides like everlastosides A-M 155-160 (Morikawa et al., 2009), and other miscellaneous compounds, such as polyacetylenes, sulphur containing compounds, coumarins like

4.6. Miscellaneous compounds The compounds of Helichrysum spp. are not limited to the abovementioned compounds. This genus contains some other compounds belonging to other classes of natural products such as coumarate

11

12

_

H. italicum and grapefruit (Citrus × paradisi) extracts

4-hydroxy-3-(3-methyl-2-butenyl)acetophenone and 4hydroxy-3-(2-hydroxy-3-isopentenyl)acetophenone

149 and 1

_

Methanol extracts of H. sanguineum (L.) Kostel Arzanol and arenol Arzanol

_ 9, 10 9

Aureusidin 6-O-β-D-glucopyranoside, chalconaringenin 2´-Oβ-D-glucopyranoside

Methanol extract of H. foetidum Moench

_

85, 92

2-(2-methyl-butanoyl)-4-prenylphloroglucinol

45

The aqueous extracts (decoction) from the aerial parts of H. stoechas, as well as chlorogenic acid, cynarin, and arzanol Narirutin, naringin, eriodictyol, luteolin, galuteolin, astragalin, kaempferol

Arzanol, methylarzanol, and helipyrone

9, 24, and 4

9

Arzanol

9

Arzanol

Helinivene A and B

42 and 43

9

Compound /Extract

Compound No.

Table 4 Biological activities reported from the compounds of Helichrysum spp.

Anti-diabetic

Anti-diabetic

Anti-atherosclerotic

Antiacetylcholinesterase

Anti-inflammatory

Anti-inflammatory

Antioxidant and radical scavenging activity Anti-tyrosinase Anti-inflammatory and anti-HIVe

Antioxidant

Antioxidant

Antioxidant

Antioxidant

Antioxidant and anti-tyrosinase

Biological activities

(Popoola et al., 2015b)

In vitro, FRAP, ORAC, TEACa and Fe2+-induced microsomal lipid peroxidation assays Antioxidant activity at IC50 = 5.12 ± 0.90; 3.55 ± 1.92 ppm Antityrosinase activity at IC50 = 35.63 ± 4.67 and 26.72 ± 5.05 ppm The protective effect against the oxidative modification of lipid components induced by Cu2+ ions in human low density lipoprotein (LDL) and by tertbutyl hydroperoxide (TBH) in cell membranes Preserved lipoproteins from oxidative damage at 2 h of oxidation, and showed a remarkable protective effect on the reduction of polyunsaturated fatty acids and cholesterol levels, inhibiting the increase of oxidative products In vitro, autoxidation and iron (EDTAb)-mediated oxidation of linoleic acid at 37 °C, thermal (140 °C) autoxidation of cholesterol Protect linoleic acid against free radical attack In vitro, Cu-induced LDL oxidation assay Inhibit LDL oxidation at concentrations 0.5-10 μM In vitro, ABTSc assay, DPPHd radical-scavenging, ß-carotene/linoleic acid assay, scavenging of hydrogen peroxide test, superoxide anion scavenging test and hypochlorous acid scavenging test DPPH assay, IC50 = 12.90 ppm IC50 35.63 and 26.72 ppm, respectively Inhibit HIV-1 replication in T cells and the release of pro-inflammatory cytokines in stimulated primary monocytes The chronic inflammation induced by 12-O-tetradecanoylphorbol 13-acetate, the phospholipase A(2)-induced mouse paw oedema test, the carrageenaninduced mouse paw oedema test, and the writhing induced by acetic acid in the mouse Inhibit oedema formation, showing a similar profile to that obtained with cyproheptadine, inhibitor of both cyclooxygenase and 5lipoxygenase In vivo, inhibit 5-lipoxygenase (EC 7.13.11.34) activity and related leukotriene formation in neutrophils, as well as the activity of cyclooxygenase (COX)-1 (EC1.14.99.1) and the formation of COX-2-derived prostaglandin (PG)E2 in vitro (IC50 = 2.3–9 mM), inhibits microsomal PGE2 synthase (mPGES)-1 (EC 5.3.99.3, IC50 = 0.4 mM) rather than COX-2, block COX-2/ mPGES-1-mediated PGE2 biosynthesis in lipopolysaccharide-stimulated human monocytes and human whole blood, suppress the inflammatory response of the carrageenan-induced pleurisy in rats (3.6 ppm, i.p.), with significantly reduced levels of PGE2 in the pleural exudates In vitro Flowers and stems/leaves extracts inhibited antiacetylcholinesterase with IC50 values of 260.7 and 654.8 ppm AS model using thoracic aortas vascular ring Inhibit the expression of VEGFf, CRPg, JNK2h, p38 and NO (nitric oxide) at different level, reduce the expression of CRP, inhibit the kinases activity of JNK2 and p38, and then suppress the mitogen-activated protein kinase (MAPK) pathway, which resulted in the decrease of NO synthesis, VEGF expression and endothelial adhesion factor expression Dipeptidyl peptidase-IV inhibitory activity in vivo Inhibit the increase in blood glucose elevation in sucrose-loaded mice (500 ppm p.o.), inhibit the enzymatic activity against dipeptidyl peptidase-IV (IC50 = 41.2 ppm) In vitro Inhibit digestive α-amylase and α-glucosidase activities and SGLT1mediated methylglucoside uptake in Caco-2 cells in the presence of Na(+), decreased blood glucose levels after an oral maltose tolerance test, reduced postprandial glucose levels after the oral starch tolerance test, improve hyperinsulinemia and HOMAi index in a dietary model of insulin resistance in rats

