Antiparasitic activity in Asteraceae with special attention to ethnobotanical use by the tribes of Odisha, India

Parasite. 2018; 25: 10. Published online 2018 Mar 12. doi: 10.1051/parasite/2018008 PMCID: PMC5847338 Language: English | French Sujogya Kumar Panda1,2,* and Walter Luyten2 Author information ► Article notes ► Copyright and License information ► Go to: Abstract The purpose of this review is to survey the antiparasitic plants of the Asteraceae family and their applicability in the treatment of parasites. This review is divided into three major parts: (a) literature on traditional uses of Asteraceae plants for the treatment of parasites; (b) description of the major classes of chemical compounds from Asteraceae and their antiparasitic effects; and (c) antiparasitic activity with special reference to flavonoids and terpenoids. This review provides detailed information on the reported Asteraceae plant extracts found throughout the world and on isolated secondary metabolites that can inhibit protozoan parasites such as Plasmodium, Trypanosoma, Leishmania, and intestinal worms. Additionally, special attention is given to the Asteraceae plants of Odisha, used by the tribes of the area as antiparasitics. These plants are compared to the same plants used traditionally in other regions. Finally, we provide information on which plants identified in Odisha, India and related compounds show promise for the development of new drugs against parasitic diseases. For most of the plants discussed in this review, the active compounds still need to be isolated and tested further. Keywords: Asteraceae, Plasmodium, Trypanosoma, Leishmania, Odisha (India), antiparasitic drugs Go to: Introduction − Antiparasitic research Parasite diseases are a major source of disease in both humans and animals and result in significant economic losses. Protozoan parasites threaten the lives of billions of people worldwide and are associated with significant morbidity and large economic impacts [88]. The lack of proper vaccines and the emergence of drug resistance make the search for new drugs for treatment and prophylaxis more urgent, including from alternative sources like plants. In 2005, Pink et al. published a review emphasizing that new antiparasitic drugs are urgently needed to treat and control diseases such as malaria, leishmaniasis, sleeping sickness and filariasis [124]. The discovery of quinine from Cinchona succirubra (Rubiaceae) and its subsequent development as an antimalarial drug represent a milestone in the history of antiparasitic drugs from nature. The 2015 Nobel Prize in Physiology or Medicine was awarded for the discovery of artemisinin and avermectin, which fundamentally changed the treatment of parasitic diseases around the globe. Both compounds are natural products, once again showing that nature can be a powerful source of medicines. A breakthrough for the development of antimalarial drugs was the identification of the sesquiterpene artemisinin from Artemisia annua (Asteraceae), which can even kill multidrug-resistant strains of Plasmodium falciparum [3,62]. Several semisynthetic derivatives of artemisinin (e.g., the water-soluble artesunate) have been developed and are used in clinical practice today [62]. There are three major protozoan parasitic infections, caused by Plasmodium, Leishmania and Trypanosoma species. Plasmodium is the most significant of the protozoan parasites that infect humans. Found in tropical and sub-tropical regions of the world, malaria parasites threaten the lives of 3.3 billion people and cause 0.6–1.1 million deaths annually [70]. Six species of Plasmodium are responsible for causing malaria in humans [144], with Plasmodium falciparum and Plasmodium vivax being the most common and major causes. Leishmaniasis is caused by Leishmania sp., generating 1–1.5 million new cases annually [104]. The disease is endemic in 98 countries and is one of the neglected tropical diseases where the majority of the affected individuals are rural, underprivileged, and economically disadvantaged. African sleeping sickness (trypanosomiasis), is caused by two parasitic protozoans: Trypanosoma brucei gambiense (West Africa) and Trypanosoma brucei rhodesiense (East Africa) [15]. African trypanosomiasis threatens the lives of approximately 60 million people in sub-Saharan Africa and is fatal if untreated [70]. Another species of Trypanosoma (T. cruzi) is responsible for Chagas disease (American trypanosomiasis), and threatens the lives of millions primarily in Mexico, Latin America and the United States. The World Health Organization estimates that 8–10 million people are infected annually. There is also no vaccine for Chagas disease and no clinical trials of new drugs are under way; current treatment depends on only two chemotherapeutics − benznidazole and nifurtimox. Go to: Medicinal uses of Asteraceae with special reference to the tribes of Odisha (Orissa), India The family Asteraceae (Compositae) is also known as