Original Article
Immunomodulatory effects of two silymarin isomers in a Balb/c mouse model of allergic asthma
Entezar Mehrabi Nasaba, Seyyede Masoume Atharib, Saadat Ghafarzadec, Abdol-Rahman Mehrabi Nasabd, Seyyed Shamsadin Atharie,
Corresponding author
a Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
b Department of Biology, Faculty of Basic Sciences, Maragheh University, Maragheh, Iran
c Department of Veterinary Medicine, Shabestar Branch, Islamic Azad University, Shabestar, Iran
d Department of Plant Protection, College of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran
e Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Read
6499
Timeswas read the article
923
Total PDF
5576
Total HTML
Share statistics
array:23 [ "pii" => "S030105462030029X" "issn" => "03010546" "doi" => "10.1016/j.aller.2020.01.003" "estado" => "S300" "fechaPublicacion" => "2020-11-01" "aid" => "1119" "copyright" => "SEICAP" "copyrightAnyo" => "2020" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2020;48:646-53" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:18 [ "pii" => "S0301054620300768" "issn" => "03010546" "doi" => "10.1016/j.aller.2020.03.012" "estado" => "S300" "fechaPublicacion" => "2020-11-01" "aid" => "1154" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2020;48:654-65" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Dust mite-derived <span class="elsevierStyleItalic">Enterobacterial fimbriae</span> H protein enforces the allergen specific immunotherapy in asthma mice" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "654" "paginaFinal" => "665" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 3579 "Ancho" => 2500 "Tamanyo" => 720011 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">FimH induces IL-10 from DCs and Tregs in vitro. BMDCs were treated with PBS, or different concentration FimH, or LPS for 4<span class="elsevierStyleHsp" style=""></span>h, and then qRT-PCR performed. (A) The results of qRT-PCR. After 24<span class="elsevierStyleHsp" style=""></span>h, the supernatants were collected to perform ELISA. (B) The results of ELISA. After 24<span class="elsevierStyleHsp" style=""></span>h, the cells stained with CD11c and IL-10 to perform flow cytometer. (C) The results of flow cytometer. BMDCs and spleen lymphocytes were co-cultured in the exist of Der f 1 and/or FimH for 5 days, then the cells were collected to stain with anti-CD4, anti-IL-10 and anti-IL-17 to perform flow cytometer. (D) The representative flow profiles. The data (mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SEMs) were generated form three independent experiments and processed by Graphpad software. The significant differences between two groups were tested by unpaired two-tailed <span class="elsevierStyleItalic">T</span>-test. *<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05; **<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01; ***<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; ns, no significant difference.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "X. Yang, H. Wang, D. Zhao, J. Wang, X. Liu, X. Yuan, M. Zhang, G. Li, P. Ran, P. Yang, Z. Liu" "autores" => array:11 [ 0 => array:2 [ "nombre" => "X." "apellidos" => "Yang" ] 1 => array:2 [ "nombre" => "H." "apellidos" => "Wang" ] 2 => array:2 [ "nombre" => "D." "apellidos" => "Zhao" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Wang" ] 4 => array:2 [ "nombre" => "X." "apellidos" => "Liu" ] 5 => array:2 [ "nombre" => "X." "apellidos" => "Yuan" ] 6 => array:2 [ "nombre" => "M." "apellidos" => "Zhang" ] 7 => array:2 [ "nombre" => "G." "apellidos" => "Li" ] 8 => array:2 [ "nombre" => "P." "apellidos" => "Ran" ] 9 => array:2 [ "nombre" => "P." "apellidos" => "Yang" ] 10 => array:2 [ "nombre" => "Z." "apellidos" => "Liu" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054620300768?idApp=UINPBA00004N" "url" => "/03010546/0000004800000006/v1_202011271043/S0301054620300768/v1_202011271043/en/main.assets" ] "itemAnterior" => array:18 [ "pii" => "S0301054620300860" "issn" => "03010546" "doi" => "10.1016/j.aller.2020.01.008" "estado" => "S300" "fechaPublicacion" => "2020-11-01" "aid" => "1161" "copyright" => "SEICAP" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Allergol Immunopathol (Madr). 2020;48:640-5" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Venom allergy and knowledge about anaphylaxis among beekeepers and their families" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "640" "paginaFinal" => "645" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Zeynep Hızlı Demirkale, E. Yücel, Sevgi Sipahi Çimen, A. Süleyman, C. Özdemir, A. Kara, Z. Tamay" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Zeynep" "apellidos" => "Hızlı Demirkale" ] 1 => array:2 [ "nombre" => "E." "apellidos" => "Yücel" ] 2 => array:2 [ "nombre" => "Sevgi" "apellidos" => "Sipahi Çimen" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Süleyman" ] 4 => array:2 [ "nombre" => "C." "apellidos" => "Özdemir" ] 5 => array:2 [ "nombre" => "A." "apellidos" => "Kara" ] 6 => array:2 [ "nombre" => "Z." "apellidos" => "Tamay" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054620300860?idApp=UINPBA00004N" "url" => "/03010546/0000004800000006/v1_202011271043/S0301054620300860/v1_202011271043/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Immunomodulatory effects of two silymarin isomers in a Balb/c mouse model of allergic asthma" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "646" "paginaFinal" => "653" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Entezar Mehrabi Nasab, Seyyede Masoume Athari, Saadat Ghafarzade, Abdol-Rahman Mehrabi Nasab, Seyyed Shamsadin Athari" "autores" => array:5 [ 0 => array:3 [ "nombre" => "Entezar Mehrabi" "apellidos" => "Nasab" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Seyyede Masoume" "apellidos" => "Athari" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Saadat" "apellidos" => "Ghafarzade" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Abdol-Rahman Mehrabi" "apellidos" => "Nasab" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:4 [ "nombre" => "Seyyed Shamsadin" "apellidos" => "Athari" "email" => array:1 [ 0 => "SS.Athari@zums.ac.ir" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Biology, Faculty of Basic Sciences, Maragheh University, Maragheh, Iran" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Veterinary Medicine, Shabestar Branch, Islamic Azad University, Shabestar, Iran" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Plant Protection, College of Agriculture, Ferdowsi University of Mashhad, Mashhad, Iran" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 704 "Ancho" => 2436 "Tamanyo" => 116450 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The structures of the studied silymarin isomers. Isosilybin A (A) and silydianin (B).