Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases

Iridoids, which have beneficial health properties, include a wide group of cyclopentane [c] pyran monoterpenoids present in plants and insects. The cleavage of the cyclopentane ring leads to secoiridoids. Mainly, secoiridoids have shown a variety of pharmacological effects including anti-diabetic, antioxidant, anti-inflammatory, immunosuppressive, neuroprotective, anti-cancer, and anti-obesity, which increase the interest of studying these types of bioactive compounds in depth. Secoiridoids are thoroughly distributed in several families of plants such as Oleaceae, Valerianaceae, Gentianaceae and Pedialaceae, among others. Specifically, Olea europaea L. (Oleaceae) is rich in oleuropein (OL), dimethyl-OL, and ligstroside secoiridoids, and their hydrolysis derivatives are mostly OL-aglycone, oleocanthal (OLE), oleacein (OLA), elenolate, oleoside-11-methyl ester, elenoic acid, hydroxytyrosol (HTy), and tyrosol (Ty). These compounds have proved their efficacy in the management of diabetes, cardiovascular and neurodegenerative disorders, cancer, and viral and microbial infections. Particularly, the antioxidant, anti-inflammatory, and immunomodulatory properties of secoiridoids from the olive tree (Olea europaea L. (Oleaceae)) have been suggested as a potential application in a large number of inflammatory and reactive oxygen species (ROS)-mediated diseases. Thus, the purpose of this review is to summarize recent advances in the protective role of secoiridoids derived from the olive tree (preclinical studies and clinical trials) in diseases with an important pathogenic contribution of oxidative and peroxidative stress and damage, focusing on their plausible mechanisms of the action involved.España Ministerio de Economía y Competitivida

Extra-virgin olive oil and its phenolic extract prevent inflammatory response and joint damage in murine experimental arthritis

he consumption of EVOO in Mediterranean countries has shown beneficial effects. A wide range of evidence indicates that the phenolic compounds present in EVOO are endowed with anti-inflammatory properties. In this work, we evaluated the effects of dietary EVOO and treatment with its phenolic extract (PE) in a model of RA, the collagen-induced arthritis (CIA) in mice. On day 0, DBA-1/J mice were immunized with bovine collagen type II (CII). On day 21, the mice received a booster injection. We have demonstrated that EVOO and its PE decreases joint edema, cell migration, cartilage degradation and bone erosion. Our data indicate that dietary EVOO and PE treatment inhibit JNK, p38 and signal transducer and STAT-3. In addition, both EVOO and PE decrease NF-κB translocation leading to the down-regulation of the arthritic process. These results support the interest of natural diet components in the development of therapeutic products for arthritic conditions.El aceite de oliva extra virgen y su fracción polifenólica previenen la respuesta inflamatoria y el daño articular en un modelo de artritis experimental en murino. El consumo de Aceite de oliva virgen extra (AOVE) en los países mediterráneos ha demostrado tener efectos beneficiosos. Una amplia gama de pruebas indica que los compuestos fenólicos presentes en el AOVE tienen propiedades anti-inflamatorias. En este trabajo, se evaluaron los efectos de AOVE y el tratamiento en dieta de su fracción polifenólica (FP) en un modelo de la artritis reumatoide inducida por colágeno (CIA) en ratones. En el día 0, los ratones DBA-1/J se inmunizaron con colágeno bovino tipo II (CII). En el día 21, los ratones recibieron una inyección de refuerzo. Hemos demostrado que el AOVE y su FP disminuyen conjuntamente el edema, la migración celular, la degradación del cartílago y erosión ósea. Nuestros datos indican que la dieta con AOVE y el tratamiento con FP inhiben JNK, p38 y el transductor de señal y activador de la transcripción 3 (STAT-3). Además, tanto el AOVE como la FP disminuyen la translocación NF- κB que conduce a la mejora del proceso artrítico. Estos resultados apoyan el interés de una dieta con componentes naturales y el desarrollo de productos terapéuticos para desordenes artríticos.Ministerio de Economia y Competitividad AGL 2011-26949Junta de Andalucía P-10AGR-660