(continued on next page)

(De La Garza et al., 2013)

(Morikawa et al., 2015)

(Mao et al., 2017)

(Silva et al., 2017)

(J. Bauer et al., 2011)

(Albayrak et al., 2008) (Popoola et al., 2015b) (Appendino et al., 2007b) (A. Sala et al., 2003)

(Mutanyatta-Comar et al., 2006) (Tirillini et al., 2013)

(Rosa et al., 2007)

(Rosa et al., 2011)

Ref.

Study design/Result

M. Akaberi, et al.

Industrial Crops & Products 138 (2019) 111471

Antiproliferative

H. plicatum DC. subsp. plicatum ethanol extract

The methanol extract of H. graveolens flowers as well as apigenin

H. plicatum DC. subsp. plicatum extract

Methanol extract of H. stoechas

97 and 98

_

_

13

i

h

g

f

e

d

c

b

a

Anti-protozoal

Nephro protective

Anti-cancer

Anti-cancer

the ferric reducing ability of plasma; the oxygen radical absorbance capacity; trolox equivalent antioxidant capacity. ethylenediaminetetraacetic acid. 2,2′-azinobis-3-ethylbenzothiazoline-6-sulphonic acid. 1,1-diphenyl-2-picrylhydrazyl. human immunodeficiency viruses. vascular endothelial growth factor. c-reactive protein. c-Jun N-terminal kinases. homeostatic model assessment.

Dichloromethane extract of H. oocephalum

Anti urolithiasis

Naringenin 7-O-β-D-glucopyranoside, apigenin 7-O-βDglucopyranoside, apigenin 7-O-gentiobioside, and apigenin 7,4-di-O-β-D-glucopyranoside Tomoroside A and B

11-14, 20-23, 3335, 58-65

Wound healing

Ethanol extract of H. plicatum flowers

_

Anti-aging, antioxidant and moderate antityrosinase and anti-elastase

H. teretifolium total extract and isolated flavonoids 4'methoxyquercetin and quercetin

_

Biological activities

Compound /Extract

Compound No.

Table 4 (continued)

In vitro, NCI-H460 and NCI-H460/R cells 97 inhibited topo IIα and hif-1α expression and stimulated doxorubicin anticancer effect, while 98 increased the expression of hif-1α, probably acting as antioxidant and redox status modulator In vivo (rats); 100 ppm; gentamicin-induced nephrotoxicity Decreased serum blood urea nitrogen, and creatinin, liver and kidney oxidant markers and tubular necrosis as well as by an increase in antioxidant enzymes, increased liver and kidney tissue malondialdehyde levels In vivo; the linear incision and the circular excision wound models Possessed significant anti-inflammatory, antioxidant, anti-hyaluronidase and anticollagenase activities In vivo (rats); 125, 250, and 500 ppm; 1% ethylene glycol and 1% ammonium chloride-induced urolithiasis Decreased levels of both serum and urine biochemical parameters, Urine CaOx level, improved histopathological parameters In vitro (HeLa cells); MTT assay; 0.008, 0.016, 0.031, 0.063,0.125, 0.250, 0.500 and 1.000 mg/mL; non-treated cells (control) Dose-dependent antiproliferative effects at concentrations over 0.06 mg/mL with an IC50 of 0.15 mg/mL In vitro; Leishmania donovani (MHOM-ET-67/L82) axenically grown amastigotes; 100 to 0.001 ppm 34 with IC50 1.79 ± 0.17 μM showed the highest activity

Compounds quercetin and 4'-methoxyquercetin demonstrated the highest inhibitory activities on Fe2+-induced lipid peroxidation (IC50 = 2.931; 6.449 ppm); tyrosinase (8.092; 27.573) and elastase (43.342; 86.548) In vitro; isolated rat ileum Inhibit the spontaneous ileum contractions and contractions induced by acetylcholine, histamine, barium and potassium ions Inhibitory activity on tumor necrosis factor-α (1 ppb)-induced cytotoxicity on cancerous cell lines

Study design/Result

(Akaberi et al., 2019)

(Les et al., 2017)

(Süntar et al., 2013)

(Apaydin Yildirim et al., 2017)

(Aljančić et al., 2014)

(Wang et al., 2009)

(Bigovic et al., 2010)

(Popoola et al., 2015a)

Ref.

