Abstract
Leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from Leishmania genus. Conventional treatments are high costly, and promote a sort of side effects. Besides, protozoan resistance to treatments has been reported. Natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC50) values 16.4 and 9.8 μg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC50 values 126.6 and 23.8 μg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC50 values 5.0 and 0.9 μg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca2+ i] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis.
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Aggarwal BB, Shishodia S (2006) Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71:1397–1421. doi:10.1016/j.bcp.2006.02.009
Alizadeh BH, Foroumadi A, Ardestani SK, Poorrajab F, Shafiee A (2008) Leishmanicidal evaluation of novel synthetic chromenes. Arch Pharm 341:787–793. doi:10.1002/ardp.200800128
Ashford RW (2000) The leishmaniases as emerging and reemerging zoonoses. Int J Parasitol 30:1269–1281
Azevedo E, Oliveira LT, Castro Lima AK, Terra R, Dutra PM, Salerno VP (2012) Interactions between Leishmania braziliensis and macrophages are dependent on the cytoskeleton and myosin Va. J Parasitol Res 2012:275436. doi:10.1155/2012/275436
Bogdan C, Rollinghoff M (1998) The immune response to Leishmania: mechanisms of parasite control and evasion. Int J Parasitol 28:121–134
Bonatto SJ et al (2004) Lifelong exposure to dietary fish oil alters macrophage responses in Walker 256 tumor-bearing rats. Cell Immunol 231:56–62. doi:10.1016/j.cellimm.2004.12.001
Carneiro SM, Carvalho FA, Santana LC, Sousa AP, Neto JM, Chaves MH (2012) The cytotoxic and antileishmanial activity of extracts and fractions of leaves and fruits of Azadirachta indica (A Juss.) Biol res 45:111–116. doi:10.4067/S0716-97602012000200002
Cortazar TM, Coombs GH, Walker J (2007) Leishmania panamensis: comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine. Exp Parasitol 116:475–482. doi:10.1016/j.exppara.2007.02.018
Devipriya N, Srinivasan M, Sudheer AR, Menon VP (2007a) Effect of ellagic acid, a natural polyphenol, on alcohol-induced prooxidant and antioxidant imbalance: a drug dose dependent study. Singap med J 48:311–318
Devipriya N, Sudheer AR, Menon VP (2007b) Dose-response effect of ellagic acid on circulatory antioxidants and lipids during alcohol-induced toxicity in experimental rats. Fundam Clin Pharmacol 21:621–630. doi:10.1111/j.1472-8206.2007.00551.x
Dias CN, Rodrigues KA, Carvalho FA, Carneiro SM, Maia JG, Andrade EH, Moraes DF (2013) Molluscicidal and leishmanicidal activity of the leaf essential oil of Syzygium cumini (L.) SKEELS from Brazil. Chem Biodivers 10:1133–1141. doi:10.1002/cbdv.201200292
Gantt KR et al (2001) Oxidative responses of human and murine macrophages during phagocytosis of Leishmania chagasi. J Immunol 167:893–901
Goncalves JC et al (2013) The monoterpene (−)-carvone: a novel agonist of TRPV1 channels. Cytometry Part A 83:212–219. doi:10.1002/cyto.a.22236
Gonçalves JCR et al (2016) Antitumoral activity of novel 1,4-naphthoquinone derivative involves L-type calcium channel activation in human colorectal cancer cell line. J Appl Biomed 14:229–234. doi:10.1016/j.jab.2016.03.002
Grando FC et al (2009) Modulation of peritoneal macrophage activity by the saturation state of the fatty acid moiety of phosphatidylcholine. Braz J Med Biol Res = Rev Bras Pesqui Med Biol 42:599–605
Iino T, Nakahara K, Miki W, Kiso Y, Ogawa Y, Kato S, Takeuchi K (2001) Less damaging effect of whisky in rat stomachs in comparison with pure ethanol. Role of ellagic acid, the nonalcoholic component. Digestion 64:214–221