Epigenetic linkage of systemic lupus erythematosus and nutrition

The term “epigenetics” refers to a series of meiotically/mitotically inheritable alterations in gene expression, related to environmental factors, without disruption on DNA sequences of bases. Recently, the pathophysiology of autoimmune diseases (ADs) has been closely linked to epigenetic modifications. Actually, epigenetic mechanisms can modulate gene expression or repression of targeted cells and tissues involved in autoimmune/inflammatory conditions acting as keys effectors in regulation of adaptive and innate responses. ADs, as systemic lupus erythematosus (SLE), a rare disease that still lacks effective treatment, is characterized by epigenetic marks in affected cells. Taking into account that epigenetic mechanisms have been proposed as a winning strategy in the search of new more specific and personalized therapeutics agents. Thus, pharmacology and pharmacoepigenetic studies about epigenetic regulations of ADs may provide novel individualized therapies. Focussing in possible implicated factors on development and predisposition of SLE, diet is feasibly one of the most important factors since it is linked directly to epigenetic alterations and these epigenetic changes may augment or diminish the risk of SLE. Nevertheless, several studies have guaranteed that dietary therapy could be a promise to SLE patients via prophylactic actions deprived of side effects of pharmacology, decreasing comorbidities and improving lifestyle of SLE sufferers. Herein, we review and discuss the cross-link between epigenetic mechanisms on SLE predisposition and development, as well as the influence of dietary factors on regulation epigenetic modifications that would eventually make a positive impact on SLE patients.Ministerio de Economía y Competitividad AG2017-89342-

Protective effect of ellagic acid, a natural polyphenolic compound, in a murine model of Crohn’s disease

Current epidemiological and experimental studies support a beneficial role of dietary polyphenols in several gastrointestinal diseases, including inflammatory bowel disease. The aim of this study was to gain a better understanding of the effects of a naturally occurring polyphenol, ellagic acid, present in some fruits such as pomegranate, raspberries and nuts among others, in an experimental murine model of Crohn's disease by intra-colonic administration of TNBS in rats. Analysis of the lesions were carried out by macroscopic and histological technics. Inflammation response was assessed by histology and myeloperoxidase activity. iNOS and COX-2 are upregulated by MAPKs and NF-κB nuclear transcription factor in intestinal epithelial cells thus, we determined the expression of iNOS, COX-2 and the involvement of the p38, JNK, ERK1/2 MAPKs and NF-κB signalling in the protective effect of EA by western blotting. Oral administration of EA (10–20 mg/kg) diminished the severity and extension of the intestinal injuries induced by TNBS although there was no observed a significant dose–response. In addition, EA increased mucus production in goblet cells in colon mucosa, decreased neutrophil infiltration and pro-inflammatory proteins COX-2 and iNOS overexpression. Also EA was capable of reducing the activation of p38, JNK and ERK1/2 MAPKs, preventing the inhibitory protein IκB-degradation and inducing an inhibition of the nuclear translocation level of p65 in colonic mucosa. In conclusion, EA reduces the damage in a rat model of Crohn's disease, alleviates the oxidative events and returns pro-inflammatory proteins expression to basal levels probably through MAPKs and NF-κB signalling pathways.Junta de Andalucía y Ministerio de Ciencia e Innovación de España AGL 2008-0247

Extra virgin olive oil polyphenolic extracts downregulate inflammatory responses in LPS-activated murine peritoneal macrophages suppressing NFκB and MAPK signalling pathways

