Exosomal Osteoclast-Derived miRNA in Rheumatoid Arthritis: From Their Pathogenesis in Bone Erosion to New Therapeutic Approaches.

Rheumatoid arthritis (RA) is an autoimmune disease that causes inflammation, pain, and ultimately, bone erosion of the joints. The causes of this disease are multifactorial, including genetic factors, such as the presence of the human leukocyte antigen (HLA)-DRB1*04 variant, alterations in the microbiota, or immune factors including increased cytotoxic T lymphocytes (CTLs), neutrophils, or elevated M1 macrophages which, taken together, produce high levels of pro-inflammatory cytokines. In this review, we focused on the function exerted by osteoclasts on osteoblasts and other osteoclasts by means of the release of exosomal microRNAs (miRNAs). Based on a thorough revision, we classified these molecules into three categories according to their function: osteoclast inhibitors (miR-23a, miR-29b, and miR-214), osteoblast inhibitors (miR-22-3p, miR-26a, miR-27a, miR-29a, miR-125b, and miR-146a), and osteoblast enhancers (miR-20a, miR-34a, miR-96, miR-106a, miR-142, miR-199a, miR-324, and miR-486b). Finally, we analyzed potential therapeutic targets of these exosomal miRNAs, such as the use of antagomiRs, blockmiRs, agomiRs and competitive endogenous RNAs (ceRNAs), which are already being tested in murine and ex vivo models of RA. These strategies might have an important role in reestablishing the regulation of osteoclast and osteoblast differentiation making progress in the development of personalized medicine.

Analysis of Novel Immunological Biomarkers Related to Rheumatoid Arthritis Disease Severity.

Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are the most frequently used rheumatoid arthritis (RA) diagnostic markers, but they are unable to anticipate the patient's evolution or response to treatment. The aim of this study was to identify possible severity biomarkers to predict an upcoming flare-up or remission period. To address this objective, sera and anticoagulated blood samples were collected from healthy controls (HCs; n = 39) and from early RA (n = 10), flare-up (n = 5), and remission (n = 16) patients. We analyzed leukocyte phenotype markers, regulatory T cells, cell proliferation, and cytokine profiles. Flare-up patients showed increased percentages of cluster of differentiation (CD)3+CD4- lymphocytes (p < 0.01) and granulocytes (p < 0.05) but a decreased natural killer (NK)/T lymphocyte ratio (p < 0.05). Analysis of leukocyte markers by principal component analysis (PCA) and receiver operating characteristic (ROC) curves showed that CD45RO+ (p < 0.0001) and CD45RA+ (p < 0.0001) B lymphocyte expression can discriminate between HCs and early RA patients, while CD3+CD4- lymphocyte percentage (p < 0.0424) and CD45RA+ (p < 0.0424), CD62L+ (p < 0.0284), and CD11a+ (p < 0.0185) B lymphocyte expression can differentiate between flare-up and RA remission subjects. Thus, the combined study of these leukocyte surface markers could have potential as disease severity biomarkers for RA, whose fluctuations could be related to the development of the characteristic pro-inflammatory environment.

Dried apple enriched with mandarin juice counteracts tamoxifen-induced oxidative stress in rats.

The effect of a product made of dehydrated apples enriched with mandarin juice by vacuum impregnation on markers of oxidative stress (plasma antioxidant capacity, carbonyl groups (CGs), 8-hydroxydeoxyguanosine (8OHdG) and α-tocopherol) was tested in rats. Six groups of animals were studied: one group was fed a standard diet; two groups were supplemented with dehydrated apple either impregnated or not with mandarin juice throughout 28 days; and three groups (one unsupplemented and two supplemented) were additionally treated with tamoxifen (TAM) for 21 days used for induction of oxidative stress. The rats treated with TAM showed an increase in aminotransferases, CGs and 8OHdG. All of these effects were significantly decreased in the animals after apple snack consumption; the addition of mandarin juice into the apple mainly accounts for increased levels of α-tocopherol in plasma and liver. These findings suggest that the food product have a protective action against oxidative stress induced by TAM in rats.

Mandarin juice improves the antioxidant status of hypercholesterolemic children.

BACKGROUND: Oxidative stress has been linked to such degenerative diseases as atherosclerosis, and it has been suggested that increased dietary intake of antioxidants may reduce its progression. OBJECTIVE: To determine the effect of mandarin juice consumption on biomarkers related to oxidative stress in hypercholesterolemic children. MATERIALS AND METHODS: The diet of 48 children with plasma cholesterol >200 mg/dL and low-density lipoprotein cholesterol >130 mg/dL was supplemented for 28 days with 500 mL/day of pure (100%) mandarin juice (Citrus clementina Hort. ex Tan.). The composition of the mandarin juice was analyzed, and its antioxidant antiradical activity was evaluated in vitro. Malondialdehyde