Cystic echinococcosis (CE) remains an important challenge both in humans and animals. There is no safe and suitable remedy for CE, so the discovery of new compounds with promising scolicidal effects, particularly from herbal sources, is of great importance for therapeutic uses in the treatment and prevention of CE reappearance. Sesquiterpenes are C15 organic compounds made up of three isoprene units and mostly occurring as fragrant components of essential oils. They are of economic importance for the cosmetic and pharmaceutical industry, and recently attracted the attention of the scientific community for their remarkable parasiticidal properties. In the present study, we have focused on three known sesquiterpenes, isofuranodiene (IFD), α-bisabolol (BSB), and farnesol (FOH), as important phytoconstituents of the essential oils of wild celery (Smyrnium olusatrum), chamomile (Matricaria chamomilla), and acacia farnese (Vachellia farnesiana), respectively. Protoscoleces were recovered from fertile hydatid cysts and were exposed to different concentrations of the three tested compounds for different exposure times. The viability of protoscoleces was confirmed by 0.1% eosin staining. Results of scolicidal activity evaluations showed that IFD possessed the best effect against Echinococcus granulosus protoscoleces (LC50 and LC90 values of 8.87 and 25.48 µg/mL, respectively), followed by BSB (LC50 of 103.2 µg/mL) and FOH (LC50 of 113.68 µg/mL). The overall toxicity of IFD differed significantly from those of FOH and BSB, while there was no significant difference in toxicity between the latter compounds (p > 0.05). The present study showed that IFD seems to be a promising scolicidal agent and can be further tested to become a candidate for CE treatment.

Crop Research Institute Drnovska 507 Ruzyne 161 06 Prague 6 Czech Republic

Department of Veterinary Parasitology Babol Branch Islamic Azad University Babol 19585 466 Iran

Faculty of Veterinary Medicine Amol University of Special Modern Technologies Amol 4618649767 Iran

Faculty of Veterinary Medicine Babol Branch Islamic Azad University Babol 19585 466 Iran

School of Pharmacy University of Camerino via Sant'Agostino 1 62032 Camerino Italy

Zobrazit více v PubMed

Youssefi M.R., Mirshafiei S., Moshfegh Z., Soleymani N., Rahimi M.T. Cystic echinococcosis is an occupational disease? J. Parasit. Dis. 2016;40:586–590. doi: 10.1007/s12639-014-0543-2. PubMed DOI PMC

Kohansal M.H., Nourian A., Rahimi M.T., Daryani A., Spotin A., Ahmadpour E. Natural products applied against hydatid cyst protoscoleces: a review of past to present. Acta Trop. 2017;176:385–394. doi: 10.1016/j.actatropica.2017.09.013. PubMed DOI

Rahimi-Esboei B., Ebrahimzadeh M., Fathi H., Rezaei Anzahaei F. Scolicidal effect of Allium sativum flowers on hydatid cyst protoscoleces. Eur. Rev. Med. Pharmacol. Sci. 2016;20:129–132. PubMed

Niazi M., Saki M., Sepahvand M., Jahanbakhsh S., Khatami M., Beyranvand M. In vitro and ex vivo scolicidal effects of Olea europaea L. to inactivate the protoscolecs during hydatid cyst surgery. Ann. Med. Surg. 2019;42:7–10. doi: 10.1016/j.amsu.2019.04.006. PubMed DOI PMC

Arif S.H., Wani N.A., Zargar S.A., Wani M.A., Tabassum R., Hussain Z., Baba A.A., Lone R.A. Albendazole as an adjuvant to the standard surgical management of hydatid cyst liver. Int. J. Surg. 2008;6:448–451. doi: 10.1016/j.ijsu.2008.08.003. PubMed DOI

Pavela R., Maggi F., Cianfaglione K., Bruno M., Benelli G. Larvicidal activity of essential oils of five Apiaceae taxa and some of their main constituents against Culex quinquefasciatus. Chem. Biodivers. 2018;15:e1700382. doi: 10.1002/cbdv.201700382. PubMed DOI

Fakhar M., Chabra A., Rahimi-Esboei B., Rezaei F. In vitro protoscolicidal effects of fungal chitosan isolated from Penicillium waksmanii and Penicillium citrinum. J. Paras. Dis. 2015;39:162–167. doi: 10.1007/s12639-013-0300-y. PubMed DOI PMC

Posadzki P., Watson L., Ernst E. Herb–drug interactions: an overview of systematic reviews. Br. J. Clin. Pharmacol. 2013;75:603–618. doi: 10.1111/j.1365-2125.2012.04350.x. PubMed DOI PMC

Dewick P.M. The biosynthesis of C 5–C 25 terpenoid compounds. Nat. Prod. Rep. 2002;19:181–222. doi: 10.1039/b002685i. PubMed DOI