Islamuddin M, Chouhan G, Farooque A, Dwarakanath BS, Sahal D, Afrin F (2015) Th1-biased immunomodulation and therapeutic potential of Artemisia annua in murine visceral leishmaniasis. PLoS Negl Trop dis 9:e3321. doi:10.1371/journal.pntd.0003321
de Jesus NZ et al (2012) Tannins, peptic ulcers and related mechanisms. Int J Mol Sci 13:3203–3228. doi:10.3390/ijms13033203
Kaye P, Scott P (2011) Leishmaniasis: complexity at the host-pathogen interface. Nat rev Microbiol 9:604–615. doi:10.1038/nrmicro2608
Kayser O, Kiderlen AF, Croft SL (2003) Natural products as antiparasitic drugs. Parasitol res 90(Suppl 2):S55–S62. doi:10.1007/s00436-002-0768-3
Kheirandish F, Delfan B, Mahmoudvand H, Moradi N, Ezatpour B, Ebrahimzadeh F, Rashidipour M (2016) Antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract. Biomed Pharmacother 82:208–215. doi:10.1016/j.biopha.2016.04.040
Kolodziej H, Kiderlen AF (2005) Antileishmanial activity and immune modulatory effects of tannins and related compounds on Leishmania parasitised RAW 264.7 cells. Phytochemistry 66:2056–2071. doi:10.1016/j.phytochem.2005.01.011
Kondrashin AV, Baranova AM, Morozova LF, Stepanova EV (2011) Global trends in malaria control. Progress and topical tasks in malaria control programs Med Parazitol 3–8
Lachaud L, Bourgeois N, Plourde M, Leprohon P, Bastien P, Ouellette M (2009) Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis in patients coinfected with HIV type 1 and Leishmania infantum. Clin Infect Dis Off Publ Infect Dis Soc Am 48:e16–e22. doi:10.1086/595710
Lee WL, Harrison RE, Grinstein S (2003) Phagocytosis by neutrophils. Microbes Infect 5:1299–1306
Liew FY, Millott S, Parkinson C, Palmer RM, Moncada S (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from l-arginine. J Immunol 144:4794–4797
Lodge R, Descoteaux A (2005) Leishmania donovani promastigotes induce periphagosomal F-actin accumulation through retention of the GTPase Cdc42. Cell Microbiol 7:1647–1658. doi:10.1111/j.1462-5822.2005.00582.x
Lofgren SE, Miletti LC, Steindel M, Bachere E, Barracco MA (2008) Trypanocidal and leishmanicidal activities of different antimicrobial peptides (AMPs) isolated from aquatic animals. Exp Parasitol 118:197–202. doi:10.1016/j.exppara.2007.07.011
Lopes L, Godoy LM, de Oliveira CC, Gabardo J, Schadeck RJ, de Freitas BD (2006) Phagocytosis, endosomal/lysosomal system and other cellularaspects of macrophage activation by Canova medication. Micron 37:277–287. doi:10.1016/j.micron.2005.08.005
Lu Y et al (2010) Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells. Eur J Pharmacol 641:102–107. doi:10.1016/j.ejphar.2010.05.043
de Macedo-Silva ST, de Oliveira Silva TL, Urbina JA, de Souza W, Rodrigues JC (2011) Antiproliferative, ultrastructural, and physiological effects of amiodarone on promastigote and amastigote forms of Leishmania amazonensis. Mol Biol Int 2011:876021. doi:10.4061/2011/876021
Madalosso G, Fortaleza CM, Ribeiro AF, Cruz LL, Nogueira PA, Lindoso JA (2012) American visceral leishmaniasis: factors associated with lethality in the state of sao paulo. Braz J Trop Med 2012:281572. doi:10.1155/2012/281572
de Medeiros M, da Silva AC, Cito AM, Borges AR, de Lima SG, Lopes JA, Figueiredo RC (2011) In vitro antileishmanial activity and cytotoxicity of essential oil from Lippia sidoides Cham. Parasitol Int 60:237–241. doi:10.1016/j.parint.2011.03.004