the daisy family, sunflower family or thistle family. Asteraceae is derived from the term “aster” meaning “star” in Latin, and refers to the characteristic inflorescence with flower heads composed of florets (small flowers), and surrounded by bracts [12]. The family Asteraceae is one of the largest families comprising 1600–1700 genera and 24,000–30,000 species [30]. The family has 12 subfamilies and 43 tribes, and is distributed worldwide [16], but is most abundant in the temperate and warm-temperate regions. Most of the species are herbs and shrubs, while trees are fewer in number. Asteraceae have been commonly used in the treatment of various diseases since ancient times, as attested by classical literature. For this review, we collected literature from scientific journals, books, theses and reports via a library and electronic search (using databases viz. PubMed, Google Scholar and Scopus). Several researchers have systematically investigated Asteraceae for their therapeutic utility. More than 7000 compounds have already been isolated, and 5000 have been identified from this family, often associated with some bioactivity [3]. Members of the Asteraceae are claimed to have various properties: antipyretic, anti-inflammatory, detoxifying, antibacterial, wound-healing, antihemorrhagic, antalgic (also for headaches), anti-spasmodic, and anti-tussive, and have been considered beneficial for flatulence, dyspepsia, dysentery, lumbago, leucorrhoea, hemorrhoids, hypotension, and most importantly, some are hepatoprotective, antitumor and antiparasitic [68]. The majority of studies on Asteraceae throughout the world have focused on chemical analysis (nearly 7000 compounds already isolated). There are many papers on in vitro studies, especially on antimicrobial, antioxidant and anticarcinogenic properties, using selected cells and crude extracts or purified compounds. In the few published reviews on pure compounds, the structure-activity relations were studied as well as their mechanism of action. Despite the discovery of a large number of compounds in Asteraceae around the world, and the reported antiparasitic properties of members of the Asteraceae family, not many bioactivity studies on Asteraceae species have yet been carried out. In India, the family is represented by 900 species from 167 genera. Due to their bioactive properties, plants from the Asteraceae family are commonly used in the traditional treatment of various diseases (Table 1). For instance, Ageratum conyzoides has been commonly used in India including in the state of Odisha, where the plant is traditionally used for diarrhoea, dysentery, intestinal colic [118] and malaria. This plant is well-known for the presence of phytochemicals such as alkaloids, coumarins, flavonoids, benzofurans, sterols and terpenoids, with the following identified compounds: friedelin, various sterols (including β-sitosterol and stigmasterol), various flavonoids, caryophyllene, coumarin, quercetin, as well as fumaric and caffeic acid [51]. Bidens pilosa is also found in Odisha, and is moreover widely used as folk medicine by indigenous tribes of the Amazon in the treatment of malaria [13]. About 201 compounds comprising 70 aliphatics, 60 flavonoids, 25 terpenoids, 19 phenylpropanoids, 13 aromatics, 8 porphyrins, and 6 other compounds, have been identified from this plant, as compiled previously [67]. However, the relation between Bidens pilosa phytochemicals and various bioactivities is not yet fully established, and should become a future research focus [7]. Blumea lacera is used for the treatment of all kinds of fever, including malaria, and contains phytocompounds such as fenchone, coniferyl alcohol derivatives, campesterol, flavonoids, lupeol, hentriacontane, hentriacontane, α-amyrin, β-sitosterol and triterpenes [7,80,105]. Calendula officinalis has found many medicinal applications and contains various terpenoids (sitosterols, stigmasterols, erythrodiol, brein, ursadiol and its derivatives; several triterpene glycosides like calendulaglycoside A; glucosides of oleanolic acid, etc.), various flavonoids (quercetin, isoquercetin, isorhamnetin-3-O-β-D-glycoside, narcissin, calendoflaside, calendoflavoside, calendoflavobioside, rutin, quercetin-3-O-glucoside and quercetin-3-O-rutinoside), coumarins, saponins and quinones [87]. Table 1 Table 1 Traditional uses of plants of the Asteraceae family Whole plant extracts of Caesulia axillaris are frequently used by the coastal tribes of Odisha to cure malaria [107,113], but no scientific studies have yet been published on this plant. Centipeda minima is widely distributed in Odisha, and is frequently used by the local tribes for the treatment of parasites [112], but no compounds responsible for its antiparasitic activities have yet been identified. Eclipta prostrata (synonym E. alba) is frequently used by the tribes for the treatment of malaria [113,130]. The plant is well studied for its phytochemistry, with documented presence of