Extra virgin olive oil (EVOO) is obtained from the fruit of the olive tree Olea europaea L. Phenolic compounds present in EVOO have recognized anti-oxidant and anti-inflammatory properties. However, the activity of the total phenolic fraction extracted from EVOO and the action mechanisms involved are not well defined. The present study was designed to evaluate the potential anti-inflammatory mechanisms of the polyphenolic extract (PE) from EVOO on LPS-stimulated peritoneal murine macrophages. Nitric oxide (NO) production was analyzed by the Griess method and intracellular reactive oxygen species (ROS) by fluorescence analysis. Moreover, changes in the protein expression of the pro-inflammatory enzymes, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1), as well as the role of nuclear transcription factor kappa B (NFκB) and mitogen-activated protein kinase (MAPK) signalling pathways, were analyzed by Western blot. PE from EVOO reduced LPS-induced oxidative stress and inflammatory responses through decreasing NO and ROS generation. In addition, PE induced a significant down-regulation of iNOS, COX-2 and mPGES-1 protein expressions, reduced MAPK phosphorylation and prevented the nuclear NFκB translocation. This study establishes that PE from EVOO possesses anti-inflammatory activities on LPS-stimulated murine macrophages.Ministerio de Ciencia e Innovación AGL 2008-02475Ministerio de Ciencia e Innovación AGL 2011-26949Junta de Andalucía P-10AGR-6609Ministerio de Economía y Competitividad INNCORPORA-PT

Remdesivir y reducción de mortalidad en pacientes con COVID-19: análisis sistematizado de subgrupos de los ensayos clínicos

Objective: Remdesivir has not shown survival benefit for patients with severe COVID-19. However, subgroup analysis of ACTT-1 Study Group showed an apparent reduction in mortality for patients who required non-high-flow oxygen. Presentation of SOLIDARITY study results were associated by a meta-analysis combining mortality results by subsets from randomized clinical trials. The aim is a methodological assessment of reliability and clinical applicability about findings by subgroups on the effect of remdesivir on mortality in patients with COVID-19. Method: A validated tool was used to evaluate the findings of subgroup analyses in randomized clinical trials, including meta-analysis attached to SOLIDARITY study. It is structured in preliminary questions to reject subset analyses without relevant minimum conditions, and a specific checklist. The latter considers certain criteria: statistical association, which encompassed p of interaction, prespecification of subgroups, sample size, number of factors analyzed, and overall study result; biological plausibility of observed differences; and consistency between results of similar studies. A score was assigned to each criterion and the tool related global summation to a recommendation on the applicability of subset results in clinical decision making. Results: Preliminary questions had positive answers, so checklist was applied. Statistical association obtained “null” assessment (–3 points), including a “doubtful” p of interaction (p = 0.0650) among subgroups and mortality reached no statistical significance for global population. These findings reduced the reliability of subset analysis. Biological plausibility was considered “probable” (+3 points) because antiviral could have a greater effect before the inflammatory process and clinical worsening. Consistency between results of similar studies was evaluated as “possible” (+2 points) analysis for compatibility of ACTT-1 and SOLIDARITY study results. The recommendation about application of subset analysis results according to the risk of patients was “null”. Conclusions: This structured interpretation of subgroup analysis suggested too much uncertainty in hypothesis about remdesivir could reduce mortality in patients with severe COVID-19 who required non-high-flow oxygen. It was probably a random finding. Therefore, a randomized clinical trial about effect of remdesivir in mortality in patients with COVID-19 and non-high-flow oxygen is essential.Objetivo: Remdesivir no ha mostrado beneficio en supervivencia para pacientes con COVID-19 grave. Sin embargo, el análisis por subgrupos del estudio ACTT-1 mostró aparente reducción de mortalidad en pacientes que requerían oxígeno –no de alto flujo–. La difusión de resultados del estudio SOLIDARITY se acompañó de un metaanálisis que combinó resultados de mortalidad por subgrupos de los ensayos clínicos aleatorizados. El objetivo del presente estudio es analizar metodológicamente la fiabilidad y aplicabilidad clínica de los hallazgos por subgrupos sobre el efecto de remdesivir en mortalidad en pacientes con COVID-19. Método: Se usó una herramienta validada para valorar los hallazgos de los análisis por subgrupos en ensayos clínicos aleatorizados, incluido el metaanálisis anexo al estudio SOLIDARITY. La herramienta utilizada está estructurada en cuestiones preliminares para descartar análisis por subgrupos sin condiciones mínimas relevantes, y un cuestionario específico. Este último considera determinados criterios: asociación estadística, incluyendo p de interacción, preespecificación de subgrupos, tamaño muestral, número de factores valorados y resultado global del estudio; plausibilidad biológica de las diferencias observadas; y consistencia entre resultados de estudios similares. Se asignó una puntuación a cada criterio y la herramienta relacionó el sumatorio global con una recomendación sobre la aplicabilidad de los resultados de los subgrupos en la toma de decisiones clínicas. Resultados: Las cuestiones preliminares tuvieron respuestas positivas, aplicándose el cuestionario. La asociación estadística obtuvo valoración “nula” (–3 puntos), con p de interacción dudosa (p = 0,0650) y resultado de mortalidad no significativo en población global, restando fiabilidad al análisis de subgrupos. La plausibilidad biológica fue considerada “probable” (+3 puntos), ya que el antiviral pudiera tener mayor efecto antes del proceso inflamatorio y empeoramiento clínico. La consistencia se valoró “posible” (+2 puntos) por compatibilidad de resultados del estudio ACTT-1 y SOLIDARITY. La recomendación de aplicación del análisis por subgrupos según el riesgo de los pacientes fue “nula”. Conclusiones: Esta interpretación estructurada de análisis por subgrupos sugiere que la hipótesis de que remdesivir podría reducir la mortalidad en pacientes con COVID-19 grave que precisan oxígeno –no de alto flujo– presenta demasiada incertidumbre, y es probable que sea un hallazgo casual. Por tanto, es imprescindible la realización de un ensayo clínico aleatorizado sobre mortalidad en pacientes con oxígeno –no de alto flujo–