Mitropoulos P, Konidas P, Durkin-Konidas M (2010) New World cutaneous leishmaniasis: updated review of current and future diagnosis and treatment. J am Acad Dermatol 63:309–322. doi:10.1016/j.jaad.2009.06.088
Montalvo AM, Fraga J, Monzote L, Garcia M, Fonseca L (2012) Leishmaniasis diagnosis: going from microscopic observation of parasite to DNA detection. Rev Cubana med Trop 64:108–131
Murakami S, Isobe Y, Kijima H, Nagai H, Muramatu M, Otomo S (1991) Inhibition of gastric H+, K(+)-ATPase and acid secretion by ellagic acid. Planta med 57:305–308. doi:10.1055/s-2006-960103
Niedergang F, Chavrier P (2004) Signaling and membrane dynamics during phagocytosis: many roads lead to the phagos(R)ome. Curr Opin Cell Biol 16:422–428. doi:10.1016/j.ceb.2004.06.006
Nozais JP (2003) The origin and dispersion of human parasitic diseases in the old world (Africa, Europe and Madagascar). Mem Inst Oswaldo Cruz 98(Suppl 1):13–19
Nwaka S, Hudson A (2006) Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov 5:941–955. doi:10.1038/nrd2144
Ogungbe IV, Erwin WR, Setzer WN (2014) Antileishmanial phytochemical phenolics: molecular docking to potential protein targets. J Mol Graph Model 48:105–117. doi:10.1016/j.jmgm.2013.12.010
Paolini A, Curti V, Pasi F, Mazzini G, Nano R, Capelli E (2015) Gallic acid exerts a protective or an anti-proliferative effect on glioma T98G cells via dose-dependent epigenetic regulation mediated by miRNAs. Int J Oncol 46:1491–1497. doi:10.3892/ijo.2015.2864
Papoutsi Z, Kassi E, Chinou I, Halabalaki M, Skaltsounis LA, Moutsatsou P (2008) Walnut extract (Juglans regia L.) and its component ellagic acid exhibit anti-inflammatory activity in human aorta endothelial cells and osteoblastic activity in the cell line KS483. Br J Nutr 99:715–722. doi:10.1017/S0007114507837421
Radtke OA, Kiderlen AF, Kayser O, Kolodziej H (2004) Gene expression profiles of inducible nitric oxide synthase and cytokines in Leishmania major-infected macrophage-like RAW 264.7 cells treated with gallic acid. Planta med 70:924–928. doi:10.1055/s-2004-832618
Reithinger R, Coleman PG (2007) Treating cutaneous leishmaniasis patients in Kabul, Afghanistan: cost-effectiveness of an operational program in a complex emergency setting. BMC Infect dis 7:3. doi:10.1186/1471-2334-7-3
Reithinger R, Dujardin JC, Louzir H, Pirmez C, Alexander B, Brooker S (2007) Cutaneous leishmaniasis. Lancet Infect dis 7:581–596. doi:10.1016/S1473-3099(07)70209-8
Ribeiro TG et al (2015) Antileishmanial activity of standardized fractions of Stryphnodendron obovatum (Barbatimao) extract and constituent compounds. J Ethnopharmacol 165:238–242. doi:10.1016/j.jep.2015.02.047
Rizk YS et al (2014) In vitro activity of the hydroethanolic extract and biflavonoids isolated from Selaginella sellowii on Leishmania (Leishmania) amazonensis. Mem Inst Oswaldo Cruz 109:1050–1056. doi:10.1590/0074-0276140312
Roatt BM et al (2014) Immunotherapy and Immunochemotherapy in visceral Leishmaniasis: promising treatments for this neglected disease. Front Immunol 5:272. doi:10.3389/fimmu.2014.00272
Rodrigues KA et al (2013) Eugenia uniflora L. essential oil as a potential anti-Leishmania agent: effects on Leishmania amazonensis and possible mechanisms of action. Evid Based Complement Alternat Med eCAM 2013:279726. doi:10.1155/2013/279726
Rodrigues KA, Amorim LV, Dias CN, Moraes DF, Carneiro SM, Carvalho FA (2015) Syzygium cumini (L.) Skeels essential oil and its major constituent alpha-pinene exhibit anti-Leishmania activity through immunomodulation in vitro. J Ethnopharmacol 160:32–40. doi:10.1016/j.jep.2014.11.024
Roy N et al (2014a) Regulation of PKC mediated signaling by calcium during visceral leishmaniasis. PLoS One 9:e110843. doi:10.1371/journal.pone.0110843