M. Akaberi, et al.

Industrial Crops & Products 138 (2019) 111471

Industrial Crops & Products 138 (2019) 111471

(Appendino et al., 2007a) (Albayrak et al., 2008) (Albayrak et al., 2008) (Albayrak et al., 2008) (Turker and Usta, 2008) (Djihane et al., 2017)

5. Pharmacology

_ _ _ _ _

A variety of pharmacological activities have been reported for the bioactive compounds from Helichrysum spp., particularly arzanol as a prenylated heterodimeric phloroglucinyl α-pyrone derivative (Table 4). Arzanol has been reported to possess anti-inflammatory, anti-HIV, antioxidant, antibiotic, anti-cancer and antiviral activities (Rosa et al., 2017). Arzanol inhibits NFκB activation, HIV replication in T cells, release of proinflammatory mediators like IL-1β, IL-6, IL-8 and TNF-α, and biosynthesis of PGE2 by inhibiting the mPGES-1 enzyme (Kothavade et al., 2013) (Table 4). Although the activities for different extracts and pure compounds from Helichrysum spp. are diverse, the most cited ones are related to its antibacterial and antiviral properties. Table 5 shows the studied species from everlasting flowers with antimicrobial activities. In a screening study, Albayrak et al. (2010) investigated the antimicrobial activities of the phenol-rich extracts of some Turkish Helichrysum spp. including, H. arenarium (L.) Moench subsp. aucheri (Boiss), H. armenium DC. subsp. armenium, H. artvinense Davis & Kupicha, H. chionophilum Boiss. & Bal, H. compactum Boiss, H. goulandriorum E. Georgiadou, H. graveolens (Bieb.) Sweet, H. heywoodianum Davis, H. kitianum Yıldız, H. noeanum Boiss., H. orientale (L.) DC. and H. pallasii (Sprengel) Ledeb (Albayrak et al., 2010). All extracts showed strong antimicrobial activity against microorganisms including thirteen bacteria and two yeasts in the agar diffusion test (Albayrak et al., 2010). Moreover, the anti-microbial activity of the ethanol extract of H. plicatum has been investigated against various bacteria and fungi as well as the yeast Candida albicans using the microdilution method (Bigović et al., 2017). Gram-positive bacteria with MIC values of 0.02 mg/mL were more sensitive to the plant extract compared with Gram-negative ones. Moreover, the sensitivity of fungi was more than bacteria (Bigović et al., 2017). Not only the extracts showed strong antimicrobial activities, but also the isolated compounds exhibited pharmacological effects. For example, phloroglucinol derivatives 17-19 showed antifungal activities against Cladosporium herbarum (Tomás-Lorente et al., 1989). In another study, both methanol extract and the phenolic compounds from H. arenarium (L.) Moench subsp. arenarium inflorescences showed antibacterial activity against lower respiratory tract pathogens (standard strains and clinical isolates) (Gradinaru et al., 2014). The extract exhibited similar antibacterial effects against methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae clinical isolates (MIC = 2.5 mg/mL), displaying a higher activity against ampicillin-resistant Moraxella catarrhalis isolate (MIC = 0.15 mg/mL). In addition, combination of the extract with ciprofloxacin increased the anti-bacterial activity (Gradinaru et al., 2014). In addition, most of the studies on this genus have investigated the essential oil activity and composition. Thus, the majority of pharmacological studies reported for these plants, mostly investigating antimicrobial activities, are related to the essential oils (Table 3).

Diethyl ether extract Methanol extract Methanol extract Methanol extract _ Essential oil italicum pamphylicum sanguineum chasmolycicum plicatum italicum

6. Conclusion long terminal repeats.

Everlasting flowers (Helichrysum spp.) have been shown to be an interesting source of bioactive secondary metabolites with diverse properties, potentially capable of treating microbial diseases. However, more studies must be established to investigate the intact and unexplored species to find out their potential activities and the responsible bioactive components. Moreover, supplementary studies such as clinical trials are necessary for those species and properties that are already investigated and suggested by traditional and modern medicine.

a

H. H. H. H. H. H. Herpes Simplex Virus Klebsiella pneumoniae Staphylococcus aureus, Proteus vulgaris S. aureus Streptococcus pyogenes, S. aureus, S. epidermidis Candida albicans, Enterococcus cereus, and Saccharomyces cerevisiae

25 ppm and 5 μM H. italicum HIV-1-LTRa

Phloroglucinol and acetophenone derivatives Arzanol

esculetin, scopoletin, and isoscopoletin (Fig. 7) (Karasartov et al., 1992; Morikawa et al., 2009; Wang et al., 2009).