compounds such as eclipline, β-amyrin, luteolin-7-O-glucoside, apigenin, cinnaroside, stigmasterol, wedelolactone, columbin, triterpene glycosides and triterpenic acid [47]. Like Eclipta prostrata, Elephantopus scaber is also frequently used by the tribes for the treatment of malaria [118]. This plant is also well studied for its phytochemistry with documented presence of sesquiterpenelactones such as elescaberin, deoxyelephantopin, isodeoxyelephantopin, scabertopin, and isoscabertopin, and lipids like ethyl hexadecanoate, ethyl-9, 12-octadecadienoate, ethyl-(Z)-9-octadecenoate, ethyl octadecanoate, lupeol and stigmasterol [19]. Whole plant paste of Sphaeranthus indicus with a pinch of salt is taken as an anthelmintic by the tribes of Odisha [111]. The phytochemical studies of this plant suggest the presence of eudesmanolides, sesquiterpenoids, sesquiterpene lactones, sesquiterpene acids, flavone glycosides, flavonoid C-glycosides, isoflavone glycosides, sterols, sterol glycosides, alkaloids, peptide alkaloids, amino acids and sugars [125]. The essential oil from this plant has been well studied with the documented presence of bioactive compounds like sphaeranthine, sphaeranthol, spharerne, methyl chavicol, ocimene, geraniol, and methoxy frullanolides [71]. Tagetes erecta is an ornamental plant of Odisha and is often used by the tribes for the treatment of various conditions such as anaemia, irregular menstruation, abdominal pain, colic, cough and dysentery. Like Sphaeranthus indicus, this plant is also well known for its phytoconstituents such as β-sitosterol, β-daucosterol, 7-hydroxy sitosterol, lupeol, erythrodiol, erythrodiol-3-palmitate, quercetagetin, quercetagetin-7-methyl ether, quercetagetin-7-O-glucoside, gallic acid, syringic acid, quercetin, ocimene and tagetone [135]. Tridax procumbens has been extensively used in Ayurvedic medicine and is well-studied for its phytochemistry, with the presence of compounds like 8,3′-dihydroxy-3,7,4′-trimethoxy-6-O-β-D glucopyranoside flavonol, apigenin-7-O-β-D-glucoside, pentadecane, β-sitosterol, stigmasterol, β-daucesosterol and bis-(2-ethylhexyl)-phthalate [131]. Several species of Vernonia have been used in different traditional medicines all over the world. The tribes of Odisha most frequently use different species of Vernonia: V. anthelmintica, V. albicans and V. cinerea. Seeds of Vernonia anthelmintica are used as an anthelmintic, especially in children: 2-5 g with water on an empty stomach twice a day for three days [111,112]. Fruit powder is used in malaria fever, and stomach ache during amoebic dysentery [81]. Powdered Vernonia albicans plant (10-20 g) is advised to be consumed with 125 mL milk (mixed with 5-7 cardamom fruits and 10 g sugar candy) once in the morning, on an empty stomach for about three months for the treatment of filariasis [37]. The aqueous extract of the whole plant is also used in the treatment of malaria [53]. Root paste of Vernonia cinerea mixed with honey is administered orally twice a day for three days for malaria [108]. Reports are also available on the use of this plant for the treatment of elephantiasis [108]. Toyang and Verpoorte [152] published a review article on this genus Vernonia (109 species) concerning its ethnopharmacology and phytochemistry. Xanthium strumarium is a weed, widely distributed in Odisha, and commonly used as a medicinal plant. Most of its pharmacological effects can be explained by constituents like sesquiterpene lactones, glycosides, phenols, as well as polysterols present in all plant parts. The bioactive compounds reported for this plants are xanthinin, xanthumin, xanthatin (deacetylxanthinin), a toxic principle, namely a sulphated glycoside: xanthostrumarin, atractyloside, carboxyatractyloside, phytosterols, xanthanol, isoxanthanol, xanthinosin, 4-oxo-bedfordia acid, hydroquinone, xanthanolides, caffeoylquinic acids, α- and γ-tocopherol, thiazinedione and deacetyl xanthumin, β-sitosterol, γ-sitosterol, β-D-glucoside of β-sitosterol; isohexacosane, chlorobutanol, stearyl alcohol, stromasterol and oleic acid [52]. Go to: Miscellaneous antiparasitic properties of Asteraceae and their phytochemistry Over the past decades, a lot of research on antiparasitic drugs of plant origin has yielded undisputable metabolites of interest. Many plant-derived secondary metabolites of Asteraceae have exhibited target-specific activity against Plasmodium, Leishmania and Trypanosoma parasites (Table 2). Plants from the Asteraceae family are widely used as medicines due to the presence of a broad range of bioactive metabolites such as alkaloids (pyrrolizidine and pyridine), flavonoids, phenolic acids, coumarins, terpenoids (monoterpenes, sesquiterpenes, diterpenes, and triterpenes), quinoline and diterpenoid types, triterpenoid sesquiterpene lactones, pyrethrins, and saponins. Several sesquiterpenes have been reported as antiprotozoal since the discovery of artemisinin. The sesquiterpene lactone parthenin is effective against