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Dietary Flavonoids Fisetin, Luteolin and Their Derived Compounds

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Dietary Flavonoids Fisetin, Luteolin and Their Derived Compounds Food Chemistry 141 (2013) 2253–2262 Contents lists available at SciVerse ScienceDirect Food Chemistry journal homepage: www.elsevier.com/locate/foodchem Dietary flavonoids fisetin, luteolin and their derived compounds inhibit arginase, a central enzyme in Leishmania (Leishmania) amazonensis infection Leticia Correa Manjolin a, Matheus Balduíno Goncalves dos Reis a, Claudia do Carmo Maquiaveli b, ⇑ Osvaldo Andrade Santos-Filho c, Edson Roberto da Silva d, a Programa de Iniciação Científica da Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil b Programa de Pós-Graduação em Fisiologia, Departamento de Fisiologia, Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Av. Bandeirantes, 3900 Monte Alegre, Ribeirão Preto, SP CEP 14049-900, Brazil c Laboratório de Modelagem Molecular, Departamento de Síntese Orgânica, Farmanguinhos/Fundação Oswaldo Cruz, Rua Sizenando Nabuco, 100, Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil d Laboratório de Imunologia de Parasitas, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Av. Duque de Caxias Norte, 225, Pirassununga, SP 13635-900, Brazil article info abstract Article history: Fisetin, quercetin, luteolin and 7,8-hydroxyflavone show high activity in Leishmania cultures and present Received 26 October 2012 low toxicity to mammalian cells. In this work, the structural aspects of 13 flavonoids were analyzed for Received in revised form 22 March 2013 their inhibition of the arginase enzyme from Leishmania (Leishmania) amazonensis. A higher potency of Accepted 8 May 2013 arginase inhibition was observed with fisetin, which was four and ten times greater than that of quercetin Available online 18 May 2013 and luteolin, respectively. These data show that the hydroxyl group at position 3 contributed significantly to the inhibitory activity of arginase, while the hydroxyl group at position 5 did not. The absence of the Keywords: catechol group on apigenin drastically decreased arginase inhibition. Additionally, the docking of com- Leishmania pounds showed that the inhibitors interact with amino acids involved in the Mnþ2 Mnþ2 metal bridge Polyamines À Arginase formation at the catalytic site. Due to the low IC50 values of these flavonoids, they may be used as a food Polyphenols supplement in leishmaniasis treatment. Flavonoid Ó 2013 Elsevier Ltd. All rights reserved. ROS 1. Introduction Quercetin and derived flavonoids are active by oral administration in experimental cutaneous and visceral leishmani- Leishmaniasis affects 12 million people in the world and is asso- asis infections produced in vivo (Gomes, Muzitano, Costa, & ciated with malnutrition, weakness of the immune system and Rossi-Bergmann, 2010; Muzitano et al., 2009). other factors related to a lack of resources. The disease primarily We have recently shown that quercetin, quercitrin and isoqu- affects people who live in poor housing conditions with limited ac- ercitrin are potent inhibitors of Leishmania (Leishmania) amazonen- cess to food (WHO, 2012). A balanced diet enriched with fruits and sis arginase (ARG-L) (da Silva, Maquiaveli, & Magalhaes, 2012a). vegetables can prevent cancer and cardiovascular diseases and Luteolin and quercetin promote k-DNA linearization mediated by stimulates the immune system. In addition to their antioxidant topoisomerase II, decrease DNA synthesis, arrest the cell cycle activities, bioactive food components, such as polyphenols, can and promote apoptosis of parasites (Mittra et al., 2000). Flavonoid promote a healthy life (Hertog, Feskens, Hollman, Katan, & Kromh- dimers have been developed as potent antileishmanial agents out, 1993). Several flavonoids, such as luteolin, quercetin and (Wong, Chan, Chan, & Chow, 2012) and can reverse multidrug quercitrin, which are abundant dietary flavones, are active against resistance in Leishmania. some species of Leishmania (Mittra et al., 2000; Muzitano et al., New therapeutic targets have been considered to treat 2006; Sen, Mukhopadhyay, Ray, & Biswas, 2008; Tasdemir et al., neglected diseases. For diseases caused by trypanosomatids, such 2006). as Chagas disease, African sleeping sickness and leishmaniasis, the exploration of the polyamine (PA) enzyme pathway has been ⇑ Corresponding author. Tel.: +55 19 3565 4371. important in drug development (Colotti & Ilari, 2011). PAs are valu- E-mail addresses: [email protected], [email protected] (E.R. da Silva). able targets for antiparasitic chemotherapy because they play an 0308-8146/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.foodchem.2013.05.025 2254 L.C. Manjolin et al. / Food Chemistry 141 (2013) 2253–2262 essential role in the proliferation, differentiation and synthesis of 2.3. Inhibitor screening and determination of IC50 macromolecules and the antioxidant mechanism in Leishmania (Birkholtz et al., 2011; Colotti & Ilari, 2011). The PA spermidine is Screening of compounds for their ability to inhibit arginase the substrate