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Allergic asthma is a multifactorial and complex chronic disease of the respiratory system. Asthma development is influenced by genetic, epigenetic and environmental factors. The main symptoms of asthma, which is characterized by airways hyper-responsiveness (AHR) and obstruction, include cough, dyspnea and wheezing. More than 300 million people of all ages suffer from asthma worldwide.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Immunological and inflammatory processes are the main contributors to asthma attacks. In this regard, immunological and inflammatory mediators can be important targets for controlling asthma symptoms. Cytokines produced by T helper 2 lymphocytes such as IL-4, IL-5 and IL-13 play main roles in the development and progression of asthma. IL-4 induces the overproduction of immunoglobulin E (IgE), IL-5 activates eosinophils and directs them toward airways, and IL-13 increases mucus production in bronchia. AHR and airway smooth muscle spasm are finally developed in response to allergens.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2–4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">B lymphocytes from patients with allergic asthma have a tendency to overproduce IgE (total and allergen-specific). Eosinophilic infiltration and enhanced expression of type 2 cytokines in lungs also contribute to allergic asthma pathophysiology.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5–8</span></a> Allergic reactions are triggered by binding and cross-linking of allergen bound IgE antibodies to their receptors on mast cells (sensitization) inducing the release of chemical mediators from these cells. The level of sensitization and severity of inflammation in airways (especially eosinophilic infiltration) correlate with the severity of asthma.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–10</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Silymarin is a main component of <span class="elsevierStyleItalic">Silybium marinum</span> (milk thistle). The main constituents of silymarin include flavonolignans, silybin A, silybin B, isosilybin A, isosilybin B, silydianin, silychristin, isosilychristin, 2,3-dehydrosilybin and taxifolin.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11–13</span></a> Silymarin, as an antioxidant therapeutic agent with membrane-stabilizing effects, is used for treating liver inflammation and hepatic disorders. It also has protective effects against inflammatory stress in which leukotrienes are involved. The anti-inflammatory effects of silymarin have been attributed to its inhibiting effects on leukotrienes and prostaglandin production.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,13,14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Airway inflammation is an important event in the development of asthma. In allergic asthma, anti-asthmatic drugs are designed to stabilize mast cell membranes. The roles of leukotrienes and prostaglandins (bronchoconstriction and bronchial hyper-reactivity) have been demonstrated in both intrinsic and extrinsic allergic asthma.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15–17</span></a> Regarding the anti-inflammatory effects of silymarin and its components, these can be used to alleviate airway inflammation in allergic asthma. In the present study, we compared the anti-inflammatory and anti-allergic effects of two pure isomers of silymarin (isosilybin A and silydianin) in a Balb/c mouse model of allergic asthma.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Preparation of isomers</span><p id="par0030" class="elsevierStylePara elsevierViewall">Silymarin and its constituents were extracted and purified from <span class="elsevierStyleItalic">S. marianum</span> using column chromatography (standard silica gel, 230–400 mesh, Merck, Germany) and HPLC preparative high-speed counter-current chromatography (HSCCC) as previously described.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–21</span></a> The mass spectra were analyzed by the Data Analysis software version 3.4 (Bruker Daltonics, Billerica, USA). HPLC analyses were carried out using a Shimadzu Prominence LC analytical system (Shimadzu, Kyoto, Japan).<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20,21</span></a> NMR (Bruker 400 MHz) and MS analyses were performed as described previously.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22,23</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Animal model of allergic asthma</span><p id="par0035" class="elsevierStylePara elsevierViewall">Female Balb/c mice (6–8 weeks old) were purchased from the Pasteur Institute of Iran (Karaj, Iran). The animals were acclimatized under standard laboratory conditions for one week (12 h light-dark cycle, 24 ± 2 °C temperature, 55 ± 5% humidity, and pathogen-allergen free condition). The experiments were carried out observing all ethical considerations in working with laboratory animals.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Treatment schedule</span><p id="par0040" class="elsevierStylePara elsevierViewall">Seventy mice were divided into five (4 asthmatic and 1 healthy) groups (n = 14 per group, seven for histopathological analysis and seven for bronchoalveolar lavage (BAL) sampling). In the four asthmatic groups, airway inflammation was induced using ovalbumin (OVA, Sigma-Aldrich, Netherlands) as previously mentioned (Athari et al., 2016).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Briefly, the mice were sensitized by intraperitoneal injection of combination of chicken OVA (20 μg) and aluminum hydroxide (50 μl) (Sigma-Aldrich, Netherlands) on days 1 and 14.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The mice were challenged by inhalation of 1% OVA solution aerosolized by an ultrasonic nebulizer (NE-U07, Omrom, Japan) for 30 min per day on days 24, 26, 28, and 30. The sensitization and challenge experiments were performed in three and one of the four asthmatic groups. The mice in the recent four groups were also treated with pure 1% isosilybin A, 1% silydianin and budesonide solutions (aerosolized by ultrasonic nebulizer for 30 min) on days 25, 27, and 29. Budesonide, as an anti-asthma drug, was used as positive control. The mice that were both sensitized and challenged served as positive control. The mice sensitized and challenged with PBS served as negative controls. At 48 h after the last challenge on day 30, blood, BAL and lung tissue samples were collected for further analyses.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Measurement of AHR</span><p id="par0050" class="elsevierStylePara elsevierViewall">Two days after the last challenge, Methacholine challenge test was performed to assess AHR and determine enhanced pause (the Penh value). All the mice were initially exposed to PBS aerosol to obtain the baseline Penh value. Then the mice were exposed to doubling concentrations of aerosolized methacholine (Mch), (0.5, 1, 2, 4, and 8 mg/mL). Finally, the relative Penh values were determined as percentages (Athari et al., 2016).