Plasmodium falciparum in vitro, with an EC50 value of 1.29 µg/mL [123]. Parthenin is capable of blocking parasite-specific targets responsible for glutathinonylspermidine and trypanothione synthesis from cysteine and glutathione precursors in both Leishmania and Trypanosoma [32]. The sesquiterpene lactones brevilin A from Centipeda minima and dehydrozaluzanin C from Munnozia maronii were discovered and reported as antiparasitic. Similarly, sesquiterpene lactones from Neuroleaena lobata are well established for the treatment of Plasmodium infections [28]. In this plant, structure-activity relationship analysis revealed that germanocrenolide sesquiterpenes, like neurolenin A (EC50 = 0.92 µM) and B (EC50 = 0.62 µM), were more potent than furanoheliangolides like lobatin A and B (EC50 = 15.62 µM and 16.51 µM), respectively, against Leishmania promastigotes and Trypanosoma epimastigotes [28]. Based on ethnozoological studies (wild chimpanzees were observed to chew young stems of Vernonia amygdalina), antiplasmodial sesquiterpenes vernodalin and vernolide, hydroxyverniladin have been isolated [60]. Oketch-Rabah et al. [101] observed that macrocyclic germancrane dilactone 16,17-dihydrobrachycalyxolide from Vernonia brachycalyx has both antileishmanial and antiplasmodial activity. Table 2 Table 2 Therapeutic uses of important plants of the Asteraceae family reported as an antiparasitic Phenols are widely distributed in Asteraceae, and some have the ability to inhibit parasites. Gallic acid and its derivatives inhibit the proliferation of Trypanosoma cruzi trypomastigotes in vitro [58]. Higher activities were observed for the gallic acid esters ethyl-gallate and n-propyl-gallate, which had EC50 values of 2.28 and 1.47 µg/mL, respectively, possibly due to increased lipophilicity. Oketch-Rabah et al. [101] reported the antiprotozoal activity from Vernonia brachycalyx (2́ -epicycloisobrachycoumarinone epoxide and its stereoisomer). Both stereoisomers show similar in vitro activities against chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) strains for Plasmodium falciparum, as well as Leishmania major promastigotes, with EC50 values of 0.11 µg/mL and 0.15 µg/mL for Plasmodium falciparum, and 37.1 µg/mL and 39.2 µg/mL for Leishmania major, respectively. Like phenols, flavonoids are extensively present in Asteraceae plants. Elford et al. [21] demonstrated that methoxylated flavonones artemetin and casticin act synergistically with artemisinin in vitro against Plasmodium falciparum. Later, exiguaflavanone A and B, isolated from Artemisia indica (Asteraceae), were shown to exhibit in vitro activity against Plasmodium falciparum. The flavonoids can be classified into several subtypes: flavone (1), flavonol (2), flavanone (3), dihydroflavonol (4), flavan-3-ol (5), flavan-3,4-diol (6), chalcone (a structure with one opened ring), aurone, and anthocyanidine (with a positive charge on oxygen O-1). Except for these basic structures, flavonoids also exist in biflavonoid and glycosidic form in the Asteraceae family. Perez-Victoria et al. [122] suggested that flavonoids could affect transport mechanisms in Leishmania. The C-terminal nucleotide-binding domain of a P-glycoprotein-like transporter, encoded by the ltrmdr1 gene in Leishmania tropica and involved in parasite multidrug resistance (MDR), was overexpressed in Escherichia coli as a hexahistidine-tagged protein and purified. The Leishmania tropica recombinant domain efficiently bound different classes of flavonoids with the following relative affinity: flavone>flavanone>isoflavone>glucorhamnosyl-flavone. The affinity was dependent on the presence of hydroxyl groups at positions C-5 and C-3, and was further increased by a hydrophobic 1,1-dimethylallyl substituent at position C-8. Brandio et al. [13] first reported the antimalarial activity of crude extracts and their fractions from different species of Bidens, and provided evidence that this is due to the presence of polyacetylene and flavonoids. Later, Kumari et al. [63] and Tobinaga et al. [151] isolated the polyacetylene compound (R)-1,2-dihydroxytrideca-3,5,7,9,11-pentayne from leaf extracts of B. pilosa, which showed promising antimalarial activity against Plasmodium falciparum (Table 3). Moreover, this compound was tested in an in vivo model (mice infected with Plasmodium berghei NK-65 strain), and results showed that the compound can decrease the average parasitaemia in red blood cells, but further studies addressing its mechanism are required. The genus Calendula is very well studied for its phytochemistry, with triterpene alcohols, triterpene saponins, flavonoids, carotenoids and polysaccharides as the major classes of phytoconstituents. Szakie et al. [145] isolated several oleanolic acid glycoside derivatives and tested them against Heligmosomoides polygyrus; the wormicidal activity of the oleanolic acid glycosides was superior to that of the aglycone, and the level of activity was dependent on the nature of the sugar