Research Letter
Russula cutefracta inhibits antigen-induced degranulation and Syk and MAPK phosphorylation in rat basophilic leukaemia cells
M.B. Ye, Y.H. Jeon, H.L. Jin, Y.J. Kim, B.O. Lim
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Department of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea
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Negative control in the mother and in another child. Prick test with pure non-iodinated povidone (2.5%) (25<span class="elsevierStyleHsp" style=""></span>mg/ml): 6<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>6 mm, histamine: 4<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>4.5<span class="elsevierStyleHsp" style=""></span>mm.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "A.V. Michavila-Gomez, M.A. Moreno-Palanques, M. Ferrer-Vazquez, R. Ferriols-Leisart, B. Bartolomé" "autores" => array:5 [ 0 => array:2 [ "nombre" => "A.V." "apellidos" => "Michavila-Gomez" ] 1 => array:2 [ "nombre" => "M.A." "apellidos" => "Moreno-Palanques" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Ferrer-Vazquez" ] 3 => array:2 [ "nombre" => "R." "apellidos" => "Ferriols-Leisart" ] 4 => array:2 [ "nombre" => "B." "apellidos" => "Bartolomé" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611002618?idApp=UINPBA00004N" "url" => "/03010546/0000004000000004/v1_201304101110/S0301054611002618/v1_201304101110/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Research Letter</span>" "titulo" => "<span class="elsevierStyleItalic">Russula cutefracta</span> inhibits antigen-induced degranulation and Syk and MAPK phosphorylation in rat basophilic leukaemia cells" "tieneTextoCompleto" => true "saludo" => "To the Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "261" "paginaFinal" => "263" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.B. Ye, Y.H. Jeon, H.L. Jin, Y.J. Kim, B.O. Lim" "autores" => array:5 [ 0 => array:2 [ "nombre" => "M.B." "apellidos" => "Ye" ] 1 => array:2 [ "nombre" => "Y.H." "apellidos" => "Jeon" ] 2 => array:2 [ "nombre" => "H.L." "apellidos" => "Jin" ] 3 => array:2 [ "nombre" => "Y.J." "apellidos" => "Kim" ] 4 => array:4 [ "nombre" => "B.O." "apellidos" => "Lim" "email" => array:1 [ 0 => "beongou@kku.ac.kr" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Department of Life Science, College of Biomedical and Health Science, Konkuk University, Chungju, Republic of Korea" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1925 "Ancho" => 1467 "Tamanyo" => 226033 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The effect of <span class="elsevierStyleItalic">R. cutefracta</span> on Syk and MAPK phosphorylation. RBL-2H3 cells were treated as described to initiate degranulation, with or without RCE treatment. The cell lysates were subjected to Western blot analysis to detect phosphorylated forms of (A) Syk and (B) MAP kinase. PP2 (10<span class="elsevierStyleHsp" style=""></span>μM) is a general Src-family kinase inhibitor; N, no treatment; A, antigen stimulation only.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Russula cutefracta</span> (synonymous with <span class="elsevierStyleItalic">Russula cyanoxanthus</span>) is a mushroom of the genus <span class="elsevierStyleItalic">Russula</span> commonly found in parts of Europe and Asia. Although species of <span class="elsevierStyleItalic">Russula</span> have rarely been used for medicinal preparations, extracts of other mushrooms species are used as traditional remedies for various diseases in Asian countries. Recent evidence indicates that the mushroom lectins, polysaccharides, and other molecules have general anti-tumour, anti-inflammatory, and immunodulatory properties. Here, we investigated the effects of <span class="elsevierStyleItalic">R. cutefracta</span> on mast cell degranulation, an important step in allergic reactions.