Efficacy of curcumin in the treatment of experimental vulvovaginal candidiasis

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Symbols <elsevierMultimedia ident="201911300712128641"></elsevierMultimedia>, <elsevierMultimedia ident="201911300712128642"></elsevierMultimedia>, <elsevierMultimedia ident="201911300712128643"></elsevierMultimedia> represent individuals in groups A, B-proven and B-risk, respectively. The vertical axis is in logarithmic scale. For each individual, the IFN-γ response was adjusted by subtracting the corresponding basal level. IFN-γ concentrations between 0 and 0.1pg/ml were assigned a value of 0.1pg/ml to fit into the plot. Since the data have no normal distribution and are not homoscedastic, the Kruskal–Wallis non-parametric test and the post hoc Dunn's test were used for multiple comparisons of the medians (shown as thick bars within the boxes). The gray horizontal line is placed at the defined IFN-γ cutoff level (20pg/ml)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Marcela Rubio-Carrasquilla, Rodrigo Ochoa, Cristian Santa, Allan J. Guimarães, Luz Elena Cano, Ernesto Moreno" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Marcela" "apellidos" => "Rubio-Carrasquilla" ] 1 => array:2 [ "nombre" => "Rodrigo" "apellidos" => "Ochoa" ] 2 => array:2 [ "nombre" => "Cristian" "apellidos" => "Santa" ] 3 => array:2 [ "nombre" => "Allan J." "apellidos" => "Guimarães" ] 4 => array:2 [ "nombre" => "Luz Elena" "apellidos" => "Cano" ] 5 => array:2 [ "nombre" => "Ernesto" "apellidos" => "Moreno" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1130140619300555?idApp=UINPBA00004N" "url" => "/11301406/0000003600000004/v1_201911300711/S1130140619300555/v1_201911300711/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original article" "titulo" => "Efficacy of curcumin in the treatment of experimental vulvovaginal candidiasis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "192" "paginaFinal" => "199" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jessica Tauany Andrade, Geisa Fantini de Figueiredo, Luisa Ferreira Cruz, Sarah Eliza de Morais, Carla Daiane Ferreira Souza, Flávia Carmo Horta Pinto, Jaqueline Maria Siqueira Ferreira, Marcelo Gonzaga de Freitas Araújo" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Jessica Tauany" "apellidos" => "Andrade" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Geisa" "apellidos" => "Fantini de Figueiredo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Luisa Ferreira" "apellidos" => "Cruz" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Sarah" "apellidos" => "Eliza de Morais" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Carla Daiane Ferreira" "apellidos" => "Souza" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Flávia Carmo Horta" "apellidos" => "Pinto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] ] ] 6 => array:3 [ "nombre" => "Jaqueline Maria Siqueira" "apellidos" => "Ferreira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 7 => array:4 [ "nombre" => "Marcelo Gonzaga de Freitas" "apellidos" => "Araújo" "email" => array:1 [ 0 => "mgfaraujo@ufsj.edu.br" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Laboratory of Medical Microbiology, Federal University of São João Del-Rei, Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Laboratory of Pharmacology, Federal University of São João Del-Rei, Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Natural Sciences Departament, Federal University of São João Del-Rei, Campus Dom Bosco, São João Del-Rei, Minas Gerais, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia de la curcumina en el tratamiento de la candidiasis vulvovaginal experimental" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1123 "Ancho" => 1332 "Tamanyo" => 85932 ] ] "descripcion" => array:1 [ "en" => "Quantitative analysis per group. Data are expressed as mean±standard deviation of inflammatory cells/mm2. *Groups with significant difference (p<0.05) when compared with the infected control (Tukey test with statistical difference at p<0.05) do not differ from each other." ] ] ] "textoCompleto" => "The most prevalent candidiasis-causing species is Candida albicans.<a class="elsevierStyleCrossRef" href="#bib0470">45</a>C. albicans is a dimorphic commensal fungus of mucosal surfaces, commonly found in the gastrointestinal and genitourinary tracts. It is the main agent that causes vulvovaginal candidiasis (VVC). The incidence of this disease is high, affecting 75% of all women at least once during their life-time. The risks associated with the acute form of VVC include imbalances in reproductive hormones caused by pregnancy, the use of oral contraceptives, and hormone replacement therapy, as well as the use of large spectrum antibiotics, diabetes, immunosuppression therapy, and stress.<a class="elsevierStyleCrossRefs" href="#bib0285">8,17</a> Some data suggest that the local immune response provides important protection during vaginitis.<a class="elsevierStyleCrossRefs" href="#bib0380">27,31</a> The vaginal epithelium plays an essential function as an active barrier that protects the female reproductive tract against the pathogenicity of different microorganisms. The expression of immunity receptors in those cells provides sensitivity to different pathogens, and their ability to produce some inflammation mediators leads to the course of local inflammation.<a class="elsevierStyleCrossRefs" href="#bib0265">4,27</a>Despite the advances in antifungal therapy, there are many problems related to the available drugs. Some antifungals commonly used to treat VVC, such as azoles, are potentially hepatotoxic. Those drugs have been reported to produce reproductive and developmental toxicity in both humans and laboratory animals.<a class="elsevierStyleCrossRefs" href="#bib0335">18,23,42</a> Furthermore, isolates of Candida are reported to be slightly susceptible to one or more azoles.<a class="elsevierStyleCrossRefs" href="#bib0260">3,40,44</a> The search for effective compounds with a lower toxicity index leads to investigate natural products as promising candidates in antifungal therapy. The disturbing reality of the progressive emergence of less susceptible strains to antimicrobials also drives this search. A variety of chemical compounds with antimicrobial properties are present in plants, and scientific researches to determine whether those compounds have antibiotic properties against resistant pathogens are necessary.<a class="elsevierStyleCrossRefs" href="#bib0255">2,20,47</a>Species of Curcuma are widely found in Asia, and their roots are used in food and traditional medicine.<a class="elsevierStyleCrossRef" href="#bib0415">34</a> Their therapeutic properties are linked to curcuminoids, polyphenolic compounds, being curcumin (1,7-bis[4-hydroxy-3-metoxyphenyl]-1,6-heptadiene-3,5-dione) the most abundant.<a class="elsevierStyleCrossRef" href="#bib0350">21</a> Curcumin is well-known to have therapeutic potential due to its antioxidant, anticarcinogenic, antimutagenic, and antimicrobial activities, among others.<a class="elsevierStyleCrossRef" href="#bib0485">48</a> Some reports have shown that curcumin has antifungal potential against different human pathogens.<a class="elsevierStyleCrossRefs" href="#bib0385">28,30</a> Regarding its activity against Candida species, curcumin was shown to be more efficient than fluconazole in the inhibition of oral epithelia fungal adhesion.<a class="elsevierStyleCrossRef" href="#bib0375">26</a> In another study<a class="elsevierStyleCrossRef" href="#bib0430">37</a> it was reported that curcumin acts as an antifungal agent via the generation of oxidative stress, and inhibits hyphae development by targeting TUP1. In addition, the mechanisms of action of curcumin on Candida that have already been described include the inhibition of hyphae development through the action on the TUP1 gene,<a class="elsevierStyleCrossRef" href="#bib0455">42</a> the reduction of ergosterol biosynthesis, the functional modulation of fungal PM-ATPase and the inhibition of fungal exoenzymes SAP (aspartate proteases).<a class="elsevierStyleCrossRefs" href="#bib0365">24,25</a> Besides the antifungal effectiveness, there is evidence that curcumin acts as an anti-inflammatory agent by inhibiting cyclooxygenases and lipoxygenases, and also regulates the production of pro-inflammatory cytokines.<a class="elsevierStyleCrossRefs" href="#bib0290">9,22</a>Since the pharmacological potential of curcumin is notable, and there is not a robust evidence on the anti-Candidal effect of curcumin in vivo, we investigated the antifungal potential of curcumin and its mechanism of action in vitro and in the therapeutic treatment of VVC in an immunosuppressed rat model.Materials and methodsCandida strains, animals and drugThree strains belonged to the American Type Culture Collection (C. albicans ATCC 10231, Candida glabrata ATCC 2001, Candida krusei ATCC 34135), and 5 clinical isolates of Candida dubliniensis were obtained from vaginal fluid specimens; the identification was carried out by conventional methods, including growth on chromogenic medium (CHROMagar Paris, France) according to the manufacturer's instructions. The in vivo assay was performed using female Wistar rats (Rattus norvegicus), which were obtained from the Central Animal Facility of Federal University of São João Del-Rei (UFSJ), Campus Dom Bosco. Curcumin (from Curcuma longa, ≥65% of purity), the tested compound in this study, was obtained commercially from Sigma–Aldrich®, Brazil.Growth conditions and inoculaAll Candida strains were grown on Sabouraud dextrose agar (SDA) (Acumedia®, Brazil) for 48h at 35–37°C. Each inoculum of Candida used in the experiments was standardized to 1×106CFU/ml by adjusting the optical density to 0.08–0.1 at 530nm (Biotek®, Brazil).<a class="elsevierStyleCrossRef" href="#bib0255">2</a>C. albicans ATCC 10231 was used for the in vivo infection.In vitro susceptibility testThe minimum inhibitory concentration (MIC) was determined by the microdilution method according to documents M38-A2 and M27-A3 of the Clinical and Laboratory Standards Institute,<a class="elsevierStyleCrossRef" href="#bib0295">10</a> with minor modifications.