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Anti-arthritic effects of magnolol in human interleukin 1β-stimulated fibroblast-like synoviocytes and in a rat arthritis model.

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Anti-Arthritic Effects of Magnolol in Human Interleukin 1b-Stimulated Fibroblast-Like Synoviocytes and in a Rat Arthritis Model Jyh-Horng Wang1, Kao-Shang Shih2, Jing-Ping Liou3, Yi-Wen Wu1, Anita Shin-Yuan Chang4, Kang-Li Wang4, Ching-Lin Tsai1, Chia-Ron Yang4* 1 Department of Orthopedic Surgery, National Taiwan University Hospital, Taipei, Taiwan, 2 Orthopedic Department, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, 3 School of Pharmacy, Taipei Medical University, Taipei, Taiwan, 4 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan Abstract Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,59-Diallyl-biphenyl2,29-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-kB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1bstimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E2, and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1b-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo antiarthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1b (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5–25 mg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1b-induced activation of the IKK/IkB/NF-kB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases. Citation: Wang J-H, Shih K-S, Liou J-P, Wu Y-W, Chang AS-Y, et al. (2012) Anti-Arthritic Effects of Magnolol in Human Interleukin 1b-Stimulated Fibroblast-Like Synoviocytes and in a Rat Arthritis Model. PLoS ONE 7(2): e31368. doi:10.1371/journal.pone.0031368 Editor: Christianne Bandeira de Melo, Instituto de Biofisica Carlos Chagas Filho - Universidade Federal do Rio de Janeiro, Brazil Received November 3, 2011; Accepted January 9, 2012; Published February 16, 2012 Copyright: ß 2012 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work received grant support from National Science Council of Taiwan (NSC100-2320-B-002-004-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: cryang@ntu.edu.tw rofecoxib, has been developed with the aim of avoiding adverse gastrointestinal effects, but rofecoxib had to be withdrawn from the market due to cardiovascular toxicity. Furthermore, although some biologic agents, such as etanercept and infliximab, have provided major advances in treatment, they are expensive and must be injected subcutaneously or intravenously, which, in turn, increases the risk of infection [4]. Thus, side-effects remain one of the problems of the long-term use of NSAIDs and there is a need for safe and effective anti-arthritic agents for long-term use. Recent study showed that piascledine, mixture of nonsaponifiable components of avocado and soybean oils, exerts promising effect to relief inflammatory arthritis symptoms [5]; several groups also have studied small anti-inflammatory molecules derived from natural sources [6,7] with the aim of developing new treatments, but scientific evidence of their anti-arthritic efficacy is still insufficient. The biphenyl neolignan magnolol (5,59-Diallyl-biphenyl-2,29diol) is purified from the commonly used Chinese medicinal herb Magnolia officinalis, which has long been used for the treatment of fever, headache, asthma, anxiety, and diarrhea [8]. Since the Introduction Inflammatory arthritis is a synovial disease characterized by chronic inflammation of the joints and can result in disability owing to joint destruction. Proliferative fibroblast-like synoviocytes (FLSs) play crucial roles in both the propagation of inflammation and joint damage, as they produce large amounts of proinflammatory mediators, such as interleukin (IL)-1, IL-6, tumor necrosis factor-a (TNF-a), matrix metalloproteinases (MMPs), and prostaglandin E2 (PGE2) [1]. These mediators bind to specific receptors, causing gene transcription, and form complicated signaling interactions which contribute to the progression of inflammatory arthritis, e.g. leukocyte infiltration, cytokine networks formation, cartilage catabolism elevation and anabolism suppression [2]. Non-steroidal anti-inflammatory drugs (NSAIDs) are the principal treatment for arthritis patients; however, they only inhibit cyclooxygenases (COXs) and reduce