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Mast cells are important for immediate hypersensitivity and the inflammatory response and the rat basophilic leukaemia cell line, RBL-2H3, has proven useful for studying the biology of mast cells.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Allergy, or immediate (Type I) hypersensitivity, is one of four types of hypersensitivity.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The binding of antigen to the high affinity IgE receptor (Fc¿RI) on the surface of mast cells and basophils induces the release of histamine, prostaglandin, arachidonic acid metabolites, proteases, heparin sulphate, serotonin, leukotrienes, and proinflammatory cytokines from secretory vesicles called granules.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Basophils and mast cells express high levels of Fc¿RI consisting of an α chain, a β chain, and two disulfide-linked γ chains.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> The α chain of Fc¿RI contributes to high affinity IgE binding whereas the β and γ chains, which contain immunoreceptor tyrosine-based activation motifs (ITAMs), initiate the downstream signalling cascade leading to release of preformed and newly synthesised mediators.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> The spleen tyrosine kinase (Syk) plays an essential role in the IgE-dependent activation of mast cells. For example, cross-linking of Fc¿RI results in phosphorylation of the ITAMs on the β and γ chains by Lyn, a Src family kinase.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The phosphorylated γ chains then bind and activate Syk, which has an essential role for Fc¿RI-proximal signalling pathways.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> However, many more kinases including Fyn, PI3-kinase, PLC-γ, and MAPKs are important for mast cell activation and degranulation.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Therefore, the inhibition of these kinases by natural compounds found in <span class="elsevierStyleItalic">R. cutefracta</span> might suppress the release of hypersensitivity-inducing mediators in mast cells, thereby leading to inhibition of the allergic response.</p><p id="par0020" class="elsevierStylePara elsevierViewall">As a first step toward using <span class="elsevierStyleItalic">R. cutefracta</span> as a treatment for allergy, dried <span class="elsevierStyleItalic">R. cutefracta</span> (80<span class="elsevierStyleHsp" style=""></span>g) was used to prepare <span class="elsevierStyleItalic">R. cutefracta</span> extract (RCE) by three extractions with ethanol. After filtration, excess water was removed with a rotary evaporator under vacuum at 50<span class="elsevierStyleHsp" style=""></span>°C. Next, we determined whether RCE is toxic by assessing the viability of mast cells. RBL-2H3 cells were treated with various concentrations of RCE for 12<span class="elsevierStyleHsp" style=""></span>h and cell viability was determined by MTT assay. Untreated cells were used as a negative control (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). We did not observe any increase in cell death due to RCE, although we tested a range of concentrations from 10<span class="elsevierStyleHsp" style=""></span>μg/ml to 100<span class="elsevierStyleHsp" style=""></span>μg/ml (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). Therefore, in the range of concentrations used in our study, RCE was not toxic to mast cells.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">Mast cell degranulation is a cellular process whereby secretory vesicles release hypersensitivity-inducing molecules including histamine, proteoglycans and proteases. β-Hexosaminidase is another molecule present within mast cell granules and this marker has been used widely to monitor degranulation.