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> To determine AHR, a catheter was inserted into the trachea and then connected to a mechanical ventilator after mice were anesthetized and tracheotomized (Inspira ASV; Harvard Apparatus).</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">BAL fluid collection</span><p id="par0055" class="elsevierStylePara elsevierViewall">The BAL fluid was collected after washing lungs via the trachea using 1 mL PBS. The cells of the BAL fluid were collected on cytospin slides and stained with Wright’s stain solution. Differential cell counting was then performed. The BAL supernatant was stored at −70 °C for cytokine analysis.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cytokine levels in BAL fluid</span><p id="par0060" class="elsevierStylePara elsevierViewall">IL-4, IL-5 and IL-13 levels were measured in the BAL fluid using specific ELISA kits (Abcam, USA).</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Quantitative real time PCR</span><p id="par0065" class="elsevierStylePara elsevierViewall">Total RNA of cells in the BAL fluid was isolated using TRIzol (Invitrogen life technologies, NY, USA) according to the manufacturer’s instructions. RNA samples were reverse transcribed to cDNA using a cDNA synthesis kit (Maxima First Strand cDNA Synthesis Kit, Thermo Scientific, Rockford, IL, USA). The recent kit included dsDNase enzyme, which specifically removed contaminating genomic DNA from the samples. Quantitative PCR was performed using a Rotor-Gene SYBR Green PCR Kit and Rotor-Gene Q thermal cycler (Qiagen, Hilden, Germany). The Rotor-Gene SYBR Green PCR Kit was already enhanced to work with Qiagen cyclers (for minimum optimization procedure). Primers for the target (IL-4, IL-5, IL-13, and MUC5ac) and internal control (GAPDH) genes were adapted from Athari et al., 2016.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Serum IgE level</span><p id="par0070" class="elsevierStylePara elsevierViewall">Two days after the last challenge, blood samples were obtained, and sera were separated and stored. Total IgE (BD Biosciences, USA) and OVA-specific IgE (Cusabio Biotech, USA) levels were measured using appropriate ELISA kits.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Histological study</span><p id="par0075" class="elsevierStylePara elsevierViewall">Lung tissue samples were isolated and fixed in buffered formalin and then trimmed and embedded in paraffin. Tissue sections were stained with H&E solution and periodic acid Schiff (PAS). The ratio of mucus production was scored as the intensity of staining in 10 randomly selected microscopy fields at 400× magnification. The goblet cells were enumerated in several randomly selected microscopy fields, and the result was expressed as the goblet cell index (GCI). Eosinophils were counted in histological lung sections at 1000x magnification. The number of eosinophils was reported as the mean of five repetitions as described by Athari et al. (2016).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">The results were expressed as means ± S.E.M. One-way ANOVA followed by Newman-Keuls and two-tailed independent student’s <span class="elsevierStyleItalic">t</span>-test were used for comparing variables between groups. The statistical significance threshold was considered as P < 0.05. The analyses were performed in GraphPad Prism version 5.0.</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Effects of silymarin isomers on AHR</span><p id="par0085" class="elsevierStylePara elsevierViewall">AHR was significantly higher in the positive (OVA sensitized and challenged) (8.8 ± 0.15) compared with negative (PBS challenged) (2.3 ± 0.08) group (P < 0.05). The two silymarin isomers also reduced AHR (isosilybin A: 4.2 ± 0.15, silydianin: 3.2 ± 0.09) with respect to controls. Budesonide, the commercial anti-asthmatic drug, completely prevented the development of AHR (2.6 ± 0.10) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Effects of silymarin isomers on blood and BAL eosinophil counts</span><p id="par0090" class="elsevierStylePara elsevierViewall">The percentages of eosinophils were higher in blood (4.75 ± 0.11%) and BAL fluid (68.0 ± 4.0%) in positive controls compared with negative control group (0.70 ± 0.09% and 6.0 ± 7.0%, respectively, P < 0.05). Treatment with isosilybin A (1.0 ± 0.08%, P < 0.05), silydianin (1.1 ± 0.11%, P < 0.05) and budesonide (1.2 ± 0.2%, P < 0.05) significantly reduced blood eosinophils. Furthermore, the BAL fluid eosinophil count reduced after treatment with isosilybin A (19.0 ± 5.0%, P < 0.05), silydianin (18.0 ± 0.1%, P < 0.05) and budesonide (23.0 ± 4.0%, P < 0.05) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Effects of silymarin isomers on cytokine levels in BAL fluid</span><p id="par0095" class="elsevierStylePara elsevierViewall">The levels of IL-4 (87 ± 7 vs. 53 ± 6 pg/mL, P < 0.05), IL-5 (79 ± 8 versus 38 ± 9 pg/mL, P < 0.05) and IL-13 (132 ± 11 vs. 66 ± 8 pg/mL, P < 0.05) were significantly higher in the positive than the negative control group (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). Treatment with isosilybin A and silydianin did not affect OVA-induced IL-13 production (128 ± 10 and 134 ± 21 pg/mL, respectively). On the other hand, isosilybin A, silydianin and budesonide significantly attenuated IL-4 (59 ± 5, 62 ± 2, and 61 ± 7 pg/mL respectively) and IL-5 (46 ± 7, 39 ± 2, and 49 ± 11 pg/mL respectively) levels (P < 0.05).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Effects of silymarin isomers on gene expressions of cytokines and mucin</span><p id="par0100" class="elsevierStylePara elsevierViewall">The mRNA levels of IL-4 (8.11 ± 1.37 vs. 1.00 ± 0.12), IL-5 (3.12 ± 0.22 vs. 1.00 ± 0.10), IL-13 (2.11 ± 0.13 vs. 1.00 ± 0.12) and MUC5AC (12.11 ± 1.09 vs. 1.00 ± 0.19) were significantly higher in the positive compared with the negative control group (P < 0.05, <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). In mice treated with isosilybin A, silydianin and budesonide, there were significant reductions in mRNA expressions of IL-4 (1.91 ± 0.24, 1.74 ± 0.11, and 1.90 ± 0.32, respectively) and IL-5 (1.61 ± 0.24, 1.72 ± 0.14, and 1.60 ± 0.18, respectively) compared with the positive control group (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) (P < 0.05 for all comparisons). However, in mice treated with either isosilybin A or silydianin, there were no significant differences in mRNA expressions of IL-13 (2.01 ± 0.21 vs. 2.08 ± 0.03, respectively) and MUC5AC (11.33 ± 1.11 vs. 12.12 ± 0.10, respectively) compared with the positive control group (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>) (P < 0.05 for all comparisons).