prostaglandin generation and have no effect on the production of inflammatory cytokines [3]. In addition, anti-inflammatory agents carry the risk of gastrointestinal toxicity. A new generation of NSAIDs, such as PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e31368 Magnolol Acts as a Potent Anti-Arthritic Agent NOAEL (no observed adverse effect level) of magnolol greater than 240 mg/kg body weight per day in a 90 day study in rats, it has been classified as no safety concern food additives by World Health Organization [9]. Magnolol has been shown to possess a range of pharmacological effects, including an anti-inflammatory effect [10], anti-thrombotic effect [11], anti-tumor effect [12,13], a platelet aggregation inhibitory effect [11,14], and anti-oxidant activity [15]. It has been shown to suppress the expression of inducible nitric oxide synthase [16] and COX-2 by macrophages [17], reduce the production of the atherosclerosis mediators monocyte chemotactic protein-1 and vascular cell adhesion molecule-1 by endothelial cells [18], and inhibit secretion of MMPs, IL-8, and TNF-a by different cell types [19,20]. Interestingly, no severe side effects of magnolol have been reported. These effects of magnolol would seem to be beneficial for chronic inflammatory diseases, for example, inflammatory arthritis, but, to our knowledge, the anti-arthritic efficacy of magnolol has never been evaluated. The present study was performed to examine the inhibitory effect of magnolol on the expression of pro-inflammatory cytokines and enzymes in IL-1b-stimulated FLS and to elucidate the underlying mechanisms. Magnolol was found to reduce IL-1binduced IL-6, COX-2, MMP-1, and MMP-13 expression and these effects correlated with its inhibition of NF-kB and MAPK activation. Furthermore, studies using an adjuvant-induced arthritis rat model showed that magnolol inhibited the development of arthritis, suggesting its potential as a therapeutic agent in inflammatory arthritis. degradation, but also increased phosphorylation of p65 (Figure 2A). Interestingly, magnolol pre-treatment markedly inhibited all four effects in a concentration-dependent manner (Figure 2B). The result of a promoter activity assay showed that magnolol caused concentration-dependent inhibition of IL-1bmediated NF-kB promoter activation (Figure 2C). Furthermore, after 1 h treatment with IL-1b, a significant increase in NF-kBDNA binding activity was seen in an EMSA (Figure 2D) and a dramatic increase in the translocation of NF-kB into the nucleus was observed by laser confocal microscopy (Figure 2E) and both effects were markedly inhibited by addition of magnolol (Figure 2D and E). IL-1b treatment also resulted in a significant increase in phosphorylation of JNK, p38, and ERK (Figure 3A), c-fos promoter activation (Figure 3C), AP-1-DNA binding activation (Figure 3D), and c-fos nuclear translocation (Figure 3E) and all of these effects were markedly inhibited by magnolol (Figure 3B–E). Together, these results demonstrate that magnolol significantly inhibited the NF-kB and MAPK pathways and NF-kB, AP-1 nuclear translocation. Magnolol suppresses the development of arthritis in an AIA (adjuvant-induced arthritis) model Our results showing that magnolol inhibited the production of inflammatory mediators through the NF-kB and MAPKs pathways strongly suggested that it might be effective in preventing the pathogenesis of destructive arthritis. We therefore examined the effect of magnolol in vivo by monitoring the progression and severity of an AIA model. As shown in figure 4A–C, compared to the vehicle-treated group, the group treated with 100 mg/kg of magnolol for 16 days not only showed significantly reduced limb swelling and paw volumes, but also markedly less leukocyte infiltration and synovitis. Treatment with magnolol did not affect the body weight loss (Figure 4D), suggesting that magnolol did not cause a toxic response. Furthermore, ELISA assays showed that magnolol caused a significant decrease in serum levels of IL1b, IL-6, and PGE2 (Figure 4E). These findings suggest that magnolol has potent anti-arthritic effects in vivo. Results Magnolol suppresses inflammatory mediator production by IL-1b-stimulated FLS To examine the anti-inflammatory effect of magnolol, FLS were stimulated with 10 ng/mL of