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Mast cells were incubated with DNP-specific IgE (20<span class="elsevierStyleHsp" style=""></span>ng/ml) overnight and various concentrations of RCE (10<span class="elsevierStyleHsp" style=""></span>μg/ml, 20<span class="elsevierStyleHsp" style=""></span>μg/ml, and 100<span class="elsevierStyleHsp" style=""></span>μg/ml) for 30<span class="elsevierStyleHsp" style=""></span>min, resulting in a dose-dependent decrease in degranulation, as measured by β-hexosaminidase release (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). In comparison, our control experiments with untreated cells or cells receiving antigen simulation only resulted in no degranulation and complete degranulation, respectively (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Another control experiment using PP2 (10<span class="elsevierStyleHsp" style=""></span>μM), a general Src-family kinase inhibitor, also inhibited degranulation and RCE at 30<span class="elsevierStyleHsp" style=""></span>μg/ml and 100<span class="elsevierStyleHsp" style=""></span>μg/ml were as potent as PP2 in inhibiting degranulation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). We believe that this is the first demonstration of the anti-allergy properties of <span class="elsevierStyleItalic">R. cutefracta</span>.</p><p id="par0030" class="elsevierStylePara elsevierViewall">An increase in cytosolic Ca<span class="elsevierStyleSup">2+</span> ionophore concentration ([Ca<span class="elsevierStyleSup">2+</span>]<span class="elsevierStyleInf">i</span>) is thought to be important for mast cell degranulation.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Also, it is known that thapsigargin, a potent inhibitor of Ca<span class="elsevierStyleSup">2+</span>-ATPase in the endoplasmic reticulum membrane and ionomycin, a Ca<span class="elsevierStyleSup">2+</span> ionophore, cause mast cell degranulation without Fc¿RI activation.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> To determine whether degranulation resulting from an increase in cytosolic [Ca<span class="elsevierStyleSup">2+</span>] can be inhibited by RCE, RBL-2H3 cells were incubated with DNP-specific IgE (20<span class="elsevierStyleHsp" style=""></span>ng/ml) overnight, treated with RCE at various concentrations (10<span class="elsevierStyleHsp" style=""></span>μg/ml, 20<span class="elsevierStyleHsp" style=""></span>μg/ml, and 100<span class="elsevierStyleHsp" style=""></span>μg/ml) for 30<span class="elsevierStyleHsp" style=""></span>min, and treated with thapsigargin (300<span class="elsevierStyleHsp" style=""></span>nm) or ionomycin (1<span class="elsevierStyleHsp" style=""></span>μM) for 10<span class="elsevierStyleHsp" style=""></span>min. RCE treatment after thapsigargin pre-treatment resulted in a dose-dependent inhibition of mast cell degranulation, similar to that seen with DNP-IgE-induced degranulation (compare <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B and C). Ionomycin could also cause degranulation, but the inhibition of degranulation after subsequent treatment with RCE was weaker than that observed after thapsigargin treatment (compare <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C and D). Together, these data provide evidence that non-Fc¿RI-mediated mast cell degranulation could also be inhibited by <span class="elsevierStyleItalic">R. cutefracta</span>.</p><p id="par0035" class="elsevierStylePara elsevierViewall">To understand how <span class="elsevierStyleItalic">R. cutefracta</span> suppresses mast cell activation and degranulation, we examined its effects on Fc¿RI-mediated signalling events by Western blot analyses, including phosphorylation of Syk and the MAP kinases (ERK1/2, JNK1/2 and p38). Syk is a key mediator of immunoreceptor signalling in mast cells; it is activated upon engagement of the Fc receptor and it is a critical link to many downstream events including calcium mobilisation.