<a class="elsevierStyleCrossRefs" href="#bib0250">1,29,41</a> The initial concentration of curcumin was prepared at 2000μg/ml (ethanol was used as solvent) and 0.02ml of this solution was added to a 96-well microtitre plate containing Sabouraud dextrose broth (SDB) (Acumedia®, Brazil). The initial test concentration was serially two-fold diluted. Each well was inoculated with 0.1ml of a suspension containing 2.5×103CFU/ml. The antifungals ketoconazole (Sigma–Aldrich®, Brazil) and nystatin (Sigma–Aldrich®, Brazil) were included as positive controls and ethanol (solvent) was included as the negative control. The plates were incubated for 48h at 37°C. The MIC of each compound for every isolate was determined following the addition of 0.05ml of 2% triphenyltetrazolium chloride (TTC, Sigma–Aldrich®, Brazil). Yeast growth was displayed by a change to a red color. MIC was defined as the lowest concentration of compound showing no visible fungal growth after the TTC reaction. The minimal fungicidal concentration (MFC), in turn, was determined as the absence of visible colonies in Sabouraud dextrose agar (SDA), as previously described.<a class="elsevierStyleCrossRef" href="#bib0340">19</a> All experiments were performed in triplicate.Membrane ergosterol as target of antifungal activityThe MIC of curcumin against C. albicans ATCC 10231, C. glabrata ATCC 2001 and Candida krusei ATCC 34135 was determined following a standard reference method as explained above, in the absence and presence of exogenous ergosterol (200μg/ml) to determine whether curcumin binds to the fungal membrane sterol. If the activity of curcumin was caused by binding to ergosterol, the exogenous ergosterol would prevent curcumin binding to the fungal membrane's ergosterol. As a consequence, MIC values were enhanced in the presence of exogenous ergosterol.<a class="elsevierStyleCrossRef" href="#bib0320">15</a> Nystatin at an initial concentration of 1000μg/ml was used as a control drug. Caspofungin (Sigma–Aldrich®, Brazil), an antifungal that interfere with the fungal cell wall, was used at an initial concentration of 1000μg/ml as a negative control. The MIC was determined after 48h of incubation. All experiments were performed in triplicate.Experimental VVCFemale Wistar rats (body weight 100–150g) were collectively housed in the experimental room of the Laboratory of Pharmacology of UFSJ-Campus Centro Oeste (25°C±1°C, 12-h dark–light cycle). All applicable national and institutional guidelines for the care and use of animals were followed. Animals were maintained in the environmentally controlled room for at least 5 days before the experiments started. The protocol was approved by the Animal Experimentation Ethics Committee of the Universidade Federal de São João Del-Rei (Protocol 029/2013).The rat model of vaginal infection was established to obtain a chronic and homogeneous infection.<a class="elsevierStyleCrossRef" href="#bib0255">2</a><a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> presents a schematic representation of the experimental design. Animals were immunosuppressed by the administration of one dose of cyclophosphamide (Sigma®, 50mg/kg b.w.) and estrus was induced by the subcutaneous administration of estradiol cypionate (Pfizer®, Brazil) at a dose of 0.2mg/ml once daily for four days before the infection was induced. Rats were inoculated intravaginally with 0.1ml of C. albicans ATCC 10231 (5×107CFU/ml) using a micropipette with disposable tips. Two days after inoculation (day 0) the vaginal load of C. albicans was evaluated through vaginal lavage with 0.1ml of sterile saline, and determined by the CFU assay on SDA to verify whether the infection had been established. The infection was considered sufficient if a mean count for the vaginal lavage cultures from each rat was at least 103CFU/ml.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Therapeutic treatmentTo evaluate the effect of curcumin in VVC, three different concentrations of the compound solution and its controls were administered intravaginally to the infected animals. Wistar females (n=42) were randomized equally into the following seven groups: Group 1: non-infected animals; Group 2: infected animals, not treated; Group 3: infected animals treated with miconazole vaginal cream (0.1ml) (MCZ, 10mg/g, Medley®, Brazil); Group 4: infected animals treated with 0.25% of curcumin solution (0.1ml); Group 5: infected animals treated with 0.5% of curcumin solution (0.1ml); Group 6: infected animals treated with 1% of curcumin solution (0.1ml); and Group 7: infected animals treated with a 20% ethanol solution (vehicle control group) (0.1ml). Treatments were administered to the infected animals twice a day for seven consecutive days. One, four and eight days after the infection was established, the vaginal load of C. albicans was also evaluated to verify the effectiveness of the treatments. On day 8, the animals were euthanized and vaginas were longitudinally removed. All vaginal sections were stained with hematoxylin and eosin (H&E) and observed under light microscopy. From the histological slides stained by H&E, a quantitative analysis of the total inflammatory cells (polymorphonuclear and mononuclear) was performed using a digital image analyzer (Motic Images Plus 2.0 ML); the images were generated by a Zeiss Axiolab microscope connected to a camera (Moticam 580 5.0 MP) interconnected to a computer scanner. The images were obtained from the connective tissue of the vaginal mucosa, where the leucocytes were identified by their characteristic morphology. A total of 10 fields per slide at 400x magnification were analyzed through the Image J Program (NIH, BETHESDA, USA). The results of the quantitative analysis in each group were expressed as the mean±standard deviation of inflammatory cells/mm2.Statistical analysisTo verify the evolution in the reduction of the vaginal fungal load, analyses comparing the means obtained with curcumin on the third and seventh days with that of the first day after the infection were performed. Data obtained from the groups treated with curcumin were also compared with those from non-infected, infected-not treated groups, and vehicle control group. For the quantitative histological analyses, means between groups were compared. The results were analyzed statistically by the analysis of variance (ANOVA) for completely randomized experiments, with the calculation of the F statistic and the subsequent p values. In the cases in which p value was less than 0.05, treatment means were compared by the Tukey test for multiple comparison analysis between groups, and the minimum significant difference was calculated for α=0.05. GraphPad Prism 7® software was used to perform the statistical analyses.ResultsAntifungal activity and mechanisms of actionThe MIC value of curcumin against C. glabrata was 125μg/ml, but a concentration of 500μg/ml was required to achieve the same effect for C. krusei. Similar growth inhibition endpoints (1000μg/ml) with C. albicans and the clinical isolates of C. dubliniensis recovered from VVC patients were observed. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the results of MIC and MFC of curcumin with the different Candida species, as well as the MIC values with the antifungal controls (ketoconazole and nystatin).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The results of the action of curcumin on membrane ergosterol indicate that curcumin, as well as nystatin, can bind to C. albicans ergosterol since the presence of exogenous ergosterol increased the MIC values (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), thus suggesting the possible mechanism of action. As expected, caspofungin, the negative control, did not show any MIC increase in the presence of exogenous ergosterol. In this study, the curcumin could not bind to C. krusei and C. glabrata ergosterol since the presence of exogenous ergosterol did not show increased MIC values.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Treatment of VVCThe immunosuppressed and estrogen-dependent rats were infected with C. albicans, and fungal burden was assessed after 2 days (on day 0). Once the infection was established, we examined the activity of different concentrations of curcumin and MCZ in those animals in which VVC was achieved. On the 3rd day after the beginning of the treatment a new quantification of the fungal burden (through a vaginal lavage) was carried out. In the group of infected and untreated animals and in those treated with solvent ethanol (vehicle control), the fungal burden remained high in five animal out of six during all the study time. In contrast, in the groups treated with different concentrations of curcumin (0.25, 0.5 and 1%) the fungal burden was significantly reduced. On day 7th after the beginning of the treatment, C. albicans was detected in the infected and vehicle control groups at significantly higher levels. The three groups treated with curcumin showed a complete clearance of fungal load on the 7th day after infection (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). The treatment with MCZ exerted the complete clearance of the yeasts on the last day of treatment. Fungal load data are presented in log CFU/ml.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Histological analysis of the vaginal mucosa sections stained with H&E of all the animals was performed by light microscopy; representative images are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. We observed histologically normal vaginal mucosa in the uninfected group, while in the infected non-treated group the highest concentration of an inflammatory infiltrate in the lamina propria (below the epithelium) was observed. The histological study of the groups treated with 0.25 and 0.5% curcumin showed inflammatory infiltrate in the vaginal mucosa, with polymorphonuclear infiltration predominantly. The group treated with 1% curcumin showed a reduction in the mucosal inflammatory infiltrate. Regenerative changes associated with the restoration of the vaginal mucosa following MCZ treatment could be seen. Quantitative analysis of sections stained with H&E showed a reduction in the total inflammatory cells (polymorphonuclear and mononuclear) in the group treated with 1% curcumin, with a reduction proportional to the increase in the concentration of curcumin. The group treated with 1% curcumin showed a significant reduction in the number of inflammatory cells when compared to the infected-not treated group (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>DiscussionCurcumin has been evaluated with regard to a variety of biological activities, showing antifungal activity against a number of fungal pathogens, such as Paracoccidioides brasiliensis, Aspergillus, Sporothrix schenckii, as well as different Candida species.<a class="elsevierStyleCrossRefs" href="#bib0365">24,26,30</a> Since the current antifungal drugs have limitations, the interest in discovering new and more effective drugs has increased, especially those from natural sources.The compound exhibited antifungal activity against the three species of Candida included in this study, and fungistatic activity was noted. Curcumin showed activity against C. glabrata at a considerable concentration. An increase in the incidence of invasive candidiasis caused by non-C. albicansCandida species has been observed and it is associated with high mortality and antifungal resistance.