Roy S, Kumar GA, Jafurulla M, Mandal C, Chattopadhyay A (2014b) Integrity of the actin cytoskeleton of host macrophages is essential for Leishmania donovani infection. Biochim Biophys Acta 1838:2011–2018. doi:10.1016/j.bbamem.2014.04.017
dos Santos KK et al (2012) Cytotoxic, trypanocidal, and antifungal activities of Eugenia jambolana L. J med Food 15:66–70. doi:10.1089/jmf.2010.0298
Sarjit A, Wang Y, Dykes GA (2015) Antimicrobial activity of gallic acid against thermophilic Campylobacter is strain specific and associated with a loss of calcium ions. Food Microbiol 46:227–233. doi:10.1016/j.fm.2014.08.002
Shuaibu MN et al (2008) Castalagin from Anogeissus leiocarpus mediates the killing of Leishmania in vitro. Parasitol res 103:1333–1338. doi:10.1007/s00436-008-1137-7
Soares DC, Pereira CG, Meireles MA, Saraiva EM (2007) Leishmanicidal activity of a supercritical fluid fraction obtained from Tabernaemontana catharinensis. Parasitol Int 56:135–139. doi:10.1016/j.parint.2007.01.004
Sundar S, Chakravarty J, Rai VK, Agrawal N, Singh SP, Chauhan V, Murray HW (2007) Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions. Clin Infect Dis Off Publ Infect Dis Soc Am 45:556–561. doi:10.1086/520665
Tejle K, Magnusson KE, Rasmusson B (2002) Phagocytosis and phagosome maturation are regulated by calcium in J774 macrophages interacting with unopsonized prey. Biosci rep 22:529–540
Ueda-Nakamura T et al (2006) Antileishmanial activity of Eugenol-rich essential oil from Ocimum gratissimum. Parasitol Int 55:99–105. doi:10.1016/j.parint.2005.10.006
Valadares DG et al (2011) Leishmanicidal activity of the Agaricus blazei Murill in different Leishmania species. Parasitol Int 60:357–363. doi:10.1016/j.parint.2011.06.001
Vattem DA, Ghaedian R, Shetty K (2005) Enhancing health benefits of berries through phenolic antioxidant enrichment: focus on cranberry. Asia Pac J Clin Nutr 14:120–130
Verma NK, Dey CS (2004) Possible mechanism of miltefosine-mediated death of Leishmania donovani. Antimicrob Agents Chemother 48:3010–3015. doi:10.1128/AAC.48.8.3010-3015.2004
Waldron LS, Ferrari BC, Cheung-Kwok-Sang C, Beggs PJ, Stephens N, Power ML (2011) Molecular epidemiology and spatial distribution of a waterborne cryptosporidiosis outbreak in Australia. Appl Environ Microbiol 77:7766–7771. doi:10.1128/AEM.00616-11
Yadav DK, Khan F, Negi AS (2012) Pharmacophore modeling, molecular docking, QSAR, and in silico ADMET studies of gallic acid derivatives for immunomodulatory activity. J Mol Model 18:2513–2525. doi:10.1007/s00894-011-1265-3
Yang YH, Wang Z, Zheng J, Wang R (2015) Protective effects of gallic acid against spinal cord injury-induced oxidative stress. Mol med rep 12:3017–3024. doi:10.3892/mmr.2015.3738
Yuce A, Atessahin A, Ceribasi AO, Aksakal M (2007) Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin Pharmacol Toxicol 101:345–349. doi:10.1111/j.1742-7843.2007.00129.x
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All protocols were approved by the Animal Research Ethics Committee from Federal University of Piaui, Brazil (CEEA-PI no. 053/2015).
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Alves, M.M.d.M., Brito, L.M., Souza, A.C. et al. Gallic and ellagic acids: two natural immunomodulator compounds solve infection of macrophages by Leishmania major . Naunyn-Schmiedeberg's Arch Pharmacol 390, 893–903 (2017). https://doi.org/10.1007/s00210-017-1387-y
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DOI: https://doi.org/10.1007/s00210-017-1387-y