Funcionalidad del aceite de oliva virgen extra en la artritis reumatoide experimental

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Introduction Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammation of the synovial membrane and progressive destruction of the articular cartilage and bone. (Salgado and Maneiro 2014). RA patients exhibit an inflammatory chronic condition, which usually affects symmetrically arthrodial and small joints of hands and feet Global prevalence of RA has been estimated to be around 0.5-1.0% of adults in developed countries with a large variation across regions and approximately three-times more common in the female gender. The disease may begin at any age, but around 80% of all patients initiate the disease between the ages of 35 and 50 years (Rudan et al. 2015). Although the specific triggers and exact mechanisms of tissue damage in RA is still unknown, an increase in inflammatory mediators as well as a dysregulation of the immune system with uncontrolled T cell activity, play a remarkable role in its pathogenesis. Pharmacological treatment in AR including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, disease-modifying antirheumatic drugs (DMARDs) and biological agents have improved the signs and symptoms of RA, but these drugs are only effective in a fraction of patients and have other limitations including a high cost, the requirement for parenteral administration and important side effects. Therefore, new therapeutic strategies are under investigation including nutritional therapy. The beneficial effects of the Mediterranean diet have been proven not only in cardiovascular diseases but also in diabetes, obesity, arthritis and cancer (Cardeno, Sanchez-Hidalgo, and Alarcon-de-la-Lastra 2013). Evidence points out that Mediterranean diet decreases both pain and disease activity leading to better outcomes, and decreasing the doses of anti-inflammatory drugs, which exhibit important secondary effects (Smedslund et al. 2010). Olive Oil is the characteristic culinary fat of the Mediterranean area being described as a key bio-active food (Puertollano et al. 2010). Extra virgin olive oil (EVOO) is obtained from the fruit of the olive tree (Olea europea L.) solely by mechanical or other physical means under conditions that do not alter its natural composition. Traditionally the beneficial effects of EVOO have been ascribed to its monounsaturated fatty acid (MUFA) (Bermudez et al. 2011). However, a wide range of evidence indicates that many of the beneficial effects of EVOO intake are due to its minor highly bioactive components (about 1–2 % of oil weight) (Alarcon de la Lastra et al. 2001) Among them, phenolic compounds such as hydroxytyrosol, tyrosol and oleuropein have shown anti-inflammatory and antioxidant effects (Omar et al. 2010). Current experimental studies support a beneficial role of polyphenols from EVOO in several inflammatory diseases, including RA (Martinez-Dominguez, de la Puerta, and Ruiz-Gutierrez 2001; Impellizzeri et al. 2011; Gong et al. 2009). Although EVOO has demonstrated anti-inflammatory effects, it has not reported so much evidence of its possible immunomodulatory effects. Therefore, the objectives of this thesis were: 1. To determinate the possible protective effect of dietary extra virgin olive oil (EVOO) in collagen-induced arthritis (CIA) in DBA 1/J mice, an experimental model of RA and explore the biochemical routes and possibly intracellular signalling pathways. 2. To evaluate the oral polyphenolic extract from EVOO treatment in murine collageninduced arthritis and study the biochemical routes and signalling pathway involved. 3. To investigate the effects of hydroxytyrosol (HTy) or hydroxytyrosol acetate (HTy- Ac), polyphenolics compounds from EVOO enriched-diets in experimental arthritis model in mice and elucidate the molecular mechanisms and signalling pathways involved. Results and Discussion 1. Dietary extra-virgin olive oil prevents inflammatory response and cartilage matrix degradation in murine collagen‑induced arthritis. (Rosillo et al. Eur J Nutr. 2015 In press) Three-week-old male DBA-1/J mice were randomized into four experimental groups: (1) Sham sunflower diet (SO-Sham) group received a diet elaborated with a marketable sunflower oil; (2) CIA sunflower diet (SO-CIA) group received a diet elaborated with a marketable sunflower oil; (3) Sham EVOO diet (EVOO-Sham) group were fed with a diet made with a marketable EVOO picual variety and (4) CIA EVOO diet (EVOO-CIA) group were fed with a diet made with a marketable EVOO picual variety. After 6 weeks, arthritis was induced by type II collagen. Experiments followed a protocol approved by the Animal Ethics Committee of the University of Seville, and all experiments were in accordance with the recommendations of the European Union regarding animal experimentation (Directive of the European Counsel 2010/630/EU) Our results revealed, that EVOO, as the lipid component of the diet, effectively exhibited preventive and therapeutic effects in the development of inflammatory arthritis and joint damage in CIA arthritic mice in comparison with those CIA mice fed with SO. This effect was correlated to an improved arthritis score, a minor inflammatory cells infiltration into articular tissues, reduced exudation into the synovial space, synovial hyperplasia and cartilage erosion. Overexpression of pro-inflammatory cytokines, such as IL-1β, TNF-α and IL-17 may activate osteoclasts and macrophages and recruit leukocytes in inflamed joints. Besides, it is well-known that IL-17 is able to induce the release of IL-8 and IL-6, and plays a remarkable role in the additive/synergistic effects induced by TNF-α and IL-1β (Jeong et al. 2004). Our results indicate that animals fed with EVOO diet showed a significant reduction in IL-1β, TNF-α and IL-17 proinflammatory cytokines levels in paw homogenates. Cartilage oligomeric matrix protein (COMP) is a matrix protein with a great potential as a biological marker of cartilage metabolism in arthritis (Saxne and Heinegard 1992). In addition, COMP is a putative substrate for metalloproteinases (MMPs). Particularly, MMP-3 is a proteinase secreted by synovial fibroblasts and chondrocytes and its activity results in degradation of aggrecan core protein, cartilage link protein, fibronectin and collagen. Our data showed that the production of both cartilage (COMP) and synovial (MMP-3) biomarkers was significantly inhibited by dietary EVOO treatment in CIA mice. Abnormal signalling pathways play an important role in the inflammatory process and can lead to a dysregulation of the inflammatory response being crucial in RA pathogenesis. Nuclear factor κB (NF-κB) is a crucial transcriptional activator for the expression of multiple proinflammatory genes involved in the microenvironment of the arthritic joints, playing an important role in the development of RA. (Morel and Berenbaum 2004; Okamoto et al. 2010). Our results suggested that dietary EVOO treatment suppressed NF-κB activation in CIA-induced arthritic mice. Similarly, the mitogen-activated protein kinase (MAPK) family also plays critical roles in RA pathogenesis (Han et al. 2001; Suzuki et al. 2000) regulating cytokine production, and activating the janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway through STAT-3 phosphorylation (Aaronson and Horvath 2002). Our results demonstrated that EVOO diet intake reduced significantly both MAPKs and STAT-3 activation. On the other hand, nuclear factor E2-related factor 2 (Nrf2) plays a central role for expression of heme oxigenase 1 (HO-1), antioxidant enzyme. Our data showed that HO-1 could represent a potential molecular target susceptible to EVOO modulation, since dietary EVOO treatment strongly augmented Nrf2 and HO-1 protein expression conferring a role of HO-1 in the beneficial effects of EVOO in this murine model of chronic inflammation. Altogether, our results confirm, for the first time, that EVOO intake dramatically attenuated the progression and severity of arthritis in CIA DBA/1 J mice through Nrf2/HO-1 upregulation and NF-κB, MAPKs and JAK-STAT signalling pathway inhibition, decreasing the inflammatory cascade induced by CIA.

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