IL-1b in the presence or absence of magnolol. As shown in figure 1, addition of IL-1b not only significantly increased mRNA (Figure 1A) and protein (Figure 1B and C) levels of IL-6, COX-2, MMP-1, and MMP-13 (both overexpress in inflammatory arthritis cartilage and are rate-limiting components of the collagen degradation process), but also increased production of PGE2 protein (Figure 1B). Interestingly, magnolol pre-treatment markedly inhibited the IL-1b-induced increase in IL-6, COX-2, MMP-1, and MMP-13 mRNA and protein and PGE2 secretion in a concentration-dependent manner (Figure 1A–C). This inhibition was not due to decrease total protein levels, since b-actin levels were unchanged (Figure 1B) and none of the treatments had any significant effect on cell viability at 24 h, assessed using the MTT assay (Figure 1D). Discussion Natural products have proved to be a valuable source of new therapeutic agents. A number of in vitro and in vivo studies have shown that magnolol has anti-inflammatory activities by inhibiting inflammatory mediator secretion [16–20] and suppressing inflammatory pain [23]. Another component of Magnolia officinalis, honokiol, was recently reported to inhibit the type II collageninduced increase in pro-inflammatory cytokine and MMPs levels and to suppress type II collagen-induced arthritis [24], raising the possibility that magnolol may also be useful in the treatment of inflammatory arthritis. In the present study, magnolol not only significantly inhibited the IL-1b-induced increase in IL-6, PGE2, MMP, and COX-2 protein levels, but also remarkably alleviated M. butyricum-induced arthritis in vivo by inhibiting the NF-kB and AP-1 signaling pathways, suggesting its potential therapeutic use as a novel topical anti-arthritic agent. Previous report has indicated magnolol with low toxicity [8]; however, there was reported that high concentration of magnolol (10 mg/mL) pretreatment at 30 min before cold preservation (4uC) induces in vitro hepatotoxicity in rat hepatocyte clone-9 cell line under serum-reduced conditions [25]. Since low temperature may slow down or completely discontinue translational and transcriptional machineries in cold preservation cells, so that de novo synthesis (e.g. magnolol-mediated anti-apoptotic proteins (Bcl-xL) up-regulation [26]) could not be expected. Furthermore, this experiment Magnolol inhibits NF-kB and MAPK signaling in IL-1bactivated FLS The NF-kB and MAPKs pathways play pivotal roles in the expression of inflammatory mediators by IL-1b-stimulated FLS and contribute to inflammatory arthritis [21,22]. To further characterize the molecules involved in the inhibitory effect of magnolol, we examined whether magnolol regulated these signaling pathways. FLS were treated with magnolol (0–25 mg/ mL) for 30 min prior to stimulation with 10 ng/mL of IL-1b in the continued presence of magnolol for different time periods, then levels of the phosphorylated or total forms of IKKa/b, IkBa, and p65 were measured using Western blotting. IL-1b treatment for 30 min not only caused significant phosphorylation of IKKa/b at serine 180/181, phosphorylation of IkBa at serine 32, and IkBa PLoS ONE | www.plosone.org 2 February 2012 | Volume 7 | Issue 2 | e31368 Magnolol Acts as a Potent Anti-Arthritic Agent Figure 1. Magnolol inhibits the IL-1b-induced production of pro-inflammatory mediators in a concentration-dependent manner. (A) 16106 fibroblast-like synoviocytes (FLS) were treated with magnolol (0–25 mg/mL) for 30 min, then were incubated for 5 h with or without 10 ng/mL of IL-1b in the continued presence of magnolol, then levels of IL-6, COX-2, MMP-1, and MMP-13 mRNAs were measured by RT-PCR. (B, C) FLS were incubated with magnolol (0–25 mg/mL) for 30 min, then with IL-1b (10 ng/mL) for 24 h in the continued presence of magnolol, then supernatants were assayed for (B) IL-6 or PGE2 or (C) MMP-1 or MMP-13 by ELISA; and the whole cell extracts were subjected to Western blot analysis for COX-2 (B). (D) Viability of FLS determined after 24 h treatment with 0.25–25 mg/mL of magnolol compared to the control group using the MTT assay. In (B)–(D), the data are the mean 6 standard error of the mean (SEM), with n = 3. * p,0.05 and ** p,0.01 compared to the indicated groups. doi:10.1371/journal.pone.0031368.g001 condition was