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Effects of silymarin isomers on serum IgE levels</span><p id="par0105" class="elsevierStylePara elsevierViewall">The levels of total and OVA-specific IgE were significantly higher in the positive (2210 ± 57 and 246 ± 9 ng/mL, respectively) compared with the negative (48 ± 5 and 0 ± 0 ng/mL, respectively) control groups (P < 0.05). Treatment with isosilybin A (total IgE: 298 ± 11, OVA-specific IgE: 30 ± 17 ng/mL, P < 0.05), silydianin (total IgE: 280 ± 29, OVA-specific IgE: 38 ± 4 ng/mL, P < 0.05) and budesonide (total IgE: 256 ± 54, OVA-specific IgE: 35 ± 3 ng/mL, P < 0.05) reduced IgE levels in OVA sensitized and challenged groups (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Effects of silymarin isomers on lung histology</span><p id="par0110" class="elsevierStylePara elsevierViewall">In the positive control group, mucus hyper-secretion (3.7 ± 0.2-fold) and goblet cell hyperplasia (score: 3.3) were significantly higher compared with negative control group (P < 0.05, <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>). Mucus hyper-secretion was not significantly different between mice treated with either isosilybin A (3.7 ± 0.0-fold) or silydianin (3.6 ± 0.6-fold) in comparison with the positive control group (P > 0.05). The scores of eosinophilic infiltrations significantly decreased in mice treated with isosilybin A (perivascular: 0.7 ± 0.2, peribronchial: 0.8 ± 0.2) and silydianin (perivascular: 0.6 ± 0.4, peribronchial: 0.7 ± 0.01) compared with animals that received budesonide (perivascular: 1.8 ± 0.2, peribronchial: 1 ± 0.4). Moreover, the budesonide, silymarin and silymarin treated groups showed a lower number of eosinophils (<a class="elsevierStyleCrossRef" href="#fig0030">Fig. 6</a>) compared to positive control group (3.2 ± 0.1).</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">In this study, the therapeutic effects of two purified silymarin isomers, isosilybin A and silydianin (<a class="elsevierStyleCrossRef" href="#fig0035">Fig. 7</a>), were investigated in a Balb/c mouse model of allergic asthma. The isosilybins A and silydianin were isolated using the powerful technique of HSCCC.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> These two isomers have shown anti-inflammatory, anti-spasmodic, and immunomodulatory effects delivering them as beneficial therapeutic agents to control the allergic mechanisms and immunological pathways that contribute to allergic asthma. Nevertheless, silymarin isomers are unable to control mucus production, which limits their therapeutic application.</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In the present study, we demonstrated that isosilybin A and silydianin reduced AHR in a way that was comparable with budesonide (commercial anti-asthmatic drug). It has been shown that silymarin has a protective effect against bronchospasm in allergic asthma.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> This effect can be mediated through membrane-stabilizing and the anti-inflammatory activities of silymarin, as well as its inhibitory effects on arachidonic acid pathway.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Furthermore, silymarin can inhibit acute phase response through suppressing inflammatory factors. Based on these, it has been suggested that silymarin can be used as a protective agent to manage asthma attacks and histaminic disorders.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Isosilybin A and silydianin isomers also reduced the number of eosinophils in BAL fluid which can inhibit eosinophilic attacks in asthma. Eosinophils are important in asthma pathogenesis and can be key targets for treatment of the disease.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In this regard, silymarin and its isomers (isosilybin A and silydianin) may be useful to manage complications of asthma triggered by eosinophils.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Cytokines, in particular Th2-derived cytokines, have significant roles in allergic responses, airways eosinophilia, and AHR in allergic asthma. IL-4 promotes IgE production and Th2 lymphocytes differentiation,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> and IL-5 orchestrates the proliferation, activation, migration, and infiltration of eosinophils into airways.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26,27</span></a> IL-13, on the other hand, induces mucus hyper-secretion and airway obstruction in allergic asthma.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28,29</span></a> In this study, we showed that isomers of silymarin, isosilybin A and silydianin, had regulatory effects on the balance of Th2 cytokines in mouse model of allergic asthma. Mice treated with isosilybin A and silydianin had reduced levels of IL-4 and IL-5; however, IL-13 level was not affected in the OVA-challenged groups. Reduced IL-4 level by these isomers can mitigate allergic reactions.</p><p id="par0135" class="elsevierStylePara elsevierViewall">IgE is one of the important mediators of allergic reactions in asthma. In this study, we observed that silymarin isomers decreased serum levels of total and OVA-specific IgE. Low levels of IgE promoted by reduction in IL-4 can inhibit allergic processes in asthmatic animals.</p><p id="par0140" class="elsevierStylePara elsevierViewall">As mentioned, isosilybin A and silydianin attenuated IgE production, eosinophilic inflammation, and AHR in the mouse model of allergic asthma. Despite that, these isomers had no effects on mucus hypersecretion. Assessments on the BAL fluid revealed that although isosilybin A and silydianin reduced IL-4 and IL-5 mRNA expressions, they had no effects on IL-13 and MUC5AC gene expressions. The gene regulatory effects of isosilybin A and silydianin can be mediated by modulating cell signaling pathways and transcription factors. In a study by Deep et al. in 2010, they reported that isosilybin A inhibited Akt phosphorylation and cellular proliferation. Furthermore, isosilybin A treatment modulated the level of NF-κB in the nucleus influencing cellular proliferation and activation.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">In our study, isosilybin A and silydianin isomers of silymarin effectively inhibited perivascular and peribronchial eosinophilic infiltrations in the lungs of mouse models of allergic asthma. These isomers also prevented goblet cell hyperplasia and AHR. Nevertheless, no significant effects were observed on mucus hyper-secretion. Jang et al. in 2012 showed that administration of skullcapflavone II, a flavonoid derived from <span class="elsevierStyleItalic">Scutellaria baicalensis</span>, reduced eosinophilic infiltration and inflammation, as well as AHR, but not mucus production.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In this study, the two studied isomers reduced the Penh value which is an important indicator for predicting acute asthma attacks. The balance of Th1/Th2 immune response is another key point in the management of atopic diseases.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31,32</span></a> We observed that isosilybin A and silydianin modulated the levels of IL-4 and IL-5 as Th2 cytokines.