<a class="elsevierStyleCrossRef" href="#bib0445">40</a> Among the non-C.albicans Candida species, C. glabrata stands out, having emerged as one of the most important opportunistic pathogens that are particularly capable of infecting a variety of places in the human body; this is the second most frequently isolated species in cases of VVC, preceded only by C. albicans.<a class="elsevierStyleCrossRefs" href="#bib0435">38,43,46</a> Several studies have reported the antifungal activity of curcumin. Martins et al.<a class="elsevierStyleCrossRef" href="#bib0375">26</a> showed that curcumin was able to inhibit the growth of several Candida species, and C. albicans was the most susceptible among the species studied. Furthermore, they demonstrated that curcumin dramatically inhibited the adhesion of Candida to epithelial cells. Other studies showed a synergistic effect of curcumin in combination with antifungal agents. Sharma et al. (2010) evaluated the in vitro antifungal effects of curcumin alone as well as in combination with azoles and polyenes against isolates of C. albicans. In wild type C. albicans curcumin showed a synergistic effect in combination with azoles (fluconazole and ketoconazole) and polyenes (amphotericin and nystatin). The MIC80 of curcumin in combination with fluconazole showed a 32-fold reduction, in combination with ketoconazole showed a 64-fold reduction, and a 16-fold reduction was observed when combined with amphotericin B or nystatin. These results demonstrate an important synergetic effect of curcumin in combination with important antifungal agents used in the clinical practice. In a study performed by Neelofar et al.<a class="elsevierStyleCrossRef" href="#bib0395">30</a> curcumin promoted the growth inhibition of C. albicans by using high concentrations of the compound when compared with the effective concentrations of fluconazole. Here, we observed that C. albicans and the clinical strains showed sensitivity to curcumin, with fungistatic activity being observed under the present experimental conditions.The major sterol component present in the fungal membrane is ergosterol, which plays qualitatively similar properties in fungal membranes as that cholesterol plays in mammalian cell membranes. Ergosterol serves as a bioregulator of membrane fluidity and asymmetry; consequently, the integrity of the cell membrane is dependent on these sterols.<a class="elsevierStyleCrossRef" href="#bib0270">5</a> One of the proposed mechanisms of actions for antifungal agents is binding to membrane ergosterol, which leads to fungal cell disruption and a loss of intracellular content.<a class="elsevierStyleCrossRef" href="#bib0405">32</a> In this work, we observed that the binding to membrane ergosterol might be the mechanism of action of curcumin against fungi. The cell membrane disruption in Candida by means of curcumin has been observed in other studies<a class="elsevierStyleCrossRef" href="#bib0365">24</a>; this antifungal activity supports our results. The authors demonstrated that the leakage of potassium ions from the fungal cytosol and a dissipation in the membrane potential was detected by bis-(1,3-dibutyl-barbituric acid) trimethineoxonol [DiBAC4(3)] staining. These authors also investigated an increase in membrane permeability in curcumin-treated C. albicans with an inﬂux of propidium iodide. Fluorescence analysis with 1,6-diphenyl-1,3,5-hexatriene supported the membrane-targeted mechanism of action indicating membrane disruption. Using calcein leakage assays from curcumin-treated large unilamellar vesicles and giant unilamellar vesicles, these authors found that curcumin has a membrane-active mechanism inducing the leakage of intracellular components through the ﬂappy membrane. However, the effect on membrane ergosterol in our study was species-specific; the curcumin was able to bind to ergosterol only in C. albicans ATCC 10231. This fact shows that the binding of curcumin to ergosterol is not a single-action mechanism. The action of curcumin on ergosterol and other fungal cell components should be determined in future studies.The therapeutic effect of curcumin was examined in an experimental animal model of VVC. It is known that Candida species cause opportunistic infections in hosts with altered physiological or immune responses.<a class="elsevierStyleCrossRef" href="#bib0475">46</a> In general, the development of mucosal infection models requires the use of systemic immunosuppression, which is a valid method for quickly inducing fungal colonization.<a class="elsevierStyleCrossRef" href="#bib0300">11</a> In rodent models, as well as human infection, these are stringently estrogen-dependent.<a class="elsevierStyleCrossRef" href="#bib0410">33</a> In women, VVC is extremely infrequent in the pre-pubertal period, while women become susceptible in the postmenopausal period following hormone replacement therapy. Estrogen exerts a multifunctional permissive role for vaginal candidiasis through a number of both host- and Candida-directed effects.<a class="elsevierStyleCrossRefs" href="#bib0280">7,39</a> Since the local immunity is also critical for anti-Candida defense in the vaginal mucosa, estrogen treatment is important because it transforms the epithelium to a pseudo-estrous phase and inhibits local immune defenses, increasing the glycogen content and thereby facilitating mucosal infection.<a class="elsevierStyleCrossRef" href="#bib0275">6</a> Thus, rats must be placed under stable pseudo-estrus conditions to establish experimental vaginal infection; this is usually achieved by estrogen treatment, which is sufficient to allow C. albicans infection to occur. Using the same model, several studies have shown the effectiveness of natural products against C. albicans in the treatment of VVC.<a class="elsevierStyleCrossRefs" href="#bib0255">2,13,47</a>As previously reported,<a class="elsevierStyleCrossRef" href="#bib0255">2</a> a C. albicans suspension containing 5×107CFU/ml was sufficient to establish an infection when instilled into the vagina of immunosuppressed-hormone treated rats. Other studies showed that immunosuppressed rats in a prolonged pseudo-estrus state are particularly susceptible to fungal colonization in the vaginal mucosa.<a class="elsevierStyleCrossRefs" href="#bib0255">2,35</a> The animals were treated twice a day for seven days and the doses of curcumin were selected on the basis of MIC results and previous in vitro antifungal activity studies using this compound. As shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>, after the 3rd day, the treatment with curcumin at 0.5% was able to completely clear the fungal burden in all animals, while at 0.25% and 1% the fungal burden was reduced significantly (p<0.05). On the 7th day, the infection was completely cleared in the groups treated with 0.25% and 1% curcumin. On the last day of treatment, the difference was not statistically significant (p>0.05) among the groups treated with curcumin and the one treated with miconazol, but differences were statistically significant when comparing with the infected-not treated and vehicle control groups. The inclusion of control groups was important to prove the test sensitivity and to ensure the curcumin effectiveness, since five animals remained infected in the infected-untreated group and in the vehicle control group during the entire study period.The histological study of the non-treated group showed signs of tissue reaction related to the infection, since an intense concentration of inflammatory infiltrate was observed. The groups treated with curcumin exhibited a reduction in inflammatory infiltrates, being the degree of reduction proportional to higher concentrations. Some studies have described the anti-inflammatory potential of curcumin and its ability to interact with numerous molecular targets involved in inflammation, including the altered activity of enzymes, such as cyclooxygenases and lipoxygenases, by inhibiting the tumor necrosis factor (TNF) and the pro-inflammatory transcription nuclear factor kappa B (NF-kB).<a class="elsevierStyleCrossRefs" href="#bib0315">14,16</a> Debata et al. (2013),<a class="elsevierStyleCrossRef" href="#bib0305">12</a> in a similar experiment with rats, treated the animals intravaginally for three weeks with a cream containing curcumin and then analyzed the results by histological analysis. The authors reported that the vaginal epithelium of the animals did not show any ulceration, areas of necrosis or micro-abscesses, and concluded that the intravaginal application of curcumin in a cream vehicle is feasible and safe.In conclusion, the in vitro results highlight the potential of curcumin as an effective antifungal against Candida species growth, showing a similar mechanism of action to the commercial antifungal nystatin. Its efficacy in a VVC rat model suggests that curcumin may be an important compound for the treatment of this fungal infection, and that the development of a vaginal cream formulation containing this compound should be considered.Ethical approvalAll procedures performed in the studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.Conflict of interestThe authors declare that they have no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1270302" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1175625" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1270301" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1175624" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Materials and methods" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Candida strains, animals and drug" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Growth conditions and inocula" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "In vitro susceptibility test" ] 3 => array:2 [ "identificador" => "sec0025" "titulo" => "Membrane ergosterol as target of antifungal activity" ] 4 => array:2 [ "identificador" => "sec0030" "titulo" => "Experimental VVC" ] 5 => array:2 [ "identificador" => "sec0035" "titulo" => "Therapeutic treatment" ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] ] ] 5 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Antifungal activity and mechanisms of action" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Treatment of VVC" ] ] ] 6 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Ethical approval" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interest" ] 9 => array:2 [ "identificador" => "xack436004" "titulo" => "Acknowledgements" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-02-06" "fechaAceptado" => "2019-01-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1175625" "palabras" => array:5 [ 0 => "Antifungal activity" 1 => "Candida albicans" 2 => "Curcumin" 3 => "Ergosterol" 4 => "Vulvovaginal candidiasis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1175624" "palabras" => array:5 [ 0 => "Actividad antifúngica" 1 => "Candida albicans" 2 => "Curcumina" 3 => "Ergosterol" 4 => "Candidiasis vulvovaginal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundCandida albicans is the main agent that causes vulvovaginal candidiasis. Resistance among isolates to azole antifungal agents has been reported. AimsDue to the well-known antifungal potential of curcumin, the purpose of this work was to evaluate the in vitro anticandidal activity of curcumin and its effect in the treatment of experimental vulvovaginal candidiasis. MethodsThe anticandidal activity of curcumin was investigated against eight Candida strains by the broth microdilution assay, and its mechanism of action was evaluated by testing the binding to ergosterol. Then, the effect of curcumin in the treatment of vulvovaginal candidiasis was evaluated in an immunosuppressed, estrogen treated rat model. ResultsCurcumin showed minimum inhibitory concentration values of 125–1000μg/ml, and the best result was observed against Candida glabrata. The compound was shown to be able to bind to the ergosterol present in the membrane, event that may be the mechanism of action. In addition, in the in vivo model of vulvovaginal candidiasis with C. albicans, treatments reduced the vaginal fungal burden in infected rats after seven days of treatment with different doses. ConclusionsCurcumin could be considered a promising effective antifungal agent in the treatment of vulvovaginal candidiasis." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesCandida albicans es la principal causante de la candidiasis vulvovaginal y algunos aislamientos pueden presentar resistencia a los antifúngicos azólicos. ObjetivosDebido al conocido potencial antifúngico de la curcumina, el objetivo de este trabajo fue evaluar su actividad anti-Candidain vitro y su efecto en el tratamiento de la candidiasis vulvovaginal experimental. MétodosLa actividad anti-Candida de la curcumina se evaluó frente a ocho cepas de Candida mediante un ensayo de microdilución en caldo, y su mecanismo de acción se estudió por una prueba de unión a ergosterol. Posteriormente se evaluó el efecto de la curcumina en el tratamiento de la candidiasis vulvovaginal con un modelo de rata inmunosuprimida, tratada con estrógenos. ResultadosLa curcumina mostró valores de concentración inhibitoria mínima de 125-1.000μg/ml, y el mejor resultado se observó frente a Candida glabrata. El compuesto demostró ser capaz de unirse al ergosterol de la membrana, lo que podría ser su mecanismo de acción. Además, en el modelo in vivo de candidiasis vulvovaginal con C. albicans, los tratamientos redujeron la carga fúngica vaginal en ratas infectadas después de siete días de tratamiento con diferentes dosis. ConclusionesLa curcumina podría considerarse un agente antifúngico eficaz prometedor en el tratamiento de la candidiasis vulvovaginal." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 683 "Ancho" => 2500 "Tamanyo" => 67448 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the experimental design. CPA: cyclophosphamide treatment; Est: estradiol cypionate treatment. *The vaginal load of C. albicans was evaluated through vaginal lavage on the fourth and eighth day in order to evaluate the curcumin effectiveness after three and seven days of treatment, respectively **Animals were treated twice per day for seven consecutive days." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 3933 "Ancho" => 2494 "Tamanyo" => 1022805 ] ] "descripcion" => array:1 [ "en" => "Representative photomicrographs of histological analyses of vaginal mucosa sections after different treatments: (A) non-infected animals (negative control) – vaginal mucosa with normal aspect; (B) infected and untreated animals – presence of inflammatory infiltrate in the lamina propria; (C) Infected animals treated with ethanol solution – presence of inflammatory infiltrate in the mucosa with polymorphonuclear infiltration mainly; (D) infected animals treated with MCZ (positive control) – presence of inflammatory process with polymorphonuclear infiltration mainly; (E) Infected animals treated with 0.25% curcumin – inflammatory infiltrate in the vaginal mucosa with polymorphonuclear infiltration mainly; (F) infected animals treated with 0.5% curcumin – inflammatory infiltrate in the vaginal mucosa, with polymorphonuclear infiltration mainly; (G) infected animals treated with 1% curcumin – reduction in mucosal inflammatory infiltrate compared to 0.25% and 0.5% curcumin treatments. The black arrows point to polymorphonuclear leucocytes. The red arrows point to mononuclear leucocytes. H&E stain, 400× magnification." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1123 "Ancho" => 1332 "Tamanyo" => 85932 ] ] "descripcion" => array:1 [ "en" => "Quantitative analysis per group. Data are expressed as mean±standard deviation of inflammatory cells/mm2. *Groups with significant difference (p<0.05) when compared with the infected control (Tukey test with statistical difference at p<0.05) do not differ from each other." ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Candida strains \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC curcumin<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MFC curcumin<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> ketoconazole<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> nystatin<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. albicans ATCC 10231 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. glabrata ATCC 2001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. krusei ATCC 34135 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. dubliniensis clinical isolate 11763 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. dubliniensis clinical isolate 1083 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. dubliniensis clinical isolate 1203 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. dubliniensis clinical isolate 1417 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C. dubliniensis clinical isolate 1252 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">>1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.97 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ND \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2173028.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Values in μg/ml." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "Positive control; ND: not determined." ] ] ] "descripcion" => array:1 [ "en" => "In vitro antifungal activity of curcumin." ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C. albicans ATCC 10231</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C. glabrata ATCC 2001</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">C. krusei ATCC 34135</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curcumin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nystatin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">31.25 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Caspofungin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0625 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.0625 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2173029.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Values in μg/ml. Nystatin: positive control. Caspofungin: negative control." ] ] ] "descripcion" => array:1 [ "en" => "In vitro antifungal activity of curcumin against Candida species with and without exogenous ergosterol." ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Groups \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day 0</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day 3</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day 7</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LogCFU/ml±SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LogCFU/ml±SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals (%) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LogCFU/ml±SD \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Infected control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.25±0.20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.04±0.04 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/6 (83.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.00±0.07 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4.94±0.06 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/6 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.89±0.03 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curcumin 0.25% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.46±0.13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/6 (50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1.61±0.02<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curcumin 0.5% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.48±0.07 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/6 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Curcumin 1% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.53±0.02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/6 (66.6) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.49±0.01<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.00±0.00<a class="elsevierStyleCrossRef" href="#tblfn0020">*</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vehicle \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.64±0.22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6/6 (100) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.72±0.72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/6 (83.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.20±0.27 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2173030.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "*" "nota" => "Statistically significant difference from the values obtained on day 0 (p<0.05); 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Original article

Efficacy of curcumin in the treatment of experimental vulvovaginal candidiasis

Eficacia de la curcumina en el tratamiento de la candidiasis vulvovaginal experimental

Jessica Tauany Andradea, Geisa Fantini de Figueiredob, Luisa Ferreira Cruzb, Sarah Eliza de Moraisb, Carla Daiane Ferreira Souzaa, Flávia Carmo Horta Pintoc, Jaqueline Maria Siqueira Ferreiraa, Marcelo Gonzaga de Freitas Araújob,

Corresponding author

mgfaraujo@ufsj.edu.br

Corresponding author.