Sut S., Maggi F., Nicoletti M., Baldan V., Dall’Acqua S. New drugs from old natural compounds: scarcely investigated sesquiterpenes as new possible therapeutic agents. Curr. Med. Chem. 2018;25:1241–1258. doi: 10.2174/0929867324666170404150351. PubMed DOI

Maggi F., Papa F., Giuliani C., Maleci Bini L., Venditti A., Bianco A., Nicoletti M., Iannarelli R., Caprioli G., Sagratini G., et al. Essential oil chemotypification and secretory structures of the neglected vegetable Smyrnium olusatrum L. (Apiaceae) growing in central Italy. Flavour Frag. J. 2015;30:139–159. doi: 10.1002/ffj.3221. DOI

Quassinti L., Maggi F., Barboni L., Ricciutelli M., Cortese M., Papa F., Garulli C., Kalogris C., Vittori S., Bramucci M. Wild celery (Smyrnium olusatrum L.) oil and isofuranodiene induce apoptosis in human colon carcinoma cells. Fitoterapia. 2014;97:133–141. doi: 10.1016/j.fitote.2014.06.004. PubMed DOI

Petrelli R., Ranjbarian F., Dall’Acqua S., Papa F., Iannarelli R., Kamte S.L.N., Vittori S., Benelli G., Maggi F., Hofer A., et al. An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis. Parasitol. Int. 2017;66:146–151. doi: 10.1016/j.parint.2017.01.001. PubMed DOI

Benelli G., Pavela R., Canale A., Nicoletti M., Petrelli R., Cappellacci L., Galassi R., Maggi F. Isofuranodiene and germacrone from Smyrnium olusatrum essential oil as acaricides and oviposition inhibitors against Tetranychus urticae: impact of chemical stabilization of isofuranodiene by interaction with silver triflate. J. Pest. Sci. 2017;90:693–699. doi: 10.1007/s10340-016-0829-5. DOI

Benelli G., Pavela R., Iannarelli R., Petrelli R., Cappellacci L., Cianfaglione K., Afshar F.H., Nicoletti M., Canale A., Maggi F. Synergized mixtures of Apiaceae essential oils and related plant-borne compounds: larvicidal effectiveness on the filariasis vector Culex quinquefasciatus Say. Ind. Crop. Prod. 2017;96:186–195. doi: 10.1016/j.indcrop.2016.11.059. DOI

Kavallieratos N.G., Boukouvala M.C., Ntalli N., Skourti A., Karagianni E.S., Nika E.P., Kontodimas D.C., Cappellacci L., Petrelli R., Cianfaglione K., et al. Effectiveness of eight essential oils against two key stored-product beetles, Prostephanus truncatus (Horn) and Trogoderma granarium Everts. Food Chem. Toxicol. 2020;139:111255. doi: 10.1016/j.fct.2020.111255. PubMed DOI

Li W., Shi J., Papa F., Maggi F., Chen X. Isofuranodiene, the main volatile constituent of wild celery (Smyrnium olusatrum L.), protects d-galactosamin/lipopolysacchride-induced liver injury in rats. Nat. Prod. Res. 2016;30:1162–1165. doi: 10.1080/14786419.2015.1041139. PubMed DOI

Pavela R., Pavoni L., Bonacucina G., Cespi M., Kavallieratos N.G., Cappellacci L., Petrelli R., Maggi F., Benelli G. Rationale for developing novel mosquito larvicides based on isofuranodiene microemulsions. J. Pest. Sci. 2019;92:909–921. doi: 10.1007/s10340-018-01076-3. DOI

Rosato A., Maggi F., Cianfaglione K., Conti F., Ciaschetti G., Rakotosaona R., Fracchiolla G., Clodoveo M.L., Franchini C., Corbo F. Chemical composition and antibacterial activity of seven uncommon essential oils. J. Essent. Oil Res. 2018;30:233–243. doi: 10.1080/10412905.2018.1442753. DOI

Maggi F., Papa F., Pucciarelli S., Bramucci M., Quassinti L., Barboni L., Dal Ben D., Ramadori A.T., Graiff C., Galassi R. Stabilization of the cyclodecadiene derivative isofuranodiene by silver (I) coordination. Mechanistic and biological aspects. Fitoterapia. 2017;117:52–60. doi: 10.1016/j.fitote.2016.12.009. PubMed DOI

Brunetti A., Marinelli O., Morelli M.B., Iannarelli R., Amantini C., Russotti D., Santoni G., Maggi F., Nabissi M. Isofuranodiene synergizes with temozolomide in inducing glioma cells death. Phytomedicine. 2019;52:51–59. doi: 10.1016/j.phymed.2018.09.220. PubMed DOI