different with our study. In normothermic conditions, the same group also reported that magnolol effectively improved hepatic function and hepatocyte viability from warm ischemia-reperfusion injury in rats [26]. In addition, although PGE2 levels were down-regulated in response to administration of magnolol, recent study indicated that it is difficult to attribute the PLoS ONE | www.plosone.org GI damage to one factor, PGs inhibition [27]. Further research is necessary to demonstrate the GI effect of magnolol. IL-1b, the major mediator involved in inflammatory arthritis, can stimulate fibroblast proliferation and increase production of cytokines and enzymes, which, in turn, activate macrophages and lead to continued cytokine production [2–4]. This creates a 3 February 2012 | Volume 7 | Issue 2 | e31368 Magnolol Acts as a Potent Anti-Arthritic Agent Figure 2. Magnolol inhibits NF-kB activation in IL-1b-stimulated FLS. FLS (16106 cells) were treated with or without 10 ng/mL of IL-1b for the indicated times (A) or were treated with 0–25 mg/mL of magnolol for 30 min, then stimulated with 10 ng/mL IL-1b for 30 min in the continued presence of magnolol (B), then the cells were harvested and whole cell extracts subjected to Western blot analysis for the indicated proteins. (C) Cells (16105 cells) were transiently transfected with 1 mg of pGL4.32[luc2P/NF-kB-RE/Hygro] for 24 h and treated with 0–25 mg/mL magnolol for 30 min PLoS ONE | www.plosone.org 4 February 2012 | Volume 7 | Issue 2 | e31368 Magnolol Acts as a Potent Anti-Arthritic Agent prior to stimulation with 10 ng/mL of IL-1b in the continued presence of magnolol for a further 6 h, then luciferase activity was measured as described in the Materials and Methods. The results are expressed as the mean 6 standard error of the mean (SEM), with n = 3. * p,0.05 compared to the control group; #p,0.05 for comparison of indicated groups. (D) FLS were incubated with vehicle or 10 ng/mL of IL-1b or were pretreated with 25 mg/mL of magnolol for 30 min, then incubated with IL-1b in the continued presence of magnolol for 1 h, then the DNA binding activity of the nuclear extracts was examined in an electrophoretic mobility shift assay using a specific NF-kB DNA probe. (E) Cells (16105 cells) were left untreated or were treated with 25 mg/mL of magnolol for 30 min, then stimulated with 10 ng/mL of IL-1b in the continued presence of magnolol for 1 h, when samples were prepared for confocal microscopy analysis. Scale bar = 20 mm. doi:10.1371/journal.pone.0031368.g002 Our observations provide evidence that magnolol exerts antiarthritic effects by inhibiting the expression of the IL-1bstimulated IL-6, COX-2, MMP-1, and MMP-13 inflammationassociated genes by suppressing the NF-kB and MAPKs pathways. This inhibitory effect results in an improvement in arthritic symptoms in vivo. Since inflammatory cytokines and MMPs play important roles in destructive arthritic disease, this suggests that magnolol might be a potential anti-arthritic agent. positive feedback mechanism between the FLS and mononuclear cells that aggravates synovial inflammation and results in joint destruction. Thus, targeting the intracellular pathways between activated cytokine receptors and gene expression might be an attractive strategy for the treatment of inflammatory arthritis, since different pro-inflammatory mediators can share the same signaling pathway [2]. The two principal pathways activated by IL-1 are the NF-kB and MAPK pathways and the roles of both in the pathogenesis of destructive arthritis have been studied [2–4]. equilibrium value of MeCpG steps (,+14 deg.) [31,44]. In comparison, methylation has a significantly lower stability cost when happening at major groove positions, such as 211 and 21 base pair from dyad (mutations 9 and 12), where the roll of the nucleosome bound conformation (+10 deg.) is more compatible with the equilibrium geometry of MeCpG steps. The nucleosome destabilizing effect of cytosine methylation increases with the number of methylated cytosines, following the same position dependence as the single methylations. The multiple-methylation case reveals that each major groove meth- PLOS Computational Biology | www.ploscompbiol.org 3 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning ylation destabilizes the nucleosome