side-chain at the C-3 position. The first sugar molecule of the glucuronides, i.e., the glucuronic acid attached to the aglycone, appeared to be vital for the antiparasitic properties of these compounds [145]. E. prostrata was studied by several scientists for its antiparasitic properties such as antimalarial [6], antileishmanial [56,138], and anthelmintic activities [11,50]. Khanna et al. [56] isolated dasyscyphin C from the leaves and proved its antileishmanial activities against Leishmania major, Leishmania aethiopica andLeishmania tropica (Table 3). A sesquiterpene lactone (deoxyelephantopin) was isolated by Zahari et al. [165] from E. scaber and proved active against Trypanosoma brucei rhodesience. Similarly, T. procumbens showed significant antileishmanial activity against promastigotes of Leishmania mexicana. The active principle was found to be an oxylipin, namely (3S)-16, 17- didehydrofalcarinol [76]. Table 3 Table 3 List of compounds from Asteraceae commonly reported for their antiparasitic properties. Go to: Antiparasitic activity of flavonoids and terpenoids documented in Asteraceae Flavonoids are the class of compound of highest occurrence, wide structural diversity, and chemical stability. They have been isolated on a large scale from Asteraceae species and can be used as taxonomic markers at lower hierarchical levels [75]. Flavones and flavonols are common throughout the Asteraceae, i.e., glycosides of apigenin, luteolin, kaempferol, quercetin, flavanone derivatives, (−)-epicatechin and (−)-epigallocatechin (Figure 1). Although there are fewer reports on antigiardial activity in Asteraceae, these compounds from other families are well-studied against G. lamblia. From the aerial parts of Helianthemum glomeratum (Cistaceae), kaempferol, quercetin, (−)-epicatechin and (−)-epigallocatechin have shown antigiardial activity against G. lamblia (in vitro), with IC50 values of 26.47, 8.73, 1.64 and 8.06 μg/mL, respectively [17]. Structure-activity correlation implies that the 2,3-double bond and 4-keto group of flavones might not be required for antiprotozoal activity since both (−)-epicatechin and (−)-epigallocatechin lack these structural units, yet maintain biological activity (Figure 1). Also, unlike flavones, the benzenediol moiety of (−)-epicatechin and (−) epigallocatechin is not coplanar with the heterocyclic part because C-2 of their flavan-3-ol structure is an sp3 carbon. In addition, there are several reports that glycosylated flavonoids also possess antigiardial activity. Also, a C-3 glycosylated flavone tiliroside [17,79], obtained from H. glomeratum, has been shown to possess antigiardial inhibitory activity with an IC50 value of 17.36 μg/mL. figure parasite-25-10-fig1 Figure 1 Common flavonoids of the Asteraceae family reported as antiparasitic compounds Recently, Klongsiriwet et al. [57] demonstrated that quercetin and luteolin are highly effective at 250 µM to reduce the in vitro exsheathment of Haemonchus contortus L3 larvae. Tasdemir et al. studied the antitrypanosomal and antileishmanial activities of flavonoids and their analogues in vitro and in vivo, as well as their (quantitative) structure-activity relationship [148]. They showed that fisetin, 3-hydroxyflavone, luteolin, and quercetin are the most potent antileishmanial compounds against Leishmania donovani, with IC50 of 0.6, 0.7, 0.8, and 1.0 µg/mL, respectively (Table 4). Moreover, these authors found moderate antitrypanosomal efficacy of these compounds against Trypanosoma brucei rhodesiense and Trypanosoma cruzi. The authors conclude that 7,8-dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models, and are potent and effective antiprotozoal agents. Mead and McNair [78] also studied the antiparasitic activity of flavonoids and isoflavones against Cryptosporidium parvum and Encephalitozoon intestinalis. These authors also found that quercetin and apigenin had activity against Encephalitozoon intestinalis at EC50 of 15 and 50 mM, respectively, while low activity of luteolin and quercetin was found against Cryptosporidium parvum. No inhibition was observed with either rutin or epigallocatechin gallate against either parasite. Lehane and Saliba [66] investigated the effects of a range of common dietary flavonoids on the growth of two strains of the human malaria parasite Plasmodium falciparum and concluded that luteolin showed IC50 values of 11 ± 1 µM and 12 ± 1 µM for strains 3D7 and 7G8, respectively. Although luteolin was found to prevent the progression of parasite growth beyond the young trophozoite stage, it did not affect parasite susceptibility to the antimalarial drugs chloroquine or artemisinin. Nour et al., [98] found moderate antiparasitic activity of five methoxylated flavonoids viz. 5,6,7,8,5-pentamethoxy-3,4-methylenedioxyflavone (eupalestin), 5,6,7,5-tetramethoxy-3,4-methylenedioxyflavone; 5,6,7,8,3,4,5-heptamethoxy-flavone (5-methoxynobiletine), 5,6,7,3,4,5-hexamethoxy-flavone and 4-hydroxy-5,6,7,3,5-pentamethoxy-flavone (ageconyflavone) against several parasites: Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani and Plasmodium falciparum (Table 4). Table 4 Table 4 Selected flavonoids and terpenoids (whose presence has been reported in plants of the Asteraceae family) with antiparasitic activity Terpenoids are the largest group of phytochemicals as they comprise more than 20,000 recognised molecules. Depending on the number of carbons, terpenoids are divided into classes, starting with sesquiterpenes and continuing with diterpenes, sterols, triterpenes and finally tetraterpenes. Several sesquiterpenes, sterols and triterpenes have been isolated from members of the Asteraceae family. The sesquiterpenes commonly found in leaf extracts from Asteraceae are divided into mono- and bicyclic. The most abundant sterols from Asteraceae are stigmasterol and sitosterol. Sequiterpenes isolated from Vernonia spp. have antiparasitic activity against Plasmodium falciparum. Four compounds such as vernodalin, vernodalol, vernolide, and hydroxyvernolide (Figure 2), all derived from the leaves of Vernonia amygdalina, have potent activity with IC50 values of 4, 4.2, 8.4 and 11.4 µg/mL, respectively [60]. Another compound: sesquiterpene dilactone (16,17-dihydrobrachycalyxolide), isolated from the leaves of V. brachycalyx, exhibited anti-plasmodial activity against different multidrug-resistant strains of Plasmodium falciparum (K39, 3D7, V1/S and Dd2) with IC50 values of 4.2, 13.7, 3.0, and 16 µg/mL, respectively [101]. Goffin et al. [38] isolated the sesquiterpene lactone: tagitinin C, from the ether extract of Tithonia diversifolia and demonstrated antiplasmodial activity against Plasmodium falciparum (IC50 of 0.75 µg/mL). Becker et al. [8] identified urospermal A-15-O-acetate and dehydrobrachylaenolide as the main active compound responsible for the antiplasmodial activity against Plasmodium falciparum 3D7 and W2 strains. Ganfon et al. [34] investigated the antiparasitic activities of Acanthospermum hispidum by isolating two sesquiterpene lactones (15-acetoxy-8 β-[(2-methylbutyryloxy)]-14-oxo-4,5-cis-acanthospermolide), and 9 α-acetoxy-15-hydroxy-8β-(2-methylbutyry-499 loxy)-14-oxo-4,5-transacanthospermolide), both of which exhibited in vitro antiplasmodial activity against a chloroquine-sensitive strain (3D7) with IC50 values of 2.9 and 2.23 µM, respectively (Table 4). figure parasite-25-10-fig2 Figure 2 Common terpenoids of the Asteraceae family reported as antiparasitic compounds Among the triterpenes, squalene and lupeol derivatives are the more common ones [67]. Oleanolic acid (3 β-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid with widespread occurrence in Asteraceae and was found to have antimalarial and antileishmanial activity [89,162]. Recently, Yamamoto et al. [162] studied the activity of ursolic acid on Leishmania amazonensis (in vitro and in vivo). They found that ursolic acid eliminated Leishmania amazonensis promastigotes with an EC50 of 6.4 µg/mL, comparable with miltefosine, while oleanolic acid presented only a marginal effect on promastigote forms at 100 µg/mL. The possible mechanism by which promastigotes were eliminated by ursolic acid was programmed cell death, independent of caspase 3/7, but it was highly dependent on mitochondrial activity. Also, the ursolic acid was not toxic for peritoneal macrophages from BALB/c mice, and it could eliminate intracellular amastigotes, associated with nitric oxide (NO) production. These authors conclude that ursolic acid can be considered an interesting candidate for future testing as a prototype drug for the treatment of cutaneous leishmaniasis. Enwerem et al. [22] examined the anthelmintic activity of betulinic acid on C. elegans and confirmed its strong anthelmintic activity at 100 µg/mL, comparable to piperazine. Bringmann et al. [14] observed that betulinic acid exhibited moderate to good in vitro antimalarial activity against asexual erythrocytic stages of Plasmodium falciparum. Later, Steele et al. [141] concluded that betulinic acid can inhibit Plasmodium falciparum (in vitro), while in vivo experiments failed to reduce parasitaemia (up to 500 mg/mL in a murine malaria model- mice infected with P. berghei) and exhibited some toxicity. However, Ndjakou Lenta et al. [91] isolated betulinic acid, studied its in vitro activity against the Plasmodium falciparum W2 strain, and found it to be very potent with an IC50 of 2.33 µg/mL. Nweze et al. [99] observed that β-sitosterol has modest anti-trypanosomal activity against Trypanosoma brucei S427 (in vitro IC50 12.5 µg/mL). Go to: Discussion In a review on nature-derived drugs, Zhu et al. [166] analysed “the ranking of drug-productive plant families based on the ratio of the approved drugs to reported bioactive natural products (including leads of the approved and clinical trials drugs)” and concluded that there are a few top-ranked plant families that produce high numbers of approved drugs among plant-derived