</p><p id="par0150" class="elsevierStylePara elsevierViewall">The main asthma symptoms (i.e. inflammation, AHR, airflow obstruction, and mucus hyper-secretion)<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33,34</span></a> sustained in the current study; however, remodeling was not studied. Considering all of these parameters, the effects of the two studied isomers (isosilybin A and silydianin) were similar with no significant differences were observed between them.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusion</span><p id="par0155" class="elsevierStylePara elsevierViewall">According to our study, isosilybin A and silydianin can control the main symptoms of asthma through modulating immune system responses, reducing eosinophilic inflammation as well as perivascular and peribronchial eosinophilic infiltrations, modulating IL-4 and IL-5 gene expressions, and reducing goblet cell hyperplasia, bronchospasm and AHR in animal models of allergic asthma. Nevertheless, no significant effects were observed on IL-13 production and mucus hyper-secretion. Considering their long-lasting effects and excellent safety profile, these natural isomers can be used as anti-inflammatory and anti-asthma drugs; however, they may be more efficient in combination with anti-mucus agents to prevent asthma attacks.</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflicts of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">There are no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1422139" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1300247" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1300246" "titulo" => "Abbreviations" ] 3 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 4 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Preparation of isomers" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Animal model of allergic asthma" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment schedule" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Measurement of AHR" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "BAL fluid collection" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Cytokine levels in BAL fluid" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Quantitative real time PCR" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Serum IgE level" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Histological study" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Statistical analysis" ] ] ] 5 => array:3 [ "identificador" => "sec0065" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Effects of silymarin isomers on AHR" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Effects of silymarin isomers on blood and BAL eosinophil counts" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Effects of silymarin isomers on cytokine levels in BAL fluid" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Effects of silymarin isomers on gene expressions of cytokines and mucin" ] 4 => array:2 [ "identificador" => "sec0090" "titulo" => "Effects of silymarin isomers on serum IgE levels" ] 5 => array:2 [ "identificador" => "sec0095" "titulo" => "Effects of silymarin isomers on lung histology" ] ] ] 6 => array:2 [ "identificador" => "sec0100" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0105" "titulo" => "Conclusion" ] 8 => array:2 [ "identificador" => "sec0110" "titulo" => "Conflicts of interest" ] 9 => array:2 [ "identificador" => "xack496385" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-09-29" "fechaAceptado" => "2020-01-02" "PalabrasClave" => array:1 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1300247" "palabras" => array:5 [ 0 => "Asthma" 1 => "Allergy" 2 => "Inflammation" 3 => "Isosilybin A" 4 => "Silydianin" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1300246" "palabras" => array:14 [ 0 => "AHR" 1 => "BAL" 2 => "Elisa" 3 => "Eos" 4 => "GAPDH" 5 => "HPLC" 6 => "HSCCC" 7 => "IgE" 8 => "IL" 9 => "Mch" 10 => "OVA" 11 => "PAS" 12 => "PBS" 13 => "Th" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and Objectives</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Allergic asthma is a complex chronic disease of the respiratory system presenting with cough, dyspnea, wheezing and airway obstruction. More than 300 million people of all age spectrums suffer from asthma worldwide. Immunological and inflammatory processes are main contributors to asthma. Cytokines produced by T helper 2 lymphocytes play main roles in asthma development and progression. Silymarin, a therapeutic agent with anti-oxidative properties, is a main component of <span class="elsevierStyleItalic">Silybium marinum</span>. We herein aimed to compare the anti-inflammatory and anti-allergic effects of two silymarin isomers, isosilybin A and silydianin, in the treatment of allergic asthma.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and Methods</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">After isolating and purifying isosilybin A and silydianin, Balb/c mouse model of allergic asthma was produced using ovalbumin injection. Seventy mice were categorized into five (1 normal and 4 asthmatic) groups (n = 14 per group). Mice in three of four asthmatic groups were treated with either isosilybin A, silydianin or budesonide. The 4th asthmatic group was used as positive control, with the non-asthmatic group serving as negative control. Airway hyperresponsiveness (AHR) and levels of IL-4, IL-5 and IL-13 in the BAL fluid were determined. Gene expressions of IL-4, IL-5, IL-13 and MUC5ac, as well as IgE serum level were also measured. Cellular composition of BAL fluid and lungs histopathology were finally investigated.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Isosilybin A and silydianin reduced eosinophilic infiltration of lungs, IL-4 and IL-5 levels in BAL fluid, IL-4 and IL-5 gene expressions, as well as AHR in Balb/c mouse model of asthma. However, no significant changes were observed in IL-13 level and mucus hyper-secretion.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">According to our study, isosilybin A and silydianin can control main symptoms of asthma by modulating immune responses.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and Objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] ] "multimedia" => array:7 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 862 "Ancho" => 1583 "Tamanyo" => 95747 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The effects of silymarin isomers on airway hyperresponsiveness measured as the Penh value in response to increasing doses of Mch. The Penh values were higher in the positive compared with the negative control group in all concentrations of Mch. The effects of the silymarin isomers and budesonide on airway hyperresponsiveness have been shown in sensitized and challenged mice. The results have been presented as means ± S.E.M. Statistical significance level was considered as P < 0.05.