Maggi F., Barboni L., Papa F., Caprioli G., Ricciutelli M., Sagratini G., Vittori S. A forgotten vegetable (Smyrnium olusatrum L., Apiaceae) as a rich source of isofuranodiene. Food Chem. 2012;135:2852–2862. doi: 10.1016/j.foodchem.2012.07.027. PubMed DOI

Pisani M., Quassinti L., Bramucci M., Galassi R., Maggi F., Rossi B., Damin A., Carloni P., Astolfi P. Nanostructured Liquid Crystalline Particles as Delivery Vectors for Isofuranodiene: Characterization and In-vitro Anticancer Activity. Colloid. Surf. B. 2020;192:111050. doi: 10.1016/j.colsurfb.2020.111050. PubMed DOI

Kim S., Jung E., Kim J.H., Park Y.H., Lee J., Park D. Inhibitory effects of (−)-α-bisabolol on LPS-induced inflammatory response in RAW264. 7 macrophages. Food Chem. Toxicol. 2011;49:2580–2585. doi: 10.1016/j.fct.2011.06.076. PubMed DOI

Tabari M.A., Tehrani M.A.B. Evidence for the involvement of the GABAergic, but not serotonergic transmission in the anxiolytic-like effect of bisabolol in the mouse elevated plus maze. N-S Arch. Pharmacol. 2017;390:1041–1046. doi: 10.1007/s00210-017-1405-0. PubMed DOI

Bhatia S.P., McGinty D., Letizia C.S., Api A.M. Fragrance material review on alpha-bisabolol. Food Chem. Toxicol. 2008;46:S72–S76. doi: 10.1016/j.fct.2008.06.025. PubMed DOI

Murata Y., Kokuryo T., Yokoyama Y., Yamaguchi J., Miwa T., Shibuya M., Yamamoto Y., Nagino M. The anticancer effects of novel α-bisabolol derivatives against pancreatic cancer. Anticancer Res. 2017;37:589–598. doi: 10.21873/anticanres.11352. PubMed DOI

Cavalieri E., Rigo A., Bonifacio M., de Prati A.C., Guardalben E., Bergamini C., Fato R., Pizzolo G., Suzuki H., Vinante F. Pro-apoptotic activity of α-bisabolol in preclinical models of primary human acute leukemia cells. J. Transl. Med. 2011;9:45. doi: 10.1186/1479-5876-9-45. PubMed DOI PMC

Rigo A., Vinante F. The antineoplastic agent α-bisabolol promotes cell death by inducing pores in mitochondria and lysosomes. Apoptosis. 2016;21:917–927. doi: 10.1007/s10495-016-1257-y. PubMed DOI

Bockman M.R., Kalinda A.S., Petrelli R., De La Mora-Rey T., Tiwari D., Liu F., Dawadi S., Nandakumar M., Rhee K.Y., Schnappinger D., et al. Targeting Mycobacterium tuberculosis Biotin Protein Ligase (MtBPL) with Nucleoside-Based Bisubstrate Adenylation Inhibitors. J. Med. Chem. 2015;58:7349–7369. PubMed PMC

Rigo A., Ferrarini I., Bonalumi A., Tecchio C., Montresor A., Laudanna C., Vinante F. Efficient lysis of B-chronic lymphocytic leukemia cells by the plant-derived sesquiterpene alcohol α-bisabolol, a dual proapoptotic and antiautophagic agent. Oncotarget. 2018;9:25877. doi: 10.18632/oncotarget.25398. PubMed DOI PMC

Cavalieri E., Mariotto S., Fabrizi C., de Prati A.C., Gottardo R., Leone S., Berra L.V., Lauro G.M., Ciampa A.R., Suzuki H. α-Bisabolol, a nontoxic natural compound, strongly induces apoptosis in glioma cells. Biochem. Bioph. Res. Co. 2004;315:589–594. doi: 10.1016/j.bbrc.2004.01.088. PubMed DOI

Khan R., Sultana S. Farnesol attenuates 1,2-dimethylhydrazine induced oxidative stress, inflammation, and apoptotic responses in the colon of Wistar rats. Chem. Biol. Interact. 2011;192:193–200. doi: 10.1016/j.cbi.2011.03.009. PubMed DOI

De Araújo Delmondes G., Bezerra D.S., de Queiroz Dias D., de Souza Borges A., Araújo I.M., da Cunha G.L., Bandeira F.R., Barbosa R., Bezerra Felipe C.F., Melo Coutinho H.D., et al. Toxicological and pharmacologic effects of farnesol (C15H26O): a descriptive systematic review. Food Chem. Toxicol. 2019;129:169–200. doi: 10.1016/j.fct.2019.04.037. PubMed DOI

Lapczynski A., Bhatia S.P., Letizia C.S., Api A.M. Fragrance material review on farnesol. Food Chem. Toxicol. 2008;46:149–156. doi: 10.1016/j.fct.2008.06.046. PubMed DOI