100 to 400 ppm _ _ _ _ 6.325 ppm, 0.79 ppm, 12.65 ppm

Inhibition of the TNFα-induced HIV-1-LTR transactivation in a T cell line

(Tomás-Barberán et al., 1990) (Appendino et al., 2007a)

(Nostro et al., 2000) (Tundis et al., 2005) 125 ppm 50 ppm Diethyl ether extract Methanol extract

italicum italicum italicum italicum H. H. H. H. Bacillus subtilis Micrococcus luteus Staphylococcus aureus Penicillium

Microorganism

Table 5 Helichrysum spp. with reported antimicrobial activities.

MIC Extract/compound Species

Description

Ref.

M. Akaberi, et al.

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Table 6 The phytochemicals reported from Helichrysum spp. Compound Pyrones 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Plant

Name

Ref.

H. italicum H. italicum H. italicum H. italicum and H. stoechas H. arenarium and H. stoechas H. arenarium and H. stoechas H. auriceps H. cephaloideum H. italicum ssp. microphyllum H. italicum ssp. microphyllum H. oocephalum Helichrysum spp.

Micropyrone Yangonin O12-De-Me, 12-O-[3-hydroxy-3-methylglutaroyl-(6)-β-D-glucopyranoside Yangonin O12-De-Me, 12-O-(6-O-malonyl-β-D-glucopyranoside) Helipyrone A

(Appendino et al., 2007a) (D’ Abrosca et al., 2013) (D’ Abrosca et al., 2013) (Opitz and Hänsel, 1970)

Helipyrone B (norhelipyrone)

(Rios et al., 1991)

Helipyrone C

(Rios et al., 1991)

23-methylauricepyrone Norauricepyrone Arzanol

(Bohlmann and Zdero, 1980b) (Jakupovic et al., 1986) (Appendino et al., 2007a)

Arenol

(Appendino et al., 2007a)

23-Methyl-6-O-desmethylauricepyrone 2H-Pyran-2-one, 6-ethyl-4-hydroxy-5-methyl-3-[[2,4,6-trihydroxy-3-(3-methyl-2buten-1-yl)-5-(2-methyl-1-oxopropyl)phenyl]methyl]Arenol B Arenol C Heliarzanol

(Akaberi et al., 2019) (Jakupovic et al., 1986) (Akaberi et al., 2019) (Akaberi et al., 2019) (Taglialatela-Scafati et al., 2013)

Auricepyrone 3-[3-Acetyl-5-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxybenzyl]-4-hydroxy-5,6dimethyl-H-pyran-2-one 3-[3-Acetyl-5-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxybenzyl]-4-hydroxy-5methyl-6-ethyl-H-pyran-2-one 3-[3-Acetyl-5-(3,7-dimethyl-2,6-octadienyl)-2,4,6-trihydroxybenzyl]-4-hydroxy-5methyl-6-propyl-H-pyran-2-one Achyroclinopyrone A Achyroclinopyrone B 16Z/E-Achyroclinopyrone C 16Z/E-Achyroclinopyrone D Methyl arzanol

(Bohlmann and Zdero, 1980b) (Tomás-Barberán et al., 1990; Tomás-Lorente et al., 1989) (Tomás-Barberán et al., 1990; Tomás-Lorente et al., 1989) (Tomás-Barberán et al., 1990; Tomás-Lorente et al., 1989) (Akaberi et al., 2019) (Akaberi et al., 2019) (Akaberi et al., 2019) (Akaberi et al., 2019) (Rosa et al., 2007)

Italidipyrone Italipyrone 20-prenylitalipyrone Plicatipyrone Isobutyrylhelichromenopyrone 2-methylbutyrylhelichromenopyrone Helicerastripyrone Helicepyrone Cycloarzanol Helicyclol Lepidissipyrone 8-prenyllepidissipyrone Helitalone A Helitalone B

(Hänsel et al., 1980) (Hänsel et al., 1980; Rios et al., 1991) (Hänsel et al., 1980) (Hänsel et al., 1980) (Jakupovic et al., 1986) (Jakupovic et al., 1986) (Bohlmann et al., 1984) (Akaberi et al., 2019) (Akaberi et al., 2019) (Akaberi et al., 2019) (Jakupovic et al., 1989b) (Jakupovic et al., 1989b) (Werner et al., 2019) (Werner et al., 2019)