Economic evaluation and budgetary burden of mepolizumab in severe refractory eosinophilic asthma

Objetivo: Mepolizumab está indicado como tratamiento adicional del asma eosinofílica refractaria grave. Las diferencias observadas en subgrupos poblacionales según recuento eosinofílico plasmático, existencia de pacientes con altos niveles de inmunoglobulina E candidatos a omalizumab y mepolizumab, e impacto económico de mepolizumab obligan a realizar estudios económicos para tomar decisiones clínicas eficientes. El objetivo fue realizar un análisis de coste/eficacia e impacto presupuestario de mepolizumab. Método: Se realizó la comparación de costes e impacto presupuestario del uso de mepolizumab desde la perspectiva del Sistema Nacional de Salud. Las alternativas valoradas fueron corticosteroides sistémicos inhalados + agonista β2 de larga duración y/o corticosteroides sistémicos orales en pacientes con asma alérgica grave no mediada por inmunoglobulina E, y este tratamiento junto a omalizumab en pacientes con asma eosinofílica alérgica mediada por inmunoglobulina E. La eficacia se evaluó mediante exacerbaciones clínicamente relevantes evitadas. Se valoraron los costes directos asociados a exacerbación. Resultados: El coste incremental medio de mepolizumab respecto a omalizumab es de 797 euros por paciente y año. Considerando precio alternativo con descuento de omalizumab, incluir mepolizumab para pa cientes con asma eosinofílica alérgica y mediada por inmunoglobulina E supondría incrementar el gasto público de 2,3 a 4,6 millones de euros. Teniendo en cuenta el precio notificado de omalizumab, la introducción gradual de mepolizumab en el Sistema Nacional de Salud supondría ahorrar 3,6 millones de euros en tres años. Para pacientes con asma grave no mediada por inmunoglobulina E, el coste/exacerbación evitada al añadir mepolizumab es de 15.085 euros, con un impacto presupuestario en tres años de 578,4 millones de euros, asumiendo una penetración progresiva de mepolizumab en el mercado. En los pacientes con ≥500 eosinófilos/µl, este coste disminuye a 7.767 euros por exacerbación evitada, con un impacto presupuestario de 183,2 millones de euros en tres años con penetración progresiva de mepolizumab. Conclusiones: La comparación de costes entre mepolizumab y omalizumab en pacientes con asma eosinofílica mediada por inmunoglobulina E señala como razonable utilizar el fármaco de menor coste, promoviendo competencia de precios. Asimismo, priorizar su uso en pacientes con asma eosinofílica refractaria grave no mediada por inmunoglobulina E y niveles plasmáticos ≥500 eosinófilos/µl permitiría mejorar la eficiencia y disminuir el impacto presupuestario.Objective: Mepolizumab is indicated as additional treatment of severe refractory eosinophilic asthma. Differences in subgroups according to plasmatic eosinophil count, existence of patients with high levels of immunoglobulin E candidates for omalizumab and mepolizumab, and budget impact of mepolizumab require economic studies for efficient clinical decisions. The objective was to perform a cost-efficacy and budget impact analysis of mepolizumab. Method: An analysis of comparison of costs and budgetary impact of use of mepolizumab has been performed from National Health System perspective. Evaluated alternatives were inhaled systemic corticosteroids + long-acting β2-agonist and/or oral systemic corticosteroids in patients with severe allergic asthma not mediated by immunoglobulin E, and the same treatment associated with omalizumab in patients with immunoglobulin E-mediated allergic eosinophilic asthma. Efficacy was assessed by clinically relevant exacerbations avoided. Direct costs associated with exacerbation were assessed Results: An average incremental cost of 797 euros/patient-year was estimated. Considering alternative price with discount for omalizumab, including mepolizumab for patients with immunoglobulin E-mediated allergic eosinophilic asthma would increase public spending from 2.3 to 4.6 million euros. According reported price for omalizumab, gradual introduction of mepolizumab into the National Health System would save 3.6 million euros in three years. For patients with immunoglobulin E-not mediated severe asthma, adding mepolizumab presented a cost/exacerbation avoided of 15,085 euros and a budgetary impact for three years of 578.4 million euros according a progressive penetration of mepolizumab in market. In patients with ≥ 500 eosinophils/μL, cost/exacerbation avoided is reduced to 7,767 euros and the budgetary impact is 183.2 million euros in three years according progressive penetration of mepolizumab. Conclusions: With analysis of cost comparison of mepolizumab vs. omalizumab in patients with eosinophilic immunoglobulin E-mediated asthma, it would be reasonable to prioritize the drug more economic to promote price competition. According this pharmacoeconomic study, prioritizing mepolizumab in patients with immunoglobulin E-not mediated severe refractory eosinophilic asthma and higher plasmatic eosinophil count (≥500 eosinophils/μL) would improve efficiency and decrease budgetary impac