a Laboratory of Medical Microbiology, Federal University of São João Del-Rei, Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil

b Laboratory of Pharmacology, Federal University of São João Del-Rei, Campus Centro Oeste Dona Lindu, Divinópolis, Minas Gerais, Brazil

c Natural Sciences Departament, Federal University of São João Del-Rei, Campus Dom Bosco, São João Del-Rei, Minas Gerais, Brazil

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            "entidad" => "Natural Sciences Departament&#44; Federal University of S&#227;o Jo&#227;o Del-Rei&#44; Campus Dom Bosco&#44; S&#227;o Jo&#227;o Del-Rei&#44; Minas Gerais&#44; Brazil"
            "etiqueta" => "c"
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            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
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    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Eficacia de la curcumina en el tratamiento de la candidiasis vulvovaginal experimental"
      ]
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Quantitative analysis per group&#46; Data are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation of inflammatory cells&#47;mm<span class="elsevierStyleSup">2</span>&#46; &#42;Groups with significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; when compared with the infected control &#40;Tukey test with statistical difference at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; do not differ from each other&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The most prevalent candidiasis-causing species is <span class="elsevierStyleItalic">Candida albicans</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">45</span></a><span class="elsevierStyleItalic">C&#46; albicans</span> is a dimorphic commensal fungus of mucosal surfaces&#44; commonly found in the gastrointestinal and genitourinary tracts&#46; It is the main agent that causes vulvovaginal candidiasis &#40;VVC&#41;&#46; The incidence of this disease is high&#44; affecting 75&#37; of all women at least once during their life-time&#46; The risks associated with the acute form of VVC include imbalances in reproductive hormones caused by pregnancy&#44; the use of oral contraceptives&#44; and hormone replacement therapy&#44; as well as the use of large spectrum antibiotics&#44; diabetes&#44; immunosuppression therapy&#44; and stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">8&#44;17</span></a> Some data suggest that the local immune response provides important protection during vaginitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">27&#44;31</span></a> The vaginal epithelium plays an essential function as an active barrier that protects the female reproductive tract against the pathogenicity of different microorganisms&#46; The expression of immunity receptors in those cells provides sensitivity to different pathogens&#44; and their ability to produce some inflammation mediators leads to the course of local inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">4&#44;27</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Despite the advances in antifungal therapy&#44; there are many problems related to the available drugs&#46; Some antifungals commonly used to treat VVC&#44; such as azoles&#44; are potentially hepatotoxic&#46; Those drugs have been reported to produce reproductive and developmental toxicity in both humans and laboratory animals&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">18&#44;23&#44;42</span></a> Furthermore&#44; isolates of <span class="elsevierStyleItalic">Candida</span> are reported to be slightly susceptible to one or more azoles&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">3&#44;40&#44;44</span></a> The search for effective compounds with a lower toxicity index leads to investigate natural products as promising candidates in antifungal therapy&#46; The disturbing reality of the progressive emergence of less susceptible strains to antimicrobials also drives this search&#46; A variety of chemical compounds with antimicrobial properties are present in plants&#44; and scientific researches to determine whether those compounds have antibiotic properties against resistant pathogens are necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">2&#44;20&#44;47</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Species of <span class="elsevierStyleItalic">Curcuma</span> are widely found in Asia&#44; and their roots are used in food and traditional medicine&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">34</span></a> Their therapeutic properties are linked to curcuminoids&#44; polyphenolic compounds&#44; being curcumin &#40;1&#44;7-bis&#91;4-hydroxy-3-metoxyphenyl&#93;-1&#44;6-heptadiene-3&#44;5-dione&#41; the most abundant&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">21</span></a> Curcumin is well-known to have therapeutic potential due to its antioxidant&#44; anticarcinogenic&#44; antimutagenic&#44; and antimicrobial activities&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">48</span></a> Some reports have shown that curcumin has antifungal potential against different human pathogens&#46;<a class="elsevierStyleCrossRefs" href="#bib0385"><span class="elsevierStyleSup">28&#44;30</span></a> Regarding its activity against <span class="elsevierStyleItalic">Candida</span> species&#44; curcumin was shown to be more efficient than fluconazole in the inhibition of oral epithelia fungal adhesion&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">26</span></a> In another study<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">37</span></a> it was reported that curcumin acts as an antifungal agent <span class="elsevierStyleItalic">via</span> the generation of oxidative stress&#44; and inhibits hyphae development by targeting TUP1&#46; In addition&#44; the mechanisms of action of curcumin on <span class="elsevierStyleItalic">Candida</span> that have already been described include the inhibition of hyphae development through the action on the TUP1 gene&#44;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">42</span></a> the reduction of ergosterol biosynthesis&#44; the functional modulation of fungal PM-ATPase and the inhibition of fungal exoenzymes SAP &#40;aspartate proteases&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">24&#44;25</span></a> Besides the antifungal effectiveness&#44; there is evidence that curcumin acts as an anti-inflammatory agent by inhibiting cyclooxygenases and lipoxygenases&#44; and also regulates the production of pro-inflammatory cytokines&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">9&#44;22</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Since the pharmacological potential of curcumin is notable&#44; and there is not a robust evidence on the anti-<span class="elsevierStyleItalic">Candidal</span> effect of curcumin <span class="elsevierStyleItalic">in vivo</span>&#44; we investigated the antifungal potential of curcumin and its mechanism of action <span class="elsevierStyleItalic">in vitro</span> and in the therapeutic treatment of VVC in an immunosuppressed rat model&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080"><span class="elsevierStyleItalic">Candida</span> strains&#44; animals and drug</span><p id="par0025" class="elsevierStylePara elsevierViewall">Three strains belonged to the American Type Culture Collection &#40;<span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231&#44; <span class="elsevierStyleItalic">Candida glabrata</span> ATCC 2001&#44; <span class="elsevierStyleItalic">Candida krusei</span> ATCC 34135&#41;&#44; and 5 clinical isolates of <span class="elsevierStyleItalic">Candida dubliniensis</span> were obtained from vaginal fluid specimens&#59; the identification was carried out by conventional methods&#44; including growth on chromogenic medium &#40;CHROMagar Paris&#44; France&#41; according to the manufacturer&#39;s instructions&#46; The <span class="elsevierStyleItalic">in vivo</span> assay was performed using female Wistar rats &#40;<span class="elsevierStyleItalic">Rattus norvegicus</span>&#41;&#44; which were obtained from the Central Animal Facility of Federal University of S&#227;o Jo&#227;o Del-Rei &#40;UFSJ&#41;&#44; Campus Dom Bosco&#46; Curcumin &#40;from <span class="elsevierStyleItalic">Curcuma longa</span>&#44; &#8805;65&#37; of purity&#41;&#44; the tested compound in this study&#44; was obtained commercially from Sigma&#8211;Aldrich&#174;&#44; Brazil&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Growth conditions and inocula</span><p id="par0030" class="elsevierStylePara elsevierViewall">All <span class="elsevierStyleItalic">Candida</span> strains were grown on Sabouraud dextrose agar &#40;SDA&#41; &#40;Acumedia&#174;&#44; Brazil&#41; for 48<span class="elsevierStyleHsp" style=""></span>h at 35&#8211;37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; Each inoculum of <span class="elsevierStyleItalic">Candida</span> used in the experiments was standardized to 1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">6</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml by adjusting the optical density to 0&#46;08&#8211;0&#46;1 at 530<span class="elsevierStyleHsp" style=""></span>nm &#40;Biotek&#174;&#44; Brazil&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231 was used for the <span class="elsevierStyleItalic">in vivo</span> infection&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090"><span class="elsevierStyleItalic">In vitro</span> susceptibility test</span><p id="par0035" class="elsevierStylePara elsevierViewall">The minimum inhibitory concentration &#40;MIC&#41; was determined by the microdilution method according to documents M38-A2 and M27-A3 of the Clinical and Laboratory Standards Institute&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">10</span></a> with minor modifications&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">1&#44;29&#44;41</span></a> The initial concentration of curcumin was prepared at 2000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml &#40;ethanol was used as solvent&#41; and 0&#46;02<span class="elsevierStyleHsp" style=""></span>ml of this solution was added to a 96-well microtitre plate containing Sabouraud dextrose broth &#40;SDB&#41; &#40;Acumedia&#174;&#44; Brazil&#41;&#46; The initial test concentration was serially two-fold diluted&#46; Each well was inoculated with 0&#46;1<span class="elsevierStyleHsp" style=""></span>ml of a suspension containing 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml&#46; The antifungals ketoconazole &#40;Sigma&#8211;Aldrich&#174;&#44; Brazil&#41; and nystatin &#40;Sigma&#8211;Aldrich&#174;&#44; Brazil&#41; were included as positive controls and ethanol &#40;solvent&#41; was included as the negative control&#46; The plates were incubated for 48<span class="elsevierStyleHsp" style=""></span>h at 37<span class="elsevierStyleHsp" style=""></span>&#176;C&#46; The MIC of each compound for every isolate was determined following the addition of 0&#46;05<span class="elsevierStyleHsp" style=""></span>ml of 2&#37; triphenyltetrazolium chloride &#40;TTC&#44; Sigma&#8211;Aldrich&#174;&#44; Brazil&#41;&#46; Yeast growth was displayed by a change to a red color&#46; MIC was defined as the lowest concentration of compound showing no visible fungal growth after the TTC reaction&#46; The minimal fungicidal concentration &#40;MFC&#41;&#44; in turn&#44; was determined as the absence of visible colonies in Sabouraud dextrose agar &#40;SDA&#41;&#44; as previously described&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">19</span></a> All experiments were performed in triplicate&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Membrane ergosterol as target of antifungal activity</span><p id="par0040" class="elsevierStylePara elsevierViewall">The MIC of curcumin against <span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231&#44; <span class="elsevierStyleItalic">C&#46; glabrata</span> ATCC 2001 and <span class="elsevierStyleItalic">Candida krusei</span> ATCC 34135 was determined following a standard reference method as explained above&#44; in the absence and presence of exogenous ergosterol &#40;200<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; to determine whether curcumin binds to the fungal membrane sterol&#46; If the activity of curcumin was caused by binding to ergosterol&#44; the exogenous ergosterol would prevent curcumin binding to the fungal membrane&#39;s ergosterol&#46; As a consequence&#44; MIC values were enhanced in the presence of exogenous ergosterol&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">15</span></a> Nystatin at an initial