medicines. According to Zhu et al. [166], Asteraceae is the fourth-largest drug-productive family that has yielded many approved drugs, including antiparasitic, anticancer, antiglaucoma, ant-inflammatory, antihepatotoxic, antiviral and choleretic agents. From 7229 Asteraceae species, 25 clinical drugs (17 approved and 8 in clinical trials) were documented among 1016 searchable drugs [91,99]. There are many FDA-approved nature-derived drugs that originate from Asteraceae as antiparasitics: arteether, artemether, artemisinin, artesunate, coarsucam, co-artemether, dihydroartemisinin and santonin (all from Artemisia species). Also, there are a few drugs still in clinical trials as antiparasitics, such as artemisone, arterolane and artelinic acid [92]. Traditional knowledge has proven a useful tool in the search for new plant-based medicines [18]. It has been estimated that the number of traditionally used plant species worldwide is between 10,000 and 53,000 [77]. In India alone, there are about 25,000 plant-based formulations used in folk and traditional medicine [126]. However, only a small proportion have been screened for biological activity [42,140]. Also, there are many specific regions that are less studied than others (only 1% of tropical floras have been investigated) [42]. Odisha’s unique location in Peninsular India has blessed it with an interesting assemblage of floral and faunal diversity (http://odishasbb.nic.in/index.php?lang=en). The state is on the eastern seaboard of India, located between 17° 49’ and 22° 36’ N latitudes and between 81° 36’ and 8°7 18’ E longitudes. It covers an area of 1,55,707 sq km and is broadly divided into four geographical regions, i.e. the Northern Plateau (Chhotanagpur), Central River Basins, Eastern Hills and Coastal Plains. The confluence of two major biogeographic provinces of India: the Eastern Ghats (South-West) and Chhotanagpur Plateau (North), make Odisha a rich biodiversity repository with two internationally well-recognised areas: the Similipal Biosphere Reserve and the Chilika Lagoon. The state has a biodiversity board (it is a statutory body established under the Biological Diversity Act of 2002), with a network of 19 wildlife sanctuaries, one national park, one proposed national park, one biosphere reserve, two tiger reserves and three elephant reserves (http://odishasbb.nic.in/index.php?lang=en). Throughout the state, one finds varied and widespread forests harbouring different types of vegetation such as semi-evergreen forests, tropical moist deciduous forests, tropical dry-deciduous forests and littoral and tidal swamp forests, as well as mangroves with unique, endemic, rare and endangered floral and faunal species. The climate of Odisha is characterised by tropical monsoon weather as its coast borders the Bay of Bengal. The weather is classified as summer, monsoon and winter. Searing hot summers with considerably high monsoon downpours and cool, pleasant winters mark the Odisha climate. The average rainfall varies from 1200 mm to 1700 mm across the state, and is the main source of water. Moreover, the state is vulnerable to multiple disasters such as tropical cyclones, storm surges and tsunamis due to its sub-tropical littoral location (http://nidm.gov.in/default.asp). About 62 ethnic tribal communities have been reported in Odisha, of which 13 are known as "Particularly Vulnerable Tribal Groups" (https://en.wikipedia.org/wiki/List_of_Scheduled_Tribes_in_Odisha). Districts such as Kandhamala, Koraput, Malkanigiri, Mayurbhanj, Nabrangpur, Rayagada and Sundargarh have scheduled tribes (officially designated groups of historically disadvantaged people in India) above 50% of the total population. The social, cultural and religious life of aboriginal people is influenced by nature and natural resources available in and around their habitat, which provides their food, medicine, shelter, and various other materials and cultural needs [109,110]. Sasil-Lagoudakis et al. [133] published a review entitled “phylogenies reveal the predictive power of traditional medicine in bioprospecting”. Their study, which includes the Asteraceae family, provides unique large-scale evidence that plant bioactivity underlies traditional medicine. According to these authors, “related plants are traditionally used as medicines in different regions, and these plant groups coincide with groups that are used to produce pharmaceutical drugs”. The authors conclude that “phylogenetic cross-cultural comparisons can focus screening efforts on a subset of traditionally used plants that are richer in bioactive compounds, and could revitalise the use of traditional knowledge in bioprospecting”. Gertrude et al. [36] studied the anthelmintic activity of Bidens pilosa leaf against Haemonchus contortus eggs and larvae and concluded that ethanolic extracts have the potential to inhibit the growth of Haemonchus contortus. However, further study on the isolation of the active compounds as well as in vivo studies