Helinudifolin 1,1'-[(6-Methylheptylidene)bis(3,4-dihydro-5,7-dihydroxy-2,2-dimethyl-2H-1benzopyran-6,6'-diyl)]bis[2-methyl-1-propanone] Helinivene A Helinivene B 1-(butanone)-3-prenyl-phloroglucinol 1-(2-methylbutanone)-3-prenyl-phloroglucinol 1-butanone-3-(3-methylbut-2-enylacetate)-phloroglucinol 1-(2-methylpropanone)-3-prenylphloroglucinol Caespitate 2-butanoyl-4-prenylphloroglucinol 2-(2-methylpropanoyl)-4-prenylphloroglucinol 2-methyl-1-[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)-1-butanone(Appendino et al., 2007a)

(Jakupovic et al., 1986) (Jakupovic et al., 1986)

16 17

H. oocephalum H. oocephalum H. italicum ssp. microphyllum H. auriceps H. decumbens

18

H. decumbens

19

H. decumbens

20 21 22 23 24

H.oocephalum H.oocephalum H.oocephalum H.oocephalum H. italicum ssp. Microphyllum 25 H. italicum 27 H. stoechas 28 H. stoechas 29 H. plicatum 30 H. mixtum 31 H. mixtum 32 Helichrysum spp. 33 H. oocephalum 34 H. oocephalum 35 H. oocephalum 36 H. lepidissimum 37 H. lepidissimum 38 H. italicum 39 H. italicum Phloroglucinols 40 H. nudifolium 41 H. platypterum 42 43 44 45 46 47 48 49 50 51

H. niveum H. niveum H. niveum H. niveum H. niveum H. niveum H. niveum H. paronychioides Helichrysum spp. Helichrysum spp.

52 53 54 55 56 57

H. caespititium Helichrysum spp. H. gymnocomum Helichrysum spp. H. aphelexioides H. monticola

Caespitin 2-methyl-1-[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]-1-propanone 2-methyl-1-[2,4,6-trihydroxy-3-(2-hydroxy-3-methyl-3-butenyl)phenyl]-1-propanone 5,7-dihydroxy-2-isopropyl-4H-1-benzopyran-4-one 5'-deprenylhemihumulone 3-(3,4-dihydroxyphenyl)-1-[3-(3,7-dimethyl-2,6-octadienyl)-2,4-dihydroxy-6methoxyphenyl]-1-propanone.3'-geranyl-2',3,4,4'-tetrahydroxy-6'methoxydihydrochalcone

(Popoola et al., 2015b) (Popoola et al., 2015b) (Popoola et al., 2015b) (Popoola et al., 2015b) (Popoola et al., 2015b) (Popoola et al., 2015b) (Popoola et al., 2015b) (Mutanyatta-Comar et al., 2006) (Jakupovic et al., 1986) (Bohlmann and Mahanta, 1979; Bohlmann and Suwita, 1979b; Bohlmann and Zdero, 1979) (Dekker et al., 1984) (Drawert and Beier, 1976) (Bohlmann and Mahanta, 1979) (Bohlmann et al., 1984) (Randriaminahy et al., 1992) (Jakupovic et al., 1989b)

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Table 6 (continued) Compound

Plant

58-65 H. oocephalum Benzofurans 66 H. italicum and H. stoechas 67 H. italicum subsp. microphyllum 68 H. italicum subsp. microphyllum 69 H. italicum subsp. microphyllum 70 H. italicum 71 H. stoechas 72 H. italicum 73 H. italicum 74 H. italicum ssp. microphyllum 75 H. italicum ssp. microphyllum 76 H. italicum ssp. microphyllum 77 Helichrysum spp. 78 79 80 81 82 83 84 85

Name

Ref.

Helispiroketals A-H

(Akaberi et al., 2019)

Bitalin A (R)-form

(Bohlmann and Zdero, 1970; Rosa et al., 2007)

Acetoxytremetone

(Rosa et al., 2007)

Diacetyl-2,3-dihydro-3-hydroxy-2-[1-(hydroxymethyl)ethenyl]benzofuran

(Rosa et al., 2007)

Acetoxyhydroxytremetone

(Rosa et al., 2007)

Gnaphaliol 6-methyleuparin Isocaproylbitalin A Isobenzofuranone Nonanoylbitalin A

(Jerković et al., 2016) (Proksch and Rodriguez, 1983) (Bohlmann and Zdero, 1970) (D’ Abrosca et al., 2013) (Bohlmann and Zdero, 1970)

Oleoylbitalin A

(Bohlmann and Zdero, 1970)

Propanoylbitalin A

(Bohlmann and Zdero, 1970)