concentration of 1000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml was used as a control drug&#46; Caspofungin &#40;Sigma&#8211;Aldrich&#174;&#44; Brazil&#41;&#44; an antifungal that interfere with the fungal cell wall&#44; was used at an initial concentration of 1000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml as a negative control&#46; The MIC was determined after 48<span class="elsevierStyleHsp" style=""></span>h of incubation&#46; All experiments were performed in triplicate&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Experimental VVC</span><p id="par0045" class="elsevierStylePara elsevierViewall">Female Wistar rats &#40;body weight 100&#8211;150<span class="elsevierStyleHsp" style=""></span>g&#41; were collectively housed in the experimental room of the Laboratory of Pharmacology of UFSJ-Campus Centro Oeste &#40;25<span class="elsevierStyleHsp" style=""></span>&#176;C<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; 12-h dark&#8211;light cycle&#41;&#46; All applicable national and institutional guidelines for the care and use of animals were followed&#46; Animals were maintained in the environmentally controlled room for at least 5 days before the experiments started&#46; The protocol was approved by the Animal Experimentation Ethics Committee of the Universidade Federal de S&#227;o Jo&#227;o Del-Rei &#40;Protocol 029&#47;2013&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The rat model of vaginal infection was established to obtain a chronic and homogeneous infection&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">2</span></a><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> presents a schematic representation of the experimental design&#46; Animals were immunosuppressed by the administration of one dose of cyclophosphamide &#40;Sigma&#174;&#44; 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg b&#46;w&#46;&#41; and estrus was induced by the subcutaneous administration of estradiol cypionate &#40;Pfizer&#174;&#44; Brazil&#41; at a dose of 0&#46;2<span class="elsevierStyleHsp" style=""></span>mg&#47;ml once daily for four days before the infection was induced&#46; Rats were inoculated intravaginally with 0&#46;1<span class="elsevierStyleHsp" style=""></span>ml of C&#46; albicans ATCC 10231 &#40;5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">7</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml&#41; using a micropipette with disposable tips&#46; Two days after inoculation &#40;day 0&#41; the vaginal load of <span class="elsevierStyleItalic">C&#46; albicans</span> was evaluated through vaginal lavage with 0&#46;1<span class="elsevierStyleHsp" style=""></span>ml of sterile saline&#44; and determined by the CFU assay on SDA to verify whether the infection had been established&#46; The infection was considered sufficient if a mean count for the vaginal lavage cultures from each rat was at least 10<span class="elsevierStyleSup">3</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Therapeutic treatment</span><p id="par0055" class="elsevierStylePara elsevierViewall">To evaluate the effect of curcumin in VVC&#44; three different concentrations of the compound solution and its controls were administered intravaginally to the infected animals&#46; Wistar females &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#41; were randomized equally into the following seven groups&#58; Group 1&#58; non-infected animals&#59; Group 2&#58; infected animals&#44; not treated&#59; Group 3&#58; infected animals treated with miconazole vaginal cream &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#41; &#40;MCZ&#44; 10<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#44; Medley&#174;&#44; Brazil&#41;&#59; Group 4&#58; infected animals treated with 0&#46;25&#37; of curcumin solution &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#41;&#59; Group 5&#58; infected animals treated with 0&#46;5&#37; of curcumin solution &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#41;&#59; Group 6&#58; infected animals treated with 1&#37; of curcumin solution &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#41;&#59; and Group 7&#58; infected animals treated with a 20&#37; ethanol solution &#40;vehicle control group&#41; &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>ml&#41;&#46; Treatments were administered to the infected animals twice a day for seven consecutive days&#46; One&#44; four and eight days after the infection was established&#44; the vaginal load of <span class="elsevierStyleItalic">C&#46; albicans</span> was also evaluated to verify the effectiveness of the treatments&#46; On day 8&#44; the animals were euthanized and vaginas were longitudinally removed&#46; All vaginal sections were stained with hematoxylin and eosin &#40;H&#38;E&#41; and observed under light microscopy&#46; From the histological slides stained by H&#38;E&#44; a quantitative analysis of the total inflammatory cells &#40;polymorphonuclear and mononuclear&#41; was performed using a digital image analyzer &#40;Motic Images Plus 2&#46;0 ML&#41;&#59; the images were generated by a Zeiss Axiolab microscope connected to a camera &#40;Moticam 580 5&#46;0 MP&#41; interconnected to a computer scanner&#46; The images were obtained from the connective tissue of the vaginal mucosa&#44; where the leucocytes were identified by their characteristic morphology&#46; A total of 10 fields per slide at 400x magnification were analyzed through the Image J Program &#40;NIH&#44; BETHESDA&#44; USA&#41;&#46; The results of the quantitative analysis in each group were expressed as the mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation of inflammatory cells&#47;mm<span class="elsevierStyleSup">2</span>&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical analysis</span><p id="par0060" class="elsevierStylePara elsevierViewall">To verify the evolution in the reduction of the vaginal fungal load&#44; analyses comparing the means obtained with curcumin on the third and seventh days with that of the first day after the infection were performed&#46; Data obtained from the groups treated with curcumin were also compared with those from non-infected&#44; infected-not treated groups&#44; and vehicle control group&#46; For the quantitative histological analyses&#44; means between groups were compared&#46; The results were analyzed statistically by the analysis of variance &#40;ANOVA&#41; for completely randomized experiments&#44; with the calculation of the F statistic and the subsequent <span class="elsevierStyleItalic">p</span> values&#46; In the cases in which <span class="elsevierStyleItalic">p</span> value was less than 0&#46;05&#44; treatment means were compared by the Tukey test for multiple comparison analysis between groups&#44; and the minimum significant difference was calculated for <span class="elsevierStyleItalic">&#945;</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; GraphPad Prism 7&#174; software was used to perform the statistical analyses&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Antifungal activity and mechanisms of action</span><p id="par0065" class="elsevierStylePara elsevierViewall">The MIC value of curcumin against <span class="elsevierStyleItalic">C&#46; glabrata</span> was 125<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; but a concentration of 500<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml was required to achieve the same effect for <span class="elsevierStyleItalic">C&#46; krusei</span>&#46; Similar growth inhibition endpoints &#40;1000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#41; with <span class="elsevierStyleItalic">C&#46; albicans</span> and the clinical isolates of <span class="elsevierStyleItalic">C&#46; dubliniensis</span> recovered from VVC patients were observed&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the results of MIC and MFC of curcumin with the different <span class="elsevierStyleItalic">Candida</span> species&#44; as well as the MIC values with the antifungal controls &#40;ketoconazole and nystatin&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The results of the action of curcumin on membrane ergosterol indicate that curcumin&#44; as well as nystatin&#44; can bind to <span class="elsevierStyleItalic">C&#46; albicans</span> ergosterol since the presence of exogenous ergosterol increased the MIC values &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; thus suggesting the possible mechanism of action&#46; As expected&#44; caspofungin&#44; the negative control&#44; did not show any MIC increase in the presence of exogenous ergosterol&#46; In this study&#44; the curcumin could not bind to <span class="elsevierStyleItalic">C&#46; krusei</span> and <span class="elsevierStyleItalic">C&#46; glabrata</span> ergosterol since the presence of exogenous ergosterol did not show increased MIC values&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Treatment of VVC</span><p id="par0075" class="elsevierStylePara elsevierViewall">The immunosuppressed and estrogen-dependent rats were infected with <span class="elsevierStyleItalic">C&#46; albicans&#44;</span> and fungal burden was assessed after 2 days &#40;on day 0&#41;&#46; Once the infection was established&#44; we examined the activity of different concentrations of curcumin and MCZ in those animals in which VVC was achieved&#46; On the 3rd day after the beginning of the treatment a new quantification of the fungal burden &#40;through a vaginal lavage&#41; was carried out&#46; In the group of infected and untreated animals and in those treated with solvent ethanol &#40;vehicle control&#41;&#44; the fungal burden remained high in five animal out of six during all the study time&#46; In contrast&#44; in the groups treated with different concentrations of curcumin &#40;0&#46;25&#44; 0&#46;5 and 1&#37;&#41; the fungal burden was significantly reduced&#46; On day 7th after the beginning of the treatment&#44; <span class="elsevierStyleItalic">C&#46; albicans</span> was detected in the infected and vehicle control groups at significantly higher levels&#46; The three groups treated with curcumin showed a complete clearance of fungal load on the 7th day after infection &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; The treatment with MCZ exerted the complete clearance of the yeasts on the last day of treatment&#46; Fungal load data are presented in log CFU&#47;ml&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">Histological analysis of the vaginal mucosa sections stained with H&#38;E of all the animals was performed by light microscopy&#59; representative images are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; We observed histologically normal vaginal mucosa in the uninfected group&#44; while in the infected non-treated group the highest concentration of an inflammatory infiltrate in the lamina propria &#40;below the epithelium&#41; was observed&#46; The histological study of the groups treated with 0&#46;25 and 0&#46;5&#37; curcumin showed inflammatory infiltrate in the vaginal mucosa&#44; with polymorphonuclear infiltration predominantly&#46; The group treated with 1&#37; curcumin showed a reduction in the mucosal inflammatory infiltrate&#46; Regenerative changes associated with the restoration of the vaginal mucosa following MCZ treatment could be seen&#46; Quantitative analysis of sections stained with H&#38;E showed a reduction in the total inflammatory cells &#40;polymorphonuclear and mononuclear&#41; in the group treated with 1&#37; curcumin&#44; with a reduction proportional to the increase in the concentration of curcumin&#46; The group treated with 1&#37; curcumin showed a significant reduction in the number of inflammatory cells when compared to the infected-not treated group &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">Curcumin has been evaluated with regard to a variety of biological activities&#44; showing antifungal activity against a number of fungal pathogens&#44; such as <span class="elsevierStyleItalic">Paracoccidioides brasiliensis</span>&#44; <span class="elsevierStyleItalic">Aspergillus</span>&#44; <span class="elsevierStyleItalic">Sporothrix schenckii</span>&#44; as well as different <span class="elsevierStyleItalic">Candida</span> species&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">24&#44;26&#44;30</span></a> Since the current antifungal drugs have limitations&#44; the interest in discovering new and more effective drugs has increased&#44; especially those from natural sources&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The compound exhibited antifungal activity against the three species of <span class="elsevierStyleItalic">Candida</span> included