are needed. Similarly, antileishmanial activity of Bidens pilosa leaf was reported by several researchers [31,85], but no compound responsible for this activity has been identified so far. The anthelmintic and wormicidal properties of Blumea lacera leaf were evaluated against Ascaris lumbricoides and Pheretima posthuma [119], but no bioactive compounds have been acknowledged so far. Calendula officinalis has been used traditionally by the tribes of Odisha for worm infections. Nikmehr et al. [95] found that crude methanolic extracts have antileishmanial activity, but no bioactive molecules have been isolated so far. Caesulia axillaris, a wetland plant, is used very frequently for the treatment of malaria by the coastal peoples of Odisha. However, despite its long traditional use, its scientific validation as an antiparasitic agent has not been established so far. Also, the phytochemistry of this plant is not well known, except for a few studies on its essential oils. Similarly, plants such as Centipeda minima, Sphaeranthus indicus and Tagetes erecta are used as anthelmintic plants by the tribes of Odisha for the treatment of worm infections. Yu et al. [164] found antiparasitic activity of crude extracts of Centipeda minima and its fractions against Giardia intestinalis, Entamoeba histolytica and Plasmodium falciparum. Crude extracts of Sphaeranthus indicus also showed antiparasitic effects on Ascaridia galli, Entamoeba histolytica and Setaria digitate [96,134]. Organic and aqueous extracts of Tagetes erecta show antiparasitic [41], and anthelmintic properties [106]. However, notwithstanding phytochemical studies, no anti-parasitic compounds have been identified, nor have any in vivo studies been conducted so far on these plants. The plant Elephantopus scaber showed anthelmintic activity against Pheretima posthuma in crude extract. However, further study is required to find out the active anthelmintic compounds. Both in vitro and in vivo studies were carried out and proved the anthelmintic properties of Vernonia anthelmintica against Haemonchus contortus [103,106,140]. Further study is needed to determine the active anthelmintic compounds. The tribes of Odisha frequently use two other species of Vernonia: V. albicans and V. cinerea. These plants are also interesting for future study to discover active molecules with antiparasitic properties. The antitrypanosomal activity of a crude 50% ethanol extract of Xanthium strumarium leaves was studied in vitro and in vivo. The extract exhibited trypanocidal activity against Trypanosoma evansi-infected mice [147]. The authors hypothesised that the presence of xanthinin may be responsible for its trypanocidal activity, but further study is needed to definitively identify the antitrypanosomal compound or compounds. Go to: Conclusion A search for new antiparasitic drugs has been under way over the past several decades. However, despite the abundant literature, more work is needed to yield potent, commercially available drugs based on natural products. Fortunately, academic drug discovery for neglected diseases has intensified (e.g. the Drugs for Neglected Disease Initiative http://www.dndi.org/), and this includes efforts to use natural products (e.g. Research Network Natural Products against Neglected Diseases https://www.facebook.com/ResNetNPND/app/435433039823956). Although many Asteraceae species were already studied for different antiparasitic activities, some of the species important in traditional medicines have still hardly been studied for their bioactivity. Therefore, the present review aims to encourage further exploration of their potential bioactivity and particularly their antiparasitic properties, guided by the knowledge on the use of Asteraceae plants by the tribes of Odisha and corresponding traditional uses elsewhere in the world. The work reported here highlights the traditional uses of Asteraceae plants of Odisha for the treatment of parasites. Plants such as Bidens pilosa, Blumea lacera, Caesulia axillaris, Centipeda minima and Sphaeranthus indicus deserve to be studied further, especially concerning their most relevant bioactive properties and significant bioactive compounds that could be purified with state-of-the-art methods. Go to: Conflict of interest The authors declare that they have no conflict of interest. Go to: Acknowledgment The authors are thankful to KU Leuven for providing the necessary facilities during preparation of this review article. This project received funding from the European Union’s Horizon 2020 research and innovation programme under Grant agreement No 633589. This publication reflects only the authors’ views and the Commission is not responsible for any use that may be made of the information it contains. Go to: Notes Cite this article as: Panda SK, Luyten W. 2018. Antiparasitic activity in Asteraceae with special attention to ethnobotanical use by the tribes of Odisha, India. 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