for the synthesis of trypanothione (N1, N8-bis (gluta- from L. (L.) amazonensis was performed using 125 lM concentra- tionil) spermidine) in Leishmania. Trypanothione promotes the re- tions of each compound at pH 9.5 with 50 mM CHES buffer and moval of reactive oxygen species (Fairlamb & Cerami, 1992) and 50 mM L-arginine (pH 9.5). The samples were incubated in a water reactive nitrogen species (Bocedi et al., 2010), thus protecting the bath at 37 °C for 15 min. Quantification of urea was performed by parasite from oxidative stress and endogenous reactive species enzymatic colorimetric Berthelot assay (Fawcett & Scott, 1960), produced by the host’s defence system. using commercial reagents. Briefly, the catalytic activity of the The ARG-L hydrolyses L-arginine into L-ornithine and urea in the arginase reactions was stopped by transferring 10 ll of reaction first step of PA biosynthesis. Double knockout of the ARG-L gene in mixture into 750 ll of reagent A (20 mM phosphate buffer, pH 7, L. (L.) donovani showed that arginase plays a central role in poly- containing 60 mM salicylate, 1 mM sodium nitroprusside and amine synthesis (Roberts et al., 2004). In L. (L.) major, double >500 IU of urease). This mixture was incubated at 37 °C for knockout of the ARG-L gene showed that the parasite becomes 5 min. Next, 750 ll of reagent B (sodium hypochlorite 10 mM auxotrophic for PAs (Reguera, Balaña-Fouce, Showalter, Hickerson, and NaOH 150 mM) were added, and then the samples were incu- & Beverley, 2009). ARG-L participates in a complex balance that bated at 37 °C for 10 min (Fawcett et al., 1960). Absorbance mea- determines the fate of L-arginine, and its subcellular localization surements were taken at 600 nm using a Hitachi 2810U in glycosomes may be essential for the physiological rhythm of spectrophotometer. The positive and negative controls were per- the parasite (da Silva, Zampieri, Muxel, Beverley, & Floeter-Winter, formed under the same conditions in the absence of inhibitor. 2012b). The experiments were performed in duplicate in at least three In mammals, there are two arginases: the hepatic arginase independent experiments. (ARG-1) and the extra-hepatic arginase (ARG-2). ARG-1 can be in- Determination of the concentration that inhibits 50% of the cat- duced in macrophages under the TH2 lymphocyte response alytic activity of the enzyme was carried out by varying the inhib- (Wanderley & Barcinski, 2010). The increase of ARG-1 leads to itor concentration with a 1:10 dilution factor. The experiments the consumption of L-arginine, which is also a substrate of nitric were performed in duplicate in at least three independent experi- oxide synthase. Nitric oxide synthase converts L-arginine to citrul- ments until we obtained a coefficient of non-linear regression line and nitric oxide (NO). As a consequence of increased ARG-1 R2 P 0.95. The different concentrations of the inhibitors were ob- activity, there is a decrease in the NO production that enables tained by serial dilution of the compound in water or a suitable sol- Leishmania to survive inside the macrophage. The inhibition of vent. The reactions were performed at pH 9.5 using 50 mM CHES x ARG-1 by endogenous NOHA (N -hydroxy-L-arginine) diminishes buffer in the presence of 50 mM substrate L-arginine (pH 9.5). the proliferation of Leishmania into the macrophage (Iniesta, The samples were incubated in a water bath at 37 °C for 15 min, Gómez-Nieto, & Corraliza, 2001). and the urea formed was analyzed as described above. We used This study examines the biochemical interaction between a mathematical sigmoidal (log IC50) model to determine the IC50, ARG-L and flavonoids. Additionally, a docking simulation of the using Origin 8.0 software. interaction between inhibitors and the structural model of the 0 ARG-L allows visualization of the interactions of dietary flavonoids 2.4. Determination of the constants Ki,Ki and mechanism of inhibition within the catalytic site of the enzyme. All reactions were performed in 50 mM CHES buffer, pH 9.5, containing variable concentrations of the substrate L-arginine 2. Materials and methods (12.5, 25, 50 and 100 mM) at pH 9.5. Inhibitors were used at three different concentrations close to the IC50. The different substrate 2.1. Materials and inhibitor concentrations were obtained by serial dilution. A mixture, M1, containing L-arginine (pH 9.5) at double the desirable Quercetin, isoquercitrin, quercitrin, luteolin, orientin, isoorien- concentration, and a second mixture, M2, containing the enzyme tin, fisetin, galangin, kaempferol, 7,8-dihydroxyflavone, apigenin, (2000 units) diluted in 125 mM CHES buffer (pH 9.5), were pre- vitexin, isovitexin, MnSO , L-arginine, CelLytic B, MOPS (4-mor- 4 pared. The reaction was prepared by mixing 50 ll of M1, 10 llof pholinepropanesulfonic acid), CHES (2-(cyclohexylamino)ethane- inhibitor and 40 ll of M2. The addition of M2 was synchronized sulfonic acid), PMSF (phenyl-methyl-sulfonyl fluoride), yeast every 15 s, followed by immediate incubation in a water bath for extract and tryptone were purchased from Sigma–Aldrich.
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