in this study&#44; and fungistatic activity was noted&#46; Curcumin showed activity against <span class="elsevierStyleItalic">C&#46; glabrata</span> at a considerable concentration&#46; An increase in the incidence of invasive candidiasis caused by non-<span class="elsevierStyleItalic">C&#46; albicans</span><span class="elsevierStyleItalic">Candida</span> species has been observed and it is associated with high mortality and antifungal resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">40</span></a> Among the non-<span class="elsevierStyleItalic">C&#46;</span><span class="elsevierStyleItalic">albicans Candida</span> species&#44; C&#46; glabrata stands out&#44; having emerged as one of the most important opportunistic pathogens that are particularly capable of infecting a variety of places in the human body&#59; this is the second most frequently isolated species in cases of VVC&#44; preceded only by <span class="elsevierStyleItalic">C&#46; albicans</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">38&#44;43&#44;46</span></a> Several studies have reported the antifungal activity of curcumin&#46; Martins et al&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">26</span></a> showed that curcumin was able to inhibit the growth of several <span class="elsevierStyleItalic">Candida</span> species&#44; and <span class="elsevierStyleItalic">C&#46; albicans</span> was the most susceptible among the species studied&#46; Furthermore&#44; they demonstrated that curcumin dramatically inhibited the adhesion of <span class="elsevierStyleItalic">Candida</span> to epithelial cells&#46; Other studies showed a synergistic effect of curcumin in combination with antifungal agents&#46; Sharma et al&#46; &#40;2010&#41; evaluated the <span class="elsevierStyleItalic">in vitro</span> antifungal effects of curcumin alone as well as in combination with azoles and polyenes against isolates of <span class="elsevierStyleItalic">C&#46; albicans</span>&#46; In wild type <span class="elsevierStyleItalic">C&#46; albicans</span> curcumin showed a synergistic effect in combination with azoles &#40;fluconazole and ketoconazole&#41; and polyenes &#40;amphotericin and nystatin&#41;&#46; The MIC<span class="elsevierStyleInf">80</span> of curcumin in combination with fluconazole showed a 32-fold reduction&#44; in combination with ketoconazole showed a 64-fold reduction&#44; and a 16-fold reduction was observed when combined with amphotericin B or nystatin&#46; These results demonstrate an important synergetic effect of curcumin in combination with important antifungal agents used in the clinical practice&#46; In a study performed by Neelofar et al&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">30</span></a> curcumin promoted the growth inhibition of <span class="elsevierStyleItalic">C&#46; albicans</span> by using high concentrations of the compound when compared with the effective concentrations of fluconazole&#46; Here&#44; we observed that <span class="elsevierStyleItalic">C&#46; albicans</span> and the clinical strains showed sensitivity to curcumin&#44; with fungistatic activity being observed under the present experimental conditions&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The major sterol component present in the fungal membrane is ergosterol&#44; which plays qualitatively similar properties in fungal membranes as that cholesterol plays in mammalian cell membranes&#46; Ergosterol serves as a bioregulator of membrane fluidity and asymmetry&#59; consequently&#44; the integrity of the cell membrane is dependent on these sterols&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">5</span></a> One of the proposed mechanisms of actions for antifungal agents is binding to membrane ergosterol&#44; which leads to fungal cell disruption and a loss of intracellular content&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">32</span></a> In this work&#44; we observed that the binding to membrane ergosterol might be the mechanism of action of curcumin against fungi&#46; The cell membrane disruption in <span class="elsevierStyleItalic">Candida</span> by means of curcumin has been observed in other studies<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">24</span></a>&#59; this antifungal activity supports our results&#46; The authors demonstrated that the leakage of potassium ions from the fungal cytosol and a dissipation in the membrane potential was detected by bis-&#40;1&#44;3-dibutyl-barbituric acid&#41; trimethineoxonol &#91;DiBAC4&#40;3&#41;&#93; staining&#46; These authors also investigated an increase in membrane permeability in curcumin-treated <span class="elsevierStyleItalic">C&#46; albicans</span> with an in&#64258;ux of propidium iodide&#46; Fluorescence analysis with 1&#44;6-diphenyl-1&#44;3&#44;5-hexatriene supported the membrane-targeted mechanism of action indicating membrane disruption&#46; Using calcein leakage assays from curcumin-treated large unilamellar vesicles and giant unilamellar vesicles&#44; these authors found that curcumin has a membrane-active mechanism inducing the leakage of intracellular components through the &#64258;appy membrane&#46; However&#44; the effect on membrane ergosterol in our study was species-specific&#59; the curcumin was able to bind to ergosterol only in <span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231&#46; This fact shows that the binding of curcumin to ergosterol is not a single-action mechanism&#46; The action of curcumin on ergosterol and other fungal cell components should be determined in future studies&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The therapeutic effect of curcumin was examined in an experimental animal model of VVC&#46; It is known that <span class="elsevierStyleItalic">Candida</span> species cause opportunistic infections in hosts with altered physiological or immune responses&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">46</span></a> In general&#44; the development of mucosal infection models requires the use of systemic immunosuppression&#44; which is a valid method for quickly inducing fungal colonization&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">11</span></a> In rodent models&#44; as well as human infection&#44; these are stringently estrogen-dependent&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">33</span></a> In women&#44; VVC is extremely infrequent in the pre-pubertal period&#44; while women become susceptible in the postmenopausal period following hormone replacement therapy&#46; Estrogen exerts a multifunctional permissive role for vaginal candidiasis through a number of both host- and <span class="elsevierStyleItalic">Candida</span>-directed effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">7&#44;39</span></a> Since the local immunity is also critical for anti-<span class="elsevierStyleItalic">Candida</span> defense in the vaginal mucosa&#44; estrogen treatment is important because it transforms the epithelium to a pseudo-estrous phase and inhibits local immune defenses&#44; increasing the glycogen content and thereby facilitating mucosal infection&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">6</span></a> Thus&#44; rats must be placed under stable pseudo-estrus conditions to establish experimental vaginal infection&#59; this is usually achieved by estrogen treatment&#44; which is sufficient to allow <span class="elsevierStyleItalic">C&#46; albicans</span> infection to occur&#46; Using the same model&#44; several studies have shown the effectiveness of natural products against <span class="elsevierStyleItalic">C&#46; albicans</span> in the treatment of VVC&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">2&#44;13&#44;47</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">As previously reported&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">2</span></a> a <span class="elsevierStyleItalic">C&#46; albicans</span> suspension containing 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">7</span><span class="elsevierStyleHsp" style=""></span>CFU&#47;ml was sufficient to establish an infection when instilled into the vagina of immunosuppressed-hormone treated rats&#46; Other studies showed that immunosuppressed rats in a prolonged pseudo-estrus state are particularly susceptible to fungal colonization in the vaginal mucosa&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">2&#44;35</span></a> The animals were treated twice a day for seven days and the doses of curcumin were selected on the basis of MIC results and previous <span class="elsevierStyleItalic">in vitro</span> antifungal activity studies using this compound&#46; As shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#44; after the 3<span class="elsevierStyleSup">rd</span> day&#44; the treatment with curcumin at 0&#46;5&#37; was able to completely clear the fungal burden in all animals&#44; while at 0&#46;25&#37; and 1&#37; the fungal burden was reduced significantly &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; On the 7<span class="elsevierStyleSup">th</span> day&#44; the infection was completely cleared in the groups treated with 0&#46;25&#37; and 1&#37; curcumin&#46; On the last day of treatment&#44; the difference was not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; among the groups treated with curcumin and the one treated with miconazol&#44; but differences were statistically significant when comparing with the infected-not treated and vehicle control groups&#46; The inclusion of control groups was important to prove the test sensitivity and to ensure the curcumin effectiveness&#44; since five animals remained infected in the infected-untreated group and in the vehicle control group during the entire study period&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The histological study of the non-treated group showed signs of tissue reaction related to the infection&#44; since an intense concentration of inflammatory infiltrate was observed&#46; The groups treated with curcumin exhibited a reduction in inflammatory infiltrates&#44; being the degree of reduction proportional to higher concentrations&#46; Some studies have described the anti-inflammatory potential of curcumin and its ability to interact with numerous molecular targets involved in inflammation&#44; including the altered activity of enzymes&#44; such as cyclooxygenases and lipoxygenases&#44; by inhibiting the tumor necrosis factor &#40;TNF&#41; and the pro-inflammatory transcription nuclear factor kappa B &#40;NF-kB&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">14&#44;16</span></a> Debata et al&#46; &#40;2013&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">12</span></a> in a similar experiment with rats&#44; treated the animals intravaginally for three weeks with a cream containing curcumin and then analyzed the results by histological analysis&#46; The authors reported that the vaginal epithelium of the animals did not show any ulceration&#44; areas of necrosis or micro-abscesses&#44; and concluded that the intravaginal application of curcumin in a cream vehicle is feasible and safe&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In conclusion&#44; the <span class="elsevierStyleItalic">in vitro</span> results highlight the potential of curcumin as an effective antifungal against <span class="elsevierStyleItalic">Candida</span> species growth&#44; showing a similar mechanism of action to the commercial antifungal nystatin&#46; Its efficacy in a VVC rat model suggests that curcumin may be an important compound for the treatment of this fungal infection&#44; and that the development of a vaginal cream formulation containing this compound should be considered&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Ethical approval</span><p id="par0120" class="elsevierStylePara elsevierViewall">All procedures performed in the studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflict of interest&#46;</p></span></span>"
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          "titulo" => "Materials and methods"
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              "titulo" => "Candida strains&#44; animals and drug"
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            1 => array:2 [
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              "titulo" => "Growth conditions and inocula"
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            2 => array:2 [
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              "titulo" => "In vitro susceptibility test"
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              "titulo" => "Membrane ergosterol as target of antifungal activity"