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Treating the mast cells with increasing concentrations of RCE resulted in a gradual decrease in Syk phosphorylation (as detected by α-P-Syk Tyr525/526 antibody), thus verifying the dose-dependency of RCE and mast cell degranulation (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). Some secondary signalling events following KIT activation in mast cells, including phosphorylation of the mitogen-activated protein kinases (MAPKs), are important events in the transcriptional regulation of activated mast cells.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> When mast cells were treated with increasing concentrations of RCE, we observed significant decreases in JNK phosphorylation (as detected by α-P-JNK Thr183/Tyr185 antibody) and p38 phosphorylation (as detected by α-P-p38 Thr180/Tyr182 antibody) and a slight decrease in ERK1/2 phosphorylation (as detected by α-P-Erk1/2 Thr202/Tyr204 antibody) (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B). Together, these results support our observation that RCE could inhibit mast cell degranulation by inhibiting cell signalling intermediaries. Furthermore, it is likely that RCE inhibits mast cell degranulation by preventing the phosphorylation of regulatory molecules downstream of Fc¿RI, such as Syk and the MAP kinases.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, ours is the first study demonstrating that <span class="elsevierStyleItalic">R. cutefracta</span> inhibits degranulation in mast cells. Furthermore, only a few other mushroom species including <span class="elsevierStyleItalic">Flammulina velutipes</span>, <span class="elsevierStyleItalic">Hypsizigus marmoreus</span>, and <span class="elsevierStyleItalic">Agaricus blazei</span> are known to protect against hypersensitivity. Therefore, <span class="elsevierStyleItalic">R. cutefracta</span> merits further evaluation as a natural treatment for allergy.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1824 "Ancho" => 2363 "Tamanyo" => 201025 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The effect of <span class="elsevierStyleItalic">R. cutefracta</span> on RBL-2H3 degranulation. (A) RBL-2H3 cells were treated by the indicated concentrations of RCE for 12<span class="elsevierStyleHsp" style=""></span>h and cell viability was determined by MTT assay. (B) Degranulation of RBL-2H3 cells was measured by the release of β-hexosaminidase. (C and D) Thapsigargin and ionomycin-stimulated degranulation. Thapsigargin (300<span class="elsevierStyleHsp" style=""></span>nM) and ionomycin (1<span class="elsevierStyleHsp" style=""></span>M) were used to stimulate degranulation of RBL-2H3 cells. PP2 (10<span class="elsevierStyleHsp" style=""></span>μM) is a general Src-family kinase inhibitor; N, no treatment; A, antigen stimulation only. The values are expressed as the mean<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>SEM from three independent experiments (<span class="elsevierStyleSup">*</span><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 and <span class="elsevierStyleSup">**</span><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1925 "Ancho" => 1467 "Tamanyo" => 226033 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The effect of <span class="elsevierStyleItalic">R. cutefracta</span> on Syk and MAPK phosphorylation. RBL-2H3 cells were treated as described to initiate degranulation, with or without RCE treatment. The cell lysates were subjected to Western blot analysis to detect phosphorylated forms of (A) Syk and (B) MAP kinase. PP2 (10<span class="elsevierStyleHsp" style=""></span>μM) is a general Src-family kinase inhibitor; N, no treatment; A, antigen stimulation only.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "IgE-induced histamine release from rat basophilic leukemia cell lines: isolation of releasing and nonreleasing clones" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "E.L. Barsumian" 1 => "C. Isersky" 2 => "M.G. Petrino" 3 => "R.P. 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| Year/Month | Html | Total | |