2,3-dihydro-5,7-dihydroxy-2-isopropenyl-6-(2-methylpropenoyl)benzofuran [(R)form] 3-hydroxydihydrobenzofuran glycosides 3-hydroxydihydrobenzofuran glycosides 10-acetoxytoxol bractein Platypterophthalide 5,7-dihydroxy-1(3 H)-isobenzofuranone 5,7-dimethoxy-1(3 H)-isobenzofuranone 7-hydroxy-5-methoxy-1(3 H)-isobenzofuranone. 7-Hydroxy-5-methoxyphthalide

(Bohlmann et al., 1984) (D’ Abrosca et al., 2013) (D’ Abrosca et al., 2013) (Hänsel et al., 1980) (Farkas and Pallos, 1965; Honda et al., 1991) (Jakupovic et al., 1987b) (Vrkoč et al., 1973) (Opitz and Hansel, 1971) (Opitz and Hansel, 1971)

Isoglabranin 4'-methoxyquercetin 4'-methoxykaempferol mosloflavone Arenariumoside I Arenariumoside II Arenariumoside III Arenariumoside IV Cameroonenoside A Derricidin Heliteretifolin Tomoroside A Tomoroside B Arenariumoside V Arenariumoside VI Arenariumoside VII

(Popoola et al., 2015a) (Popoola et al., 2015a) (Popoola et al., 2015a) (Popoola et al., 2015a) (Morikawa et al., 2009) (Morikawa et al., 2009) (Morikawa et al., 2009) (Morikawa et al., 2009) (Antoine et al., 2011) (do Nascimento and Mors, 1972d) (Popoola et al., 2015a) (Aljančić et al., 2014) (Aljančić et al., 2014) (Morikawa et al., 2015) (Morikawa et al., 2015) (Morikawa et al., 2015)

H. italicum H. italicum H. italicum H. bracteatum H. platypterum H. arenarium H. arenarium H. arenarium and H. polyphyllum Flavonoids and Chalcones 86 H. tereifolium 87 H. tereifolium 88 H. tereifolium 89 H. tereifolium 90 H. arenarium 91 H. arenarium 92 H. arenarium 93 H. arenarium 94 H. cameroonense 95 H. rugulosum 96 H. teretifolium 97 H. zivojinii 98 H. zivojinii 99 H. arenarium 100 H. arenarium 101 H. arenarium Sesquiterpenes 102 H. bilobum ssp. bilobum 103 H. albirosulatum 104 H. splendidum 105 H. dasyanthum 106 H. splendidum 107 H. splendidum 108 H. nudifolium 109 H. nudifolium 110 H. nudifolium 111 H. italicum 112 H. chinosphaerum 113 H. chionosphaerum 114 H. dasyanthum 115 H. italicum 116 H. arenarium 117 H. dasyanthum 118 H. petiolare 119 H. ambiguum Diterpenes 120 H. refluxum 121 H. chionosphaerum

4-Ambiguen-1-ol 10-hydroxy-3-aromadendranone 4-hydroxy-10(14),11α(13-dihydro)-guaiadien-12,8-olide 4-hydroxy-1(10),11(13)-guaiadien-12,8-olide Helisplendiolide 4-hydroxy-9-guaien-12,8-olide 8α-hydroxy-α-gurjunene 8α-acetoxy-α-gurjunene 2-isocomanone Italicene 1(10),4-bicyclogermacradien-13-oic acid Humulatrien 4,10(14)-cadinadiene-1,3,9-triol Italicene ether 5-selinen-11-ol 3,9-dihydroxy-δ-cadinene 1,9-cadinadien-3-one [(4α,6α,7α)-form] 1,3,5,7,9-cadinapentaen-14-al

(Jakupovic et al., 1989a) (Bohlmann et al., 1978) (Jakupovic et al., 1989b) (Jakupovic et al., 1989b) (Bohlmann and Suwita, 1979a) (Jakupovic et al., 1989b) (Bohlmann et al., 1978) (Bohlmann et al., 1978) (Jakupovic et al., 1986) (Honda et al., 1991) (Jakupovic et al., 1989b) (Bohlmann et al., 1980) (Jakupovic et al., 1989b) (Cool et al., 1994) (Morikawa et al., 2015) (Jakupovic et al., 1989b) (Jakupovic et al., 1989b) (Jakupovic et al., 1989a)

3,15-erythroxyladien-18-oic acid 7,13-abietadiene (ent-5α-form)

122 123 124 125

7,13-abietadien-12β-ol Atisirenic acid Erythroxydiol A 15-stachene-3,17-diol

(Bohlmann et al., 1985) (Bohlmann et al., 1980; Jakupovic et al., 1990) (Jakupovic et al., 1990) (Bohlmann et al., 1980) (Lloyd et al., 1978) (Lloyd and Fales, 1967)

H. H. H. H.

formosissinum chionosphaerum dendroideum dendroideum

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Table 6 (continued) Compound

Plant

Name

Ref.