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              "titulo" => "Experimental VVC"
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          "titulo" => "Results"
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              "titulo" => "Antifungal activity and mechanisms of action"
            ]
            1 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Treatment of VVC"
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          "titulo" => "Discussion"
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          "titulo" => "References"
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    "fechaRecibido" => "2018-02-06"
    "fechaAceptado" => "2019-01-22"
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            0 => "Antifungal activity"
            1 => "<span class="elsevierStyleItalic">Candida albicans</span>"
            2 => "Curcumin"
            3 => "Ergosterol"
            4 => "Vulvovaginal candidiasis"
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          "palabras" => array:5 [
            0 => "Actividad antif&#250;ngica"
            1 => "<span class="elsevierStyleItalic">Candida albicans</span>"
            2 => "Curcumina"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida albicans</span> is the main agent that causes vulvovaginal candidiasis&#46; Resistance among isolates to azole antifungal agents has been reported&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aims</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Due to the well-known antifungal potential of curcumin&#44; the purpose of this work was to evaluate the <span class="elsevierStyleItalic">in vitro</span> anticandidal activity of curcumin and its effect in the treatment of experimental vulvovaginal candidiasis&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The anticandidal activity of curcumin was investigated against eight <span class="elsevierStyleItalic">Candida</span> strains by the broth microdilution assay&#44; and its mechanism of action was evaluated by testing the binding to ergosterol&#46; Then&#44; the effect of curcumin in the treatment of vulvovaginal candidiasis was evaluated in an immunosuppressed&#44; estrogen treated rat model&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Curcumin showed minimum inhibitory concentration values of 125&#8211;1000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; and the best result was observed against <span class="elsevierStyleItalic">Candida glabrata</span>&#46; The compound was shown to be able to bind to the ergosterol present in the membrane&#44; event that may be the mechanism of action&#46; In addition&#44; in the <span class="elsevierStyleItalic">in vivo</span> model of vulvovaginal candidiasis with <span class="elsevierStyleItalic">C&#46; albicans</span>&#44; treatments reduced the vaginal fungal burden in infected rats after seven days of treatment with different doses&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Curcumin could be considered a promising effective antifungal agent in the treatment of vulvovaginal candidiasis&#46;</p></span>"
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            "titulo" => "Background"
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          1 => array:2 [
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            "titulo" => "Aims"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
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            "titulo" => "Results"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Candida albicans</span> es la principal causante de la candidiasis vulvovaginal y algunos aislamientos pueden presentar resistencia a los antif&#250;ngicos az&#243;licos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Debido al conocido potencial antif&#250;ngico de la curcumina&#44; el objetivo de este trabajo fue evaluar su actividad anti-<span class="elsevierStyleItalic">Candida</span><span class="elsevierStyleItalic">in vitro</span> y su efecto en el tratamiento de la candidiasis vulvovaginal experimental&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La actividad anti-<span class="elsevierStyleItalic">Candida</span> de la curcumina se evalu&#243; frente a ocho cepas de <span class="elsevierStyleItalic">Candida</span> mediante un ensayo de microdiluci&#243;n en caldo&#44; y su mecanismo de acci&#243;n se estudi&#243; por una prueba de uni&#243;n a ergosterol&#46; Posteriormente se evalu&#243; el efecto de la curcumina en el tratamiento de la candidiasis vulvovaginal con un modelo de rata inmunosuprimida&#44; tratada con estr&#243;genos&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La curcumina mostr&#243; valores de concentraci&#243;n inhibitoria m&#237;nima de 125-1&#46;000<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; y el mejor resultado se observ&#243; frente a <span class="elsevierStyleItalic">Candida glabrata</span>&#46; El compuesto demostr&#243; ser capaz de unirse al ergosterol de la membrana&#44; lo que podr&#237;a ser su mecanismo de acci&#243;n&#46; Adem&#225;s&#44; en el modelo <span class="elsevierStyleItalic">in vivo</span> de candidiasis vulvovaginal con <span class="elsevierStyleItalic">C&#46;&#160;albicans</span>&#44; los tratamientos redujeron la carga f&#250;ngica vaginal en ratas infectadas despu&#233;s de siete d&#237;as de tratamiento con diferentes dosis&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">La curcumina podr&#237;a considerarse un agente antif&#250;ngico eficaz prometedor en el tratamiento de la candidiasis vulvovaginal&#46;</p></span>"
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        "etiqueta" => "Fig&#46; 2"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Representative photomicrographs of histological analyses of vaginal mucosa sections after different treatments&#58; &#40;A&#41; non-infected animals &#40;negative control&#41; &#8211; vaginal mucosa with normal aspect&#59; &#40;B&#41; infected and untreated animals &#8211; presence of inflammatory infiltrate in the lamina propria&#59; &#40;C&#41; Infected animals treated with ethanol solution &#8211; presence of inflammatory infiltrate in the mucosa with polymorphonuclear infiltration mainly&#59; &#40;D&#41; infected animals treated with MCZ &#40;positive control&#41; &#8211; presence of inflammatory process with polymorphonuclear infiltration mainly&#59; &#40;E&#41; Infected animals treated with 0&#46;25&#37; curcumin &#8211; inflammatory infiltrate in the vaginal mucosa with polymorphonuclear infiltration mainly&#59; &#40;F&#41; infected animals treated with 0&#46;5&#37; curcumin &#8211; inflammatory infiltrate in the vaginal mucosa&#44; with polymorphonuclear infiltration mainly&#59; &#40;G&#41; infected animals treated with 1&#37; curcumin &#8211; reduction in mucosal inflammatory infiltrate compared to 0&#46;25&#37; and 0&#46;5&#37; curcumin treatments&#46; The black arrows point to polymorphonuclear leucocytes&#46; The red arrows point to mononuclear leucocytes&#46; H&#38;E stain&#44; 400&#215; magnification&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Quantitative analysis per group&#46; Data are expressed as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation of inflammatory cells&#47;mm<span class="elsevierStyleSup">2</span>&#46; &#42;Groups with significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; when compared with the infected control &#40;Tukey test with statistical difference at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; do not differ from each other&#46;</p>"
        ]
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                  <table border="0" frame="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">Candida</span> strains&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC curcumin<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MFC curcumin<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> ketoconazole<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> nystatin<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">62&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">3&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; glabrata</span> ATCC 2001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">125&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&#46;95&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; krusei</span> ATCC 34135&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">500&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; dubliniensis</span> clinical isolate 11763&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; dubliniensis</span> clinical isolate 1083&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; dubliniensis</span> clinical isolate 1203&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; dubliniensis</span> clinical isolate 1417&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">C&#46; dubliniensis</span> clinical isolate 1252&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#62;1000&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;97&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ND&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Positive control&#59; ND&#58; not determined&#46;</p>"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">In vitro</span> antifungal activity of curcumin&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">C&#46; albicans</span> ATCC 10231</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">C&#46; glabrata</span> ATCC 2001</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">C&#46; krusei</span> ATCC 34135</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC with ergosterol<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Curcumin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nystatin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">31&#46;25&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">31&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">7&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;25&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Caspofungin&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;0625&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0625&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Groups&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day 0</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Day 3</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Log<span class="elsevierStyleHsp" style=""></span>CFU&#47;ml<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Log<span class="elsevierStyleHsp" style=""></span>CFU&#47;ml<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Infected animals &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Log<span class="elsevierStyleHsp" style=""></span>CFU&#47;ml<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Infected control&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;6 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;6 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;04<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;04&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;6 &#40;83&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">3&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;07&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Positive control&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">6&#47;6 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;94<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;6 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;89<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;00<a class="elsevierStyleCrossRef" href="#tblfn0020">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Curcumin 0&#46;25&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;6 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#47;6 &#40;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;61<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;02<a class="elsevierStyleCrossRef" href="#tblfn0020">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#47;0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;00<a class="elsevierStyleCrossRef" href="#tblfn0020">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Curcumin 0&#46;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#47;6 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;48<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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Article information

ISSN: 11301406
Original language: English

DOI:10.1016/j.riam.2019.01.003

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