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1071 "Ancho" => 2500 "Tamanyo" => 157915 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The effects of silymarin isomers on eosinophil counts in blood (A) and BAL fluid (B) of ovalbumin-treated mice. The results have been shown as means ± S.D.</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2380 "Ancho" => 2917 "Tamanyo" => 339604 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The effects of silymarin isomers on the levels of IL-4 (A), IL-5 (B) and IL-13 (C) in BAL fluid. Silymarin isomers and budesonide reduced IL-4 and IL-5 levels. The level of IL-13; however, reduced only in the budesonide group.</p>" ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1732 "Ancho" => 2500 "Tamanyo" => 289122 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The effects of silymarin isomers on the mRNA expressions of IL-4 (A), IL-5 (B), IL-13 (C) and MUC5AC (D) in BAL cells using quantitative RT-PCR. The results were expressed as means ± S.E.M (n = 7). Sensitized and challenged mice treated with the isomers and budesonide had decreased levels of IL-4 and IL-5 mRNAs. The expressions of IL-13 and mucin reduced only in the budesonide group.</p>" ] ] 4 => array:8 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1257 "Ancho" => 2917 "Tamanyo" => 155290 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0025" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">The effects of silymarin isomers on the total and OVA-specific IgE levels. Sensitized and challenged mice treated with the isomers and budesonide showed decreased levels of total and OVA-specific IgE.</p>" ] ] 5 => array:8 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1004 "Ancho" => 2000 "Tamanyo" => 507714 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0030" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Histopathology of lung sections in animal models of allergic asthma. Tissues were stained with Hematoxylin & Eosin, and peribronchial inflammation, goblet cell hyperplasia (within the airway epithelium) and mucus hyper-secretion were also assessed. PAS staining was used to assess mucus production and Goblet cells. Mucus secretion and peribronchial inflammation have been indicated with black and red arrows, respectively.</p>" ] ] 6 => array:8 [ "identificador" => "fig0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 704 "Ancho" => 2436 "Tamanyo" => 116450 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0035" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The structures of the studied silymarin isomers. Isosilybin A (A) and silydianin (B).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The importance of eosinophil, platelet and dendritic cell in asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Seyyed Shamsadin Athari" 1 => "Seyyed Moehyadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Asian Pac J Trop Dis" "fecha" => "2014" "volumen" => "4" "numero" => "1" "paginaInicial" => "41" "paginaFinal" => "47" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Traditional medicine for asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Adv Biores" "fecha" => "2013" "volumen" => "7" "numero" => "3" "paginaInicial" => "112" "paginaFinal" => "113" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inflammation, asthma and tumor" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bull Env Pharmacol Life Sci" "fecha" => "2013" "volumen" => "2" "numero" => "5" "paginaInicial" => "98" "paginaFinal" => "100" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "General overview of fungal allergic asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Ali Akbar Pourfathollah" 1 => "Fateme Beyzayi" 2 => "Ali Khodadadi" 3 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Myco Res" "fecha" => "2014" "volumen" => "1" "numero" => "1" "paginaInicial" => "35" "paginaFinal" => "41" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Deeper attention to allergic asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Adv Biores" "fecha" => "2014" "volumen" => "5" "numero" => "1" "paginaInicial" => "01" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Survey the effect of herbal medicine on pathogenesis of eosinophilic chemotactic factors in experimental allergic asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Akefe Ahmadi Afshar" 1 => "Sadat Ghafarzade" 2 => "Bahram Yavari" 3 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Adv Biores" "fecha" => "2014" "volumen" => "5" "numero" => "1" "paginaInicial" => "160" "paginaFinal" => "164" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Overview of relationship of allergic asthma with diet and food intake" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Garcia" 1 => "S.S. Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Food Qua Haza Cont" "fecha" => "2015" "volumen" => "2" "paginaInicial" => "1" "paginaFinal" => "5" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "VIP-loaded PLGA as an anti-asthma nanodrug candidate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Seyyed Shamsadin Athari" 1 => "Esmaeil Mortaz" 2 => "Zahra Pourpak" 3 => "Mostafa Moin" 4 => "Seyed Mohammad Moazzeni" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Comp Clin Pathol" "fecha" => "2016" "volumen" => "25" "numero" => "4" "paginaInicial" => "791" "paginaFinal" => "796" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Benefit non-enzymatic antioxidant effects on allergic asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Nader Chaparzadeh" 1 => "Bahram Yavari" 2 => "Seyyed Shamsadin Athari" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Adv Biores" "fecha" => "2016" "volumen" => "7" "numero" => "4" "paginaInicial" => "01" "paginaFinal" => "11" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Conjugated alpha-alumina nanoparticle with vasoactive intestinal peptide as a nano-drug in treatment of allergic asthma in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Seyyed Shamsadin Athari" 1 => "Zahra Pourpak" 2 => "Gert Folkerts" 3 => "Johan Garssen" 4 => "Mostafa Moin" 5 => "Ian M. Adcock" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejphar.2016.10.014" "Revista" => array:6 [ "tituloSerie" => "Eur J Pharmacol" "fecha" => "2016" "volumen" => "791" "paginaInicial" => "811" "paginaFinal" => "820" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27771365" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Complete isolation and characterization of silybins and isosilybins from milk thistle (Silybum marianum)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N.C. Kim" 1 => "T.N. Graf" 2 => "C.M. Sparacino" 3 => "M.C. Wani" 4 => "M.E. Wall" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1039/b300099k" "Revista" => array:7 [ "tituloSerie" => "Org Biomol Chem" "fecha" => "2003" "volumen" => "1" "numero" => "10" "paginaInicial" => "1684" "paginaFinal" => "1689" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12926355" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "P.R. Davis-Searles" 1 => "Y. Nakanishi" 2 => "N.C. Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/0008-5472.CAN-04-4662" "Revista" => array:7 [ "tituloSerie" => "Cancer Res" "fecha" => "2005" "volumen" => "65" "numero" => "10" "paginaInicial" => "4448" "paginaFinal" => "4457" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15899838" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.J. Kroll" 1 => "H.S. Shaw" 2 => "N.H. Oberlies" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1177/1534735407301825" "Revista" => array:7 [ "tituloSerie" => "Integr Cancer Ther" "fecha" => "2007" "volumen" => "6" "numero" => "2" "paginaInicial" => "110" "paginaFinal" => "119" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17548790" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Protective effect of silymarin in antigen challenge- and histamine-induced bronchoconstriction in in vivo guinea-pigs" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M. Cristina Breschi" 1 => "Enrica Martinotti" 2 => "Filippo Apostoliti" 3 => "Paola Nieri" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/s0014-2999(02)01265-7" "Revista" => array:6 [ "tituloSerie" => "Eur J Pharmacol" "fecha" => "2002" "volumen" => "437" "paginaInicial" => "91" "paginaFinal" => "95" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11864645" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gastric antiulcer activity of silymarin, a lipoxygenase inhibitor, in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. Alarcon De La Lastra" 1 => "M.J. Martin" 2 => "E. Marhuenda" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.2042-7158.1992.tb03239.x" "Revista" => array:7 [ "tituloSerie" => "J Pharm Pharmacol" "fecha" => "1992" "volumen" => "44" "paginaInicial" => "929" "paginaFinal" => "931" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1361540" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0190962215019982" "estado" => "S300" "issn" => "01909622" ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "C. Dehmlow" 1 => "N. Murawsky" 2 => "H. de Grooth" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/0024-3205(96)00134-8" "Revista" => array:6 [ "tituloSerie" => "Life Sci" "fecha" => "1996" "volumen" => "58" "paginaInicial" => "1591" "paginaFinal" => "1600" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8649189" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of silymarin on different acute inflammation models and on leukocyte migration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R. De la Puerta" 1 => "E. Martinez" 2 => "L. Bravo" 3 => "M.C. Ahumada" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pharm Pharmacol" "fecha" => "1996" "volumen" => "48" "numero" => "968–" "paginaInicial" => "970" "itemHostRev" => array:3 [ "pii" => "S0190962210003270" "estado" => "S300" "issn" => "01909622" ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Isolation and purification of silychristin, silydianin and taxifolin in the co-products of the silybin refined process from the silymarin by high-speed counter-current chromatography" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Liu" 1 => "Q. Yuan" 2 => "C.F. Li" 3 => "T.X. Huang" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Process Biochem" "fecha" => "2010" "volumen" => "45" "paginaInicial" => "799" "paginaFinal" => "804" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gram-scale purification of flavonolignan diastereoisomers from Silybum marianum (milk thistle) extract in support of preclinical in vivo studies for prostate cancer chemoprevention" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.N. Graf" 1 => "M.C. Wani" 2 => "R. Agarwal" 3 => "D.J. Kroll" 4 => "N.H. Oberlies" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2007-990239" "Revista" => array:6 [ "tituloSerie" => "Planta Med" "fecha" => "2007" "volumen" => "73" "paginaInicial" => "1495" "paginaFinal" => "1501" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17948171" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chemoenzymatic preparative separation of silybins A and B" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "V. Kˇren" 1 => "R. Gaˇzak" 2 => "K. Purchartova" 3 => "P. Marhol" 4 => "D. Biedermann" 5 => "P. Sedmera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Mol Catal B: Enzym" "fecha" => "2009" "volumen" => "61" "paginaInicial" => "247" "paginaFinal" => "251" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Preparative separation of fruit extract of Silybum marianum using a high-speed counter current chromatograph with scale-up columns" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Q.Z. Du" 1 => "W.J. Cai" 2 => "Y. Ito" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Liq Chromatogr Rel Technol" "fecha" => "2002" "volumen" => "25" "paginaInicial" => "2515" "paginaFinal" => "2520" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Large-scale separation of silybin diastereoisomers using lipases" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Radek Gaˇzak" 1 => "Petr Marhol" 2 => "Kateˇrina Purchartova" 3 => "Daniela Monti" 4 => "David Biedermann" 5 => "Sergio Riva" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Proce Biochem" "fecha" => "2010" "volumen" => "45" "paginaInicial" => "1657" "paginaFinal" => "1663" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Separation and characterization of silybin, isosilybin, silydianin and silychristin in milk thistle extract by liquid chromatography–electrospray tandem mass spectrometry" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "James I. Lee" 1 => "Bih H. Hsu" 2 => "Di Wu" 3 => "Jeffrey S. Barrett" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Chromato A" "fecha" => "2006" "volumen" => "1116" "paginaInicial" => "57" "paginaFinal" => "68" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-κB and androgen receptor signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Gagan Deep" 1 => "Subhash Chander Gangar" 2 => "Nicholas H. Oberlies" 3 => "David J. Kroll" 4 => "Rajesh Agarwal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/mc.20670" "Revista" => array:7 [ "tituloSerie" => "Mol Carcinog" "fecha" => "2010" "volumen" => "49" "numero" => "10" "paginaInicial" => "902" "paginaFinal" => "912" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20721970" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Benzaldehyde suppresses murine allergic asthma and rhinitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Tae Young Jang" 1 => "Chang-Shin Park" 2 => "Kyu-Sung Kim" 3 => "Min-Jeong Heo" 4 => "Young Hyo Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Intern Immunopharmac" "fecha" => "2014" "volumen" => "22" "paginaInicial" => "444" "paginaFinal" => "450" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Protective effects of allantoin against ovalbumin (OVA)-induced lung inflammation in a murine model of asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Mee-Young Lee" 1 => "Nam-Hun Lee" 2 => "Dayoung Jung" 3 => "Jin-Ah Lee" 4 => "Chang-Seob Seo" 5 => "Hoyoung Lee" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Intern Immunopharmac" "fecha" => "2010" "volumen" => "10" "paginaInicial" => "474" "paginaFinal" => "480" "itemHostRev" => array:3 [ "pii" => "S0001731016300011" "estado" => "S300" "issn" => "00017310" ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Suppressive effect of Petasites japonicus extract on ovalbumin-induced airway inflammation in an asthmatic mouse model" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Ji-Sook Lee" 1 => "EunJu Yang" 2 => "Chi-Young Yun" 3 => "Dong-Hee Kim" 4 => "Kim In Sik" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Ethnopharm" "fecha" => "2011" "volumen" => "133" "paginaInicial" => "551" "paginaFinal" => "557" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mepacrine alleviates airway hyperresponsiveness and airway inflammation in a mouse model of asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Arjun Ram" 1 => "Ulaganathan Mabalirajan" 2 => "Shashi Kant Singh" 3 => "Vijay Pal Singh" 4 => "Balaram Ghosh" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Intern Immunopharmac" "fecha" => "2008" "volumen" => "8" "paginaInicial" => "893" "paginaFinal" => "899" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Anti-inflammatory effects of ethanolic extract from Lagerstroemia indica on airway inflammation in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Eun Ju Yang" 1 => "Ji-Sook Lee" 2 => "Bo Bae Song" 3 => "Chi-Young Yun" 4 => "Dong-Hee Kim" 5 => "Kim In Sik" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Ethnopharm" "fecha" => "2011" "volumen" => "136" "paginaInicial" => "422" "paginaFinal" => "427" "itemHostRev" => array:3 [ "pii" => "S037041061500248X" "estado" => "S300" "issn" => "03704106" ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Skullcapflavone II inhibits ovalbumin-induced airway inflammation in a mouse model of asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Ha-Young Jang" 1 => "Kyung-Seop Ahn" 2 => "Mi-Jeong Park" 3 => "Ok-Kyoung Kwon" 4 => "Hyeong-Kyu Lee" 5 => "Sei-Ryang Oh" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Intern Immunopharmac" "fecha" => "2012" "volumen" => "12" "paginaInicial" => "666" "paginaFinal" => "674" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "D-pinitol regulates Th1/Th2 balance via suppressing Th2 immune response in ovalbumin-induced asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Jun Sik Leea" 1 => "Chang-Min Leeb" 2 => "Young-Il Jeongc" 3 => "In Duk Jungb" 4 => "Bo-Hye Kimb" 5 => "Eun-Young Seonge" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.febslet.2006.11.077" "Revista" => array:6 [ "tituloSerie" => "FEBS Lett" "fecha" => "2007" "volumen" => "581" "paginaInicial" => "57" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17174308" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mangosteen xanthones mitigate ovalbumin-induced airway inflammation in a mouse model of asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "Ha-Young Jang" 1 => "Ok-Kyoung Kwon" 2 => "Sei-Ryang Oh" 3 => "Hyeong-Kyu Lee" 4 => "Kyung-Seop Ahn" 5 => "Young-Won Chin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Food Chem Toxic" "fecha" => "2012" "volumen" => "50" "paginaInicial" => "4042" "paginaFinal" => "4050" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Inhibitory effects of Duchesnea chrysantha extract on ovalbumin-induced lung inflammation in a mouse model of asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "EunJu Yang" 1 => "Ji-Sook Lee" 2 => "Chi-Young Yun" 3 => "Joo-Hwan Kim" 4 => "Jin-Sook Kim" 5 => "Dong-Hee Kim" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Ethnopharm" "fecha" => "2008" "volumen" => "118" "paginaInicial" => "102" "paginaFinal" => "107" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A synthetic compound, 4-acetyl-3-methyl-6-(3,4,5-trimethoxyphenyl) pyrano[3,4-c]pyran-1,8-dione, ameliorates ovalbumin-induced asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Hwan-Suck Chung" 1 => "Youngeun Kim" 2 => "Sei Joong Oh" 3 => "Hankyum Kim" 4 => "SeungIll Choi" 5 => "Yujuan Zhang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bmc.2013.08.045" "Revista" => array:6 [ "tituloSerie" => "Bioorg Med Chem" "fecha" => "2013" "volumen" => "21" "paginaInicial" => "6359" "paginaFinal" => "6365" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24054491" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack496385" "titulo" => "Acknowledgments" "texto" => "<p id="par0165" class="elsevierStylePara elsevierViewall">The authors would like to acknowledge <span class="elsevierStyleGrantSponsor" id="gs0005">Research Center for Food Hygiene and Safety</span>, <span class="elsevierStyleGrantSponsor" id="gs0010">Shahid Sadoughi University of Medical Sciences, Yazd, Iran</span> and <span class="elsevierStyleGrantSponsor" id="gs0015">School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran</span>. The authors also thanks Dr. Yari, Dr. Hasanzade, Mrs Dargahi, Mrs Kashafrudi and Mrs Jafari.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004800000006/v1_202011271043/S030105462030029X/v1_202011271043/en/main.assets" "Apartado" => array:4 [ "identificador" => "5554" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004800000006/v1_202011271043/S030105462030029X/v1_202011271043/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S030105462030029X?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 0 | 4 |
| 2024 October | 74 | 2 | 76 |
| 2024 September | 548 | 11 | 559 |
| 2024 August | 1045 | 11 | 1056 |
| 2024 July | 135 | 11 | 146 |
| 2024 June | 110 | 11 | 121 |
| 2024 May | 117 | 21 | 138 |
| 2024 April | 97 | 21 | 118 |
| 2024 March | 96 | 23 | 119 |
| 2024 February | 117 | 28 | 145 |
| 2024 January | 138 | 27 | 165 |
| 2023 December | 84 | 19 | 103 |
| 2023 November | 140 | 16 | 156 |
| 2023 October | 155 | 22 | 177 |
| 2023 September | 125 | 19 | 144 |
| 2023 August | 110 | 17 | 127 |
| 2023 July | 98 | 15 | 113 |
| 2023 June | 84 | 15 | 99 |
| 2023 May | 127 | 22 | 149 |
| 2023 April | 105 | 4 | 109 |
| 2023 March | 85 | 9 | 94 |
| 2023 February | 60 | 1 | 61 |
| 2023 January | 57 | 10 | 67 |
| 2022 December | 83 | 17 | 100 |
| 2022 November | 84 | 25 | 109 |
| 2022 October | 87 | 25 | 112 |
| 2022 September | 76 | 23 | 99 |
| 2022 August | 98 | 26 | 124 |
| 2022 July | 68 | 21 | 89 |
| 2022 June | 77 | 17 | 94 |
| 2022 May | 104 | 30 | 134 |
| 2022 April | 101 | 26 | 127 |
| 2022 March | 154 | 24 | 178 |
| 2022 February | 127 | 19 | 146 |
| 2022 January | 112 | 30 | 142 |
| 2021 December | 67 | 51 | 118 |
| 2021 November | 88 | 32 | 120 |
| 2021 October | 105 | 44 | 149 |
| 2021 September | 69 | 13 | 82 |
| 2021 August | 51 | 28 | 79 |
| 2021 July | 33 | 19 | 52 |
| 2021 June | 32 | 14 | 46 |
| 2021 May | 39 | 18 | 57 |
| 2021 April | 101 | 32 | 133 |
| 2021 March | 54 | 15 | 69 |
| 2021 February | 28 | 24 | 52 |
| 2021 January | 24 | 13 | 37 |
| 2020 December | 3 | 0 | 3 |
| 2020 June | 0 | 2 | 2 |
Show all