by around 1 kJ/mol (close to the average estimate of 2 kJ/mol obtained for from individual methylation studies), while each minor groove methylation destabilizes it by up to 5 kJ/mol (average free energy as single mutation is around 6 kJ/mol). This energetic position-dependence is the reverse of what was observed in a recent FRET/SAXS study [30]. The differences can be attributed to the use of different ionic conditions and different sequences: a modified Widom-601 sequence of 157 bp, which already contains multiple CpG steps in mixed orientations, and which could assume different positioning due to the introduction of new CpG steps and by effect of the methylation. The analysis of our trajectories reveals a larger root mean square deviation (RMSD) and fluctuation (RMSF; see Figures S2– S3 in Text S1) for the methylated nucleosomes, but failed to detect any systematic change in DNA geometry or in intermolecular DNA-histone energy related to methylation (Fig. S1B, S1C, S4–S6 in Text S1). The hydrophobic effect should favor orientation of the methyl group out from the solvent but this effect alone is not likely to justify the positional dependent stability changes in Figure 2, as the differential solvation of the methyl groups in the bound and unbound states is only in the order of a fraction of a water molecule (Figure S5 in Text S1). We find however, a reasonable correlation between methylation-induced changes in hydrogen bond and stacking interactions of the bases and the change in nucleosome stability (see Figure S6 in Text S1). This finding suggests that methylation-induced nucleosome destabilization is related to the poorer ability of methylated DNA to fit into the required conformation for DNA in a nucleosome. Changes in the elastic deformation energy between methylated and un-methylated DNA correlate with nucleosomal differential binding free energies To further analyze the idea that methylation-induced nucleosome destabilization is connected to a worse fit of methylated DNA into the required nucleosome-bound conformation, we computed the elastic energy of the nucleosomal DNA using a harmonic deformation method [36,37,44]. This method provides a rough estimate of the energy required to deform a DNA fiber to adopt the super helical conformation in the nucleosome (full details in Suppl. Information Text S1). As shown in Figure 2, there is an evident correlation between the increase that methylation produces in the elastic deformation energy (DDE def.) and the free energy variation (DDG bind.) computed from MD/TI calculations. Clearly, methylation increases the stiffness of the CpG step [31], raising the energy cost required to wrap DNA around the histone octamers. This extra energy cost will be smaller in regions of high positive roll (naked DNA MeCpG steps have a higher roll than CpG steps [31]) than in regions of high negative roll. Thus, simple elastic considerations explain why methylation is better tolerated when the DNA faces the histones through the major groove (where positive roll is required) that when it faces histones through the minor groove (where negative roll is required). Nucleosome methylation can give rise to nucleosome repositioning We have established that methylation affects the wrapping of DNA in nucleosomes, but how does this translate into chromatin structure? As noted above, accumulation of minor groove methylations strongly destabilizes the nucleosome, and could trigger nucleosome unfolding, or notable changes in positioning or phasing of DNA around the histone core. While accumulation of methylations might be well tolerated if placed in favorable positions, accumulation in unfavorable positions would destabilize the nucleosome, which might trigger changes in chromatin structure. Chromatin could in fact react in two different ways in response to significant levels of methylation in unfavorable positions: i) the DNA could either detach from the histone core, leading to nucleosome eviction or nucleosome repositioning, or ii) the DNA could rotate around the histone core, changing its phase to place MeCpG steps in favorable positions. Both effects are anticipated to alter DNA accessibility and impact gene expression regulation. The sub-microsecond time scale of our MD trajectories of methylated DNAs bound to nucleosomes