126 H. dendroideum 127 H. nudifolium 128 H. chionosphaerum 129 H. chionosphaerum 130 H. aureum and H. cooperi 131 H. fulvum 132 H. fulvum 133 H. chionosphaerum 134 H. chionosphaerum 135 H. davenportii 136 H. foetidum 137 Helichrysum spp. 138 H. dendroideum 139 H. dendroideum Miscellaneous compounds 140 H. nudifolium 141 Helichrysum spp.

15-stachene-3,19-diol 13(16),14-gnaphaladien-8α-ol 10(20),16-grayanotoxadien-19-oic acid [(1β,5β,9β)-form] Acetyl-16-kauren-19-oic acid 11-acetyl-16-kauren-19-oic acid 11-hydroxy-19-helvifulvanoic acid (ent-11β)-form 11-acetoxy-19-helvifulvanoic acid 19-helvifulvanol [ent-form] Helifulvanic acid 12β-hydroxy-15-kauren-19-oic acid 15α-hyroxy-16-kauren-19-oic acid Grandiflorenic acid (ent-form) 15-kaurene-17,19-diol (ent-form) 16-kaurene-3β,19-diol

(Lloyd and Fales, 1967) (Jakupovic et al., 1986) (Jakupovic et al., 1989b) (Jakupovic et al., 1989b) (Bohlmann et al., 1978) (Bohlmann et al., 1979a) (Bohlmann et al., 1979a) (Bohlmann et al., 1980) (Bohlmann et al., 1980) (Jakupovic et al., 1989a) (Barrero et al., 1998) (Herz and Kulanthaivel, 1984) (Lloyd and Fales, 1967) (Lloyd and Fales, 1967)

Helinudichromene quinone 6-acetyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran

142 143 144 145 146 147 148 149 150 151 152 153 154 155-160

6-benzoyl-5,7-dihydroxy-2-methyl-2-(4-methyl-3-pentenyl)chroman 5,7-dihydroxy-6-isobutyryl-2,2-dimethylchroman 5-hydroxy-6-isobutyryl-7-methoxy-2,2-dimethylchroman 2,2-dimethyl-8-(2-methyl-1-oxopropyl)-5,7-dimethylchroman 5-hydroxy-8-isobutyryl-2,2-dimethyl-7-methoxychroman 5,7-dihydroxy-2R,3R-dimethyl-4-chromanone 4-hydroxy-3-(3-methyl-2-butenyl)acetophenone Spinoflavone B Dihydroamorphastilbol 2,4-dihydroxy-6-(2-phenylethyl)-3-prenylbenzoic acid 3-(2-hydroxyethyl)acetophenone 4-O-β-D-glucopyranoside Acuminatolide Aureonitol, (-)-form Everlastoside F-K

(Jakupovic et al., 1986) (Bohlmann and Stöhr, 1980; de Quesada et al., 1972) (Bohlmann and Zdero, 1980a) (Jakupovic et al., 1986) (Jakupovic et al., 1986) (Jakupovic et al., 1986) (Jakupovic et al., 1986) (Mutanyatta-Comar et al., 2006) (Appendino et al., 2007a; Sala et al., 2001) (Bohlmann and Misra, 1984) (Bohlmann and Hoffmann, 1979) (Bohlmann and Hoffmann, 1979) (Sala et al., 2001) (Jakupovic et al., 1987a) (Bohlmann and Ziesche, 1979) (Morikawa et al., 2009)

H. H. H. H. H. H. H. H. H. H. H. H. H. H.

monticola platypterum platypterum platypterum platypterum paronychioides italicum rugulosum umbraculigerum umbraculigerum, italicum acuminatum aureonitens arenarium

Table 7 Scientific names of the studied plant taxa. No.

Plant name

No.