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| 2024 November | 7 | 1 | 8 |
| 2024 October | 26 | 3 | 29 |
| 2024 September | 26 | 11 | 37 |
| 2024 August | 25 | 11 | 36 |
| 2024 July | 23 | 5 | 28 |
| 2024 June | 24 | 5 | 29 |
| 2024 May | 20 | 5 | 25 |
| 2024 April | 21 | 8 | 29 |
| 2024 March | 31 | 4 | 35 |
| 2024 February | 27 | 2 | 29 |
| 2024 January | 24 | 10 | 34 |
| 2023 December | 17 | 5 | 22 |
| 2023 November | 29 | 17 | 46 |
| 2023 October | 30 | 14 | 44 |
| 2023 September | 22 | 2 | 24 |
| 2023 August | 19 | 0 | 19 |
| 2023 July | 27 | 7 | 34 |
| 2023 June | 4 | 1 | 5 |
| 2023 May | 45 | 7 | 52 |
| 2023 April | 45 | 2 | 47 |
| 2023 March | 16 | 5 | 21 |
| 2023 February | 21 | 4 | 25 |
| 2023 January | 20 | 8 | 28 |
| 2022 December | 25 | 9 | 34 |
| 2022 November | 26 | 8 | 34 |
| 2022 October | 14 | 12 | 26 |
| 2022 September | 19 | 6 | 25 |
| 2022 August | 18 | 11 | 29 |
| 2022 July | 12 | 9 | 21 |
| 2022 June | 15 | 4 | 19 |
| 2022 May | 13 | 10 | 23 |
| 2022 April | 22 | 6 | 28 |
| 2022 March | 18 | 6 | 24 |
| 2022 February | 10 | 6 | 16 |
| 2022 January | 17 | 6 | 23 |
| 2021 December | 10 | 8 | 18 |
| 2021 November | 15 | 9 | 24 |
| 2021 October | 21 | 11 | 32 |
| 2021 September | 10 | 13 | 23 |
| 2021 August | 7 | 11 | 18 |
| 2021 July | 13 | 13 | 26 |
| 2021 June | 12 | 7 | 19 |
| 2021 May | 14 | 6 | 20 |
| 2021 April | 23 | 19 | 42 |
| 2021 March | 14 | 17 | 31 |
| 2021 February | 10 | 11 | 21 |
| 2021 January | 9 | 7 | 16 |
| 2020 December | 3 | 3 | 6 |
| 2020 November | 0 | 3 | 3 |
| 2020 October | 0 | 2 | 2 |
| 2020 September | 0 | 3 | 3 |
| 2020 July | 0 | 1 | 1 |
| 2019 December | 0 | 2 | 2 |
| 2019 September | 0 | 1 | 1 |
| 2019 May | 0 | 9 | 9 |
| 2018 February | 11 | 1 | 12 |
| 2018 January | 12 | 3 | 15 |
| 2017 December | 4 | 1 | 5 |
| 2017 November | 16 | 4 | 20 |
| 2017 October | 7 | 2 | 9 |
| 2017 September | 7 | 4 | 11 |
| 2017 August | 16 | 7 | 23 |
| 2017 July | 13 | 3 | 16 |
| 2017 June | 16 | 12 | 28 |
| 2017 May | 23 | 12 | 35 |
| 2017 April | 21 | 1 | 22 |
| 2017 March | 20 | 27 | 47 |
| 2017 February | 18 | 4 | 22 |
| 2017 January | 16 | 1 | 17 |
| 2016 December | 22 | 6 | 28 |
| 2016 November | 24 | 4 | 28 |
| 2016 October | 33 | 5 | 38 |
| 2016 September | 24 | 10 | 34 |
| 2016 August | 13 | 4 | 17 |
| 2016 July | 14 | 4 | 18 |
| 2016 June | 15 | 5 | 20 |
| 2016 May | 12 | 13 | 25 |
| 2016 April | 16 | 34 | 50 |
| 2016 March | 16 | 17 | 33 |
| 2016 February | 20 | 22 | 42 |
| 2016 January | 16 | 17 | 33 |
| 2015 December | 18 | 15 | 33 |
| 2015 November | 21 | 16 | 37 |
| 2015 October | 25 | 14 | 39 |
| 2015 September | 19 | 3 | 22 |
| 2015 August | 36 | 5 | 41 |
| 2015 July | 49 | 2 | 51 |
| 2015 June | 16 | 2 | 18 |
| 2015 May | 17 | 1 | 18 |
| 2015 April | 9 | 9 | 18 |
| 2015 March | 22 | 3 | 25 |
| 2015 February | 6 | 2 | 8 |
| 2015 January | 18 | 1 | 19 |
| 2014 December | 21 | 8 | 29 |
| 2014 November | 9 | 5 | 14 |
| 2014 October | 10 | 3 | 13 |
| 2014 September | 18 | 3 | 21 |
| 2014 August | 16 | 0 | 16 |
| 2014 July | 23 | 2 | 25 |
| 2014 June | 18 | 0 | 18 |
| 2014 May | 10 | 3 | 13 |
| 2014 April | 3 | 1 | 4 |
| 2014 March | 40 | 10 | 50 |
| 2014 February | 44 | 4 | 48 |
| 2014 January | 49 | 10 | 59 |
| 2013 December | 39 | 5 | 44 |
| 2013 November | 34 | 6 | 40 |
| 2013 October | 44 | 10 | 54 |
| 2013 September | 41 | 9 | 50 |
| 2013 August | 44 | 9 | 53 |
| 2013 July | 52 | 11 | 63 |
| 2013 June | 23 | 2 | 25 |
| 2013 May | 39 | 6 | 45 |
| 2013 April | 22 | 20 | 42 |
| 2013 March | 18 | 5 | 23 |
| 2013 February | 11 | 5 | 16 |
| 2013 January | 9 | 3 | 12 |
| 2012 December | 7 | 2 | 9 |
| 2012 November | 2 | 4 | 6 |
| 2012 October | 2 | 5 | 7 |
| 2012 September | 2 | 4 | 6 |
| 2012 June | 252 | 0 | 252 |
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