Bakkali F., Averbeck S., Averbeck D., Idaomar M. Biological effects of essential oils–a review. Food Chem. Toxicol. 2008;46:446–475. doi: 10.1016/j.fct.2007.09.106. PubMed DOI

Shahnouri M., Tabari M.A., Araghi A. Neuropharmacological properties of farnesol in Murine model. Iran J. Vet. Res. 2016;17:259. PubMed PMC

Hornby J.M., Jensen E.C., Lisec A.D., Tasto J.J., Jahnke B., Shoemaker R., Dussault P., Nickerson K.W. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl. Environ. Microbiol. 2001;67:2982–2992. doi: 10.1128/AEM.67.7.2982-2992.2001. PubMed DOI PMC

Lorek J., Pöggeler S., Weide M.R., Breves R., Bockmühl D.P. Influence of farnesol on the morphogenesis of Aspergillus niger. J. Basic Microbiol. 2008;48:99–103. doi: 10.1002/jobm.200700292. PubMed DOI

Shea J.M., Del Poeta M. Lipid signaling in pathogenic fungi. Curr. Opin. Microbiol. 2006;9:352–358. doi: 10.1016/j.mib.2006.06.003. PubMed DOI

Jung Y.Y., Hwang S.T., Sethi G., Fan L., Arfuso F., Ahn K.S. Potential anti-inflammatory and anticancer properties of farnesol. Molecules. 2018;23:2827. doi: 10.3390/molecules23112827. PubMed DOI PMC

Lee J.H., Kim C., Kim S.-H., Sethi G., Ahn K.S. Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway. Cancer Lett. 2015;360:280–293. doi: 10.1016/j.canlet.2015.02.024. PubMed DOI

Kabak B., Dobson A.D. Mycotoxins in spices and herbs–An update. Crit. Rev. Food Sci. Nutr. 2017;57:18–34. doi: 10.1080/10408398.2013.772891. PubMed DOI

Tabari M.A., Youssefi M.R., Nasiri M., Hamidi M., Kiani K., Alian Samakkhah S., Maggi F. Towards green drugs against cestodes: Effectiveness of Pelargonium roseum and Ferula gummosa essential oils and their main component on Echinococcus granulosus protoscoleces. Vet. Parasitol. 2019;266:84–87. doi: 10.1016/j.vetpar.2018.12.019. PubMed DOI

Fabbri J., Maggiore M.A., Pensel P.E., Albani C.M., Denegri G.M., Elissondo M.C. Could beta-myrcene be an alternative to albendazole for the treatment of experimental cystic echinococcosis? Acta Trop. 2018;187:5–12. doi: 10.1016/j.actatropica.2018.07.013. PubMed DOI

Benelli G., Pavela R., Lupidi G., Nabissi M., Petrelli R., Kamte S.L.N., Cappellacci L., Fiorini D., Sut S., Dall’Acqua S., et al. The crop-residue of fiber hemp cv. Futura 75: From a waste product to a source of botanical insecticides. Environ. Sci. Pollut. Res. 2018;25:10515–10525. doi: 10.1007/s11356-017-0635-5. PubMed DOI

Elissondo M.C., Albani C.M., Gende L., Eguaras M., Denegri G. Efficacy of thymol against Echinococcus granulosus protoscoleces. Parasitol. Int. 2008;57:185–190. doi: 10.1016/j.parint.2007.12.005. PubMed DOI

Elissondo M.C., Pensel P.E., Denegri G.M. Could thymol have effectiveness on scolices and germinal layer of hydatid cysts? Acta Trop. 2013;125:251–257. doi: 10.1016/j.actatropica.2012.12.007. PubMed DOI

Fabbri J., Maggiore M.A., Pensel P.E., Denegri G.M., Gende L.B., Elissondo M.C. In vitro and in vivo efficacy of carvacrol against Echinococcus granulosus. Acta Trop. 2016;164:272–279. doi: 10.1016/j.actatropica.2016.09.001. PubMed DOI

Hosseini M., Yousefi M., Abouhosseini M. Comparison of the Effect of Artemisia Sieberi Essential Oil and Albendazole Drug on Protoscoleces of Hydatid Cyst under in Vitro Conditions. J. Babol Univ. Med. Sci. 2017;19:63–68.

Su V., King D., Woodrow I., McFadden G., Gleadow R. Plasmodium falciparum growth is arrested by monoterpenes from eucalyptus oil. Flavour Frag. J. 2008;23:315–318. doi: 10.1002/ffj.1880. DOI

Arruda D.C., Miguel D.C., Yokoyama-Yasunaka J.K., Katzin A.M., Uliana S.R. Inhibitory activity of limonene against Leishmania parasites in vitro and in vivo. Biomed. Pharmacother. 2009;63:643–649. doi: 10.1016/j.biopha.2009.02.004. PubMed DOI