Plant name

1

H. acuminatum (Link) DC.

54

2

H. adenocarpum DC.

55

3

H. albirosulatum Killick

56

4 5 6 7 8 9

H. ambiguum (Pers.) C.Presl H. amorginum Boiss. & Orph. H. aphelexioides DC. H. appendiculatum Less. H. arenarium (L.) Moench Basionym: Gnaphalium arenarium L. H. arenarium subsp. aucheri (Boiss) P.H.Davis & Kupicha Basionym: Helichrysum aucheri Boiss. H. argyrophyllum DC. H. armenium DC. subsp. armenium H. artemisioides Boiss. & Hausskn. H. athrixiifolium O.Hoffm. H. artvinense Davis & Kupicha H. aureum (Houtt.) Merr. Basionym: Gnaphalium aureum Houtt. H. auriceps Hilliard H. auronitens Sch.Bip. H. bilobum subsp. bilobum H. bracteatum (Vent.) Willd. Basionym: Xeranthemum bracteatum Vent. H. bracteiferum (DC.) Humbert Basionym: Stenocline bracteifera DC. H. caespititium (DC.) Sond. Basionym: Helichrysum lineare var. caespititium DC. H. callicomum Harv. H. calophalum Klatt H. cameroonense Hutch. & Dalziel H. cephaloideum DC. H. chasmolycicum P.H.Davis H. chionophilum Boiss. & Balansa H. chionosphaerum DC. H. cochleariforme DC. H. compactum Boiss.

57 58 59 60 61 62

H. italicum subsp. microphyllum (Willd.) Nym.Basionym: Gnaphalium microphyllum Willd. H. italicum subsp. picardii (Boiss. & Reut.) Franco Basionym: Helichrysum picardii Boiss. & Reut. H. italicum subsp. serotinum (Boiss.) P.Fourn. Basionym: Helichrysum serotinum var. occidentale Boiss. H. kitianum Yıldız H. kraussii Sch. Bip H. lepidissimum S.Moore H. leucocephalum Ausfeld H. litoreum Guss. H. longifolium DC.

63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83

H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H.

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

maracandicum Popov mechowianum Klatt melaleucum Rchb. miconiifolium DC. microphyllum (Willd.) Cambess. subsp. tyrrhenicum Bacch. & al. mixtum (Kuntze) Moeser Basionym: Gnaphalium mixtum Kuntze monticola Hilliard niveum Graham noeanum Boiss. nudifolium (L.) Less. Basionym: Gnaphalium nudifolium L. nudifolium var. leiopodium (DC.) Moeser Basionym: Helichrysum leiopodium DC. obconicum DC. odoratissimum (L.) Sweet Basionym: Gnaphalium odoratissimum L. oocephalum Boiss. orientale Gaertn. pallasii Ledeb. pamphylicum P.H.Davis & Kupicha panduratum O.Hoffm. ex De Wild. & T.Durand. pandurifolium Schrank paronychioides DC. patulum (L.) D.Don Basionym: Gnaphalium patulum L.

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Table 7 (continued) No.

Plant name

No.

Plant name

31 32 33 34 35 36 37

H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H. H.

84 85 86 87 88 89 90

H. pedunculatum Hilliard & B.L.Burtt H. petiolare Hilliard & B.L.Burtt H. platypterum DC. H. plicatum DC. H. plicatum subsp. isauricum Parolly H. plicatum subsp. plicatum H. polyphyllum Ledeb. H. psilolepis Harv. H. reflexum N.E.Br. H. rugulusum Less. H. rupestre Guss. ex Nyman H. rusillonii Hochr. H. sanguineum (L.) Kostel. Basionym: Gnaphalium sanguineum L. H. selaginifolium (DC.) Viguier & Humbert Basionym: Gnaphalium selaginifolium DC. Helichrysum setosum Harv. H. splendidum (Thunb.) Less. Basionym: Gnaphalium splendidum Thunb. H. stoechas Moench H. stoechas subsp. stoechas H.subglomeratum Less. H. tenax M.D. Hend var. tenax H. teretifolium (L.) D.Don Basionym: Gnaphalium teretifolium L. H. tomentosulum (Klatt) Merxm. Basionym: Stenocline tomentosula Klatt H. zivojini Černjavski & Soska

39 41 42 43 44 45 46 47 48 49 50 51 52 53

cooperi Harv. cordifolium DC. crispum (L.) D. Don [Illegitimate] dasyanthum (Willd.) Sweet davenportii F.Muell. decumbens Cambess. dendroideum N.A.Wakef. devium J.Y.Johnson dregeanum Sond. & Harv. ecklonis Sond. faradifani Scott Elliot foetidum (L.) Cass. Basionym: Gnaphalium foetidum L. formosissimum Sch.Bip. forsskahlii Hilliard & B.L.Burtt fulgidum Willd fulvum N.E.Br. goulandriorum Georgiadou graveolens (M.Bieb.) Sweet Basionym: Gnaphalium graveolens M.Bieb. gymnocephalum (DC.) Humbert Basionym: Stenocline gymnocephala DC. gymnocomum DC. heywoodianum Davis hypnoides (DC.) Viguier & Humbert Basionym: Aphelexis hypnoides DC. italicum (Roth) Don Basionym: Gnaphalium italicum Roth

92 94 95 96 97 98 99 100 101 102 103 104 105 106

Conflict of interests

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