Immunomodulatory Effects of (R)-Sulforaphane on LPS-Activated Murine Immune Cells: Molecular Signaling Pathways and Epigenetic Changes in Histone Markers

The aim of this study was to explore the immunomodulatory effects of the natural enantiomer (R)-Sulforaphane (SFN) and the possible signaling pathways involved in an ex vivo model of LPS-stimulated murine peritoneal macrophages. Furthermore, we studied the epigenetic changes induced by (R)-SFN as well as the post-translational modifications of histone H3 (H3K9me3 and H3K18ac) in relation to the production of cytokines in murine splenocytes after LPS stimulation. (R)-SFN was able to modulate the inflammatory response and oxidative stress induced by LPS stimulation in murine peritoneal macrophages through the inhibition of reactive oxygen species (ROS), nitric oxide (NO) and cytokine (IL-1β, IL-6, IL-17, IL-18 and TNF-α) production by down-regulating the expression of pro-inflammatory enzymes (iNOS, COX-2 and mPGES-1). We also found that activation of the Nrf-2/HO-1 axis and inhibition of the JAK2/STAT-3, MAPK, canonical and non-canonical inflammasome signaling pathways could have been responsible for the immunomodulatory effects of (R)-SFN. Furthermore, (R)-SFN modulated epigenetic modifications through histone methylation (H3K9me3) and deacetylation (H3K18ac) in LPS-activated spleen cells. Collectively, our results suggest that (R)-SFN could be a promising epinutraceutical compound for the management of immunoinflammatory diseases.Ministerio de Ciencia, Innovación y Universidades PID2019-104767RB-I00/AEI/10.13039/501100011033Junta de Andalucía 2021/CTS-259, CTS-259, P20-0117, FQM-10