is not large enough to capture these effects, but clear trends are visible in cases of multiple mutations occurring in unfavorable positions, where unmethylated and methylated DNA sequences are out of phase by around 28 degrees (Figure S7 in Text S1). Due to this repositioning, large or small, DNA could move and the nucleosome structure could assume a more compact and distorted conformation, as detected by Lee and Lee [29], or a slightly open conformation as found in Jimenez-Useche et al. [30]. Using the harmonic deformation method, we additionally predicted the change in stability induced by cytosine methylation for millions of different nucleosomal DNA sequences. Consistently with our calculations, we used two extreme scenarios to prepare our DNA sequences (see Fig. 3): i) all positions where the minor grooves contact the histone core are occupied by CpG steps, and ii) all positions where the major grooves contact the histone core are occupied by CpG steps. We then computed the elastic energy required to wrap the DNA around the histone proteins in unmethylated and methylated states, and, as expected, observed that methylation disfavors DNA wrapping (Figure 3A). We have rescaled the elastic energy differences with a factor of 0.23 to match the DDG prediction in figure 2B. In agreement with the rest of our results, our analysis confirms that the effect of methylation is position-dependent. In fact, the overall difference between the two extreme methylation scenarios (all-in-minor vs all-in-major) is larger than 60 kJ/mol, the average difference being around 15 kJ/ mol. We have also computed the elastic energy differences for a million sequences with CpG/MeCpG steps positioned at all possible intermediate locations with respect to the position (figure 3B). The large differences between the extreme cases can induce rotations of DNA around the histone core, shifting its phase to allow the placement of the methylated CpG steps facing the histones through the major groove. It is illustrative to compare the magnitude of CpG methylation penalty with sequence dependent differences. Since there are roughly 1.5e88 possible 147 base pairs long sequence combinations (i.e., (4n+4(n/2))/2, n = 147), it is unfeasible to calculate all the possible sequence effects. However, using our elastic model we can provide a range of values based on a reasonably large number of samples. If we consider all possible nucleosomal sequences in the yeast genome (around 12 Mbp), the energy difference between the best and the worst sequence that could form a nucleosome is 0.7 kj/mol per base (a minimum of 1 kJ/mol and maximum of around 1.7 kJ/mol per base, the first best and the last worst sequences are displayed in Table S3 in Text S1). We repeated the same calculation for one million random sequences and we obtained equivalent results. Placing one CpG step every helical turn gives an average energetic difference between minor groove and major groove methylation of 15 kJ/ mol, which translates into ,0.5 kJ/mol per methyl group, 2 kJ/ mol per base for the largest effects. Considering that not all nucleosome base pair steps are likely to be CpG steps, we can conclude that the balance between the destabilization due to CpG methylation and sequence repositioning will depend on the PLOS Computational Biology | www.ploscompbiol.org 4 November 2013 | Volume 9 | Issue 11 | e1003354 DNA Methylation and Nucleosome Positioning Figure 3. Methylated and non-methylated DNA elastic deformation energies. (A) Distribution of deformation energies for 147 bplong random DNA sequences with CpG steps positioned every 10 base steps (one helical turn) in minor (red and dark red) and major (light and dark blue) grooves respectively. The energy values were rescaled by the slope of a best-fit straight line of figure 2, which is 0.23, to por la lectura a través de la lectura de la prensa. La educación en los medios las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio adquiere pleno derecho y entidad en la sección sexta titulada «competencias sociales y cívi- técnico de los aparatos. cas» que indica que «los alum- nos deberán ser capaces de juz- gar y tendrán espíritu crítico, lo que supone ser educados en los las programaciones oficiales, ya que, a lo largo de un medios y tener conciencia de su lugar y de su influencia estudio de los textos, los documentalistas del CLEMI en la sociedad». han podido señalar más de una centena de referencias a la educación de los medios en el seno de disciplinas 4. Un entorno positivo como el francés, la historia, la geografía, las lenguas, Si nos atenemos a las cifras, el panorama de la las artes plásticas : trabajos sobre las portadas de educación en medios es muy positivo. Una gran ope- prensa, reflexiones sobre temas mediáticos, análisis de ración de visibilidad como la «Semana de la prensa y publicidad, análisis de imágenes desde todos los ángu- de los medios en la escuela», coordinada por el CLE- los, reflexión sobre las noticias en los países europeos, MI, confirma año tras año, después de 17 convocato- información y opinión rias, el atractivo que ejerce sobre los profesores y los Esta presencia se constata desde la escuela mater- alumnos. Concebida como una gran operación de nal (2 a 6 años) donde, por ejemplo, se le pregunta a complementariedad entre la escuela y los profesiona- los niños más pequeños si saben diferenciar entre un les de los medios, alrededor del aprendizaje ciudada- periódico, un libro, un catálogo, a través de activida- no de la comunicación mediática, este evento moviliza des sensoriales, si saben para qué sirve un cartel, un durante toda una semana un porcentaje elevado de periódico, un cuaderno, un ordenador si son capa- centros escolares que representan un potencial de 4,3 ces de reconocer y distinguir imágenes de origen y de millones de alumnos (cifras de 2006). Basada en el naturaleza distintas. Podríamos continuar con más voluntariado, la semana permite desarrollar activida- ejemplos en todos los niveles de enseñanza y práctica- des más o menos ambiciosas centradas en la introduc- Páginas 43-48 ción de los medios en la vida de la escuela a través de la instalación de kioscos, organización de debates con profesionales y la confección por parte de los alumnos de documentos difundidos en los medios profesionales. Es la ocasión de dar un empujón a la educación en medios y de disfrutarlos. Los medios –un millar en 2006– se asocian de maneras diversas ofreciendo ejemplares de periódicos, acceso a noticias o a imágenes, proponiendo encuentros, permitiendo intervenir a los jóvenes en sus ondas o en sus columnas Esta operación da luz al trabajo de la educación en medios y moviliza a los diferentes participantes en el proyecto. 5. La formación de los docentes La formación es uno de los pilares principales de la educación en los medios. Su función es indispensable ya que no se trata de una disciplina, sino de una enseñanza que se hace sobre la base del voluntariado y del compromiso personal. Se trata de convencer, de mostrar, de interactuar. En primer lugar es necesario incluirla en la formación continua de los docentes, cuyo volumen se ha incrementado desde 1981 con la aparición de una verdadera política de formación continua de personal. Es difícil dar una imagen completa del volumen y del público, pero si nos atenemos a las cifras del CLEMI, hay más de 24.000 profesores que han asistido y se han involucrado durante 2004-05. 5.1. La formación continua En la mayoría de los casos, los profesores reciben su formación en contextos cercanos a su centro de trabajo, o incluso en este mismo. Después de una política centrada en la oferta que hacían los formadores, se valora más positivamente la demanda por parte del profesorado, ya que sólo así será verdaderamente fructífera. Los cursos de formación se repartieron en varias categorías: desde los formatos más tradicionales (cursos, debates, animaciones), hasta actividades de asesoramiento y de acompañamiento, y por supuesto los coloquios que permiten un trabajo en profundidad ya que van acompañados de expertos investigadores y profesionales. Citemos, por ejemplo en 2005, los coloquios del CLEMI-Toulouse sobre el cine documental o el del CLEMI-Dijon sobre «Políticos y medios: ¿connivencia?». Estos coloquios, que forman parte de un trabajo pedagógico regular, reagrupan a los diferentes participantes regionales y nacionales alrededor de grandes temas de la educación en medios y permiten generar nuevos conocimientos de aproximación y una profundización. Páginas 43-48 Hay otro tipo de formación original que se viene desarrollando desde hace menos tiempo, a través de cursos profesionales, como por ejemplo, en el Festival Internacional de Foto-periodismo «Visa para la imagen», en Perpignan. La formación se consolida en el curso, da acceso a las exposiciones, a las conferencias de profesionales y a los grandes debates, pero añade además propuestas pedagógicas y reflexiones didácticas destinadas a los docentes. Estas nuevas modalidades de formación son también consecuencia del agotamiento de la formación tradicional en las regiones. Los contenidos más frecuentes en formación continua conciernen tanto a los temas más clásicos como a los cambios que se están llevando a cabo en las prácticas mediáticas. Así encontramos distintas tendencias para 2004-05: La imagen desde el ángulo de la producción de imágenes animadas, el análisis de la imagen de la información o las imágenes del J.T. La prensa escrita y el periódico escolar. Internet y la información en línea. Medios y educación de los medios. 5.2 La formación inicial La formación inicial está aun en un grado muy ini- cial. El hecho de que la educación en medios no sea una disciplina impide su presencia en los IUFM (Institutos Universitarios de Formación de Maestros) que dan una prioridad absoluta a la didáctica de las disciplinas. En 2003, alrededor de 1.400 cursillistas sobre un total de 30.000 participaron en un momento u otro de un módulo de educación en medios. Estos módulos se ofrecen en función del interés que ese formador encuentra puntualmente y forman parte a menudo de varias disciplinas: documentación, letras, historia-geografía Estamos aún lejos de una política concertada en este dominio. La optativa «Cine-audiovisual» ha entrado desde hace muy poco tiempo en algunos IUFM destinada a obtener un certificado de enseñanza de la opción audiovisual y cine. Internet tiene cabida también en los cursos de formación inicial, recientemente con la aparición de un certificado informático y de Internet para los docentes, dirigido más a constatar competencias personales que a valorar una aptitud para enseñarlos. 6. ¿Y el futuro? El problema del futuro se plantea una vez más por la irrupción de nuevas técnicas y nuevos soportes. La difusión acelerada de lo digital replantea hoy muchas cuestiones relativas a prácticas mediáticas. Muchos Comunicar, 28, 2007 47 Comunicar, 28, 2007 Enrique Martínez-Salanova '2007 para Comunicar 48 trabajos que llevan el rótulo de la educación en medios solicitan una revisión ya que los conceptos cambian. La metodología elaborada en el marco de la educación en medios parece incluso permitir la inclinación de la sociedad de la información hacia una sociedad del conocimiento, como defiende la UNESCO. En Francia, se necesitaría unir las fuerzas dispersas en función de los soportes mediáticos y orientarse más hacia la educación en medios que al dominio técnico de los aparatos. Los avances recientes en el reconocimiento de estos contenidos y las competencias que supondrían podrían permitirlo. Referencias CLEMI/ACADEMIE DE BORDEAUX (Ed.) (2003): Parcours médias au collège: approches disciplinaires et transdisciplinaires. Aquitaine, Sceren-CRDP. GONNET, J. (2001): Education aux médias. Les controverses fécondes. Paris, Hachette Education/CNDP. SAVINO, J.; MARMIESSE, C. et BENSA, F. (2005): L’éducation aux médias de la maternelle au lycée. Direction de l’Enseignement Scolaire. Paris, Ministère de l’Education Nationale, Sceren/CNDP, Témoigner. BEVORT, E. et FREMONT, P. (2001): Médias, violence et education. Paris, CNDP, Actes et rapports pour l’éducation. – www.clemi.org: fiches pédagogiques, rapports et liens avec les pages régionales/académiques. – www.ac-nancy-metz.fr/cinemav/quai.html: Le site «Quai des images» est dédié à l’enseignement du cinéma et de l’audiovisuel. – www.france5.fr/education: la rubrique «Côté profs» a une entrée «education aux médias». – www.educaunet.org: Programme européen d’éducation aux risques liés à Internet. dResedfeleexliobnuetsacón Páginas 43-48
Anti-arthritic effects of magnolol in human interleukin 1β-stimulated fibroblast-like synoviocytes and in a rat arthritis model.
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Anti-arthritic effects of magnolol in human interleukin 1β-stimulated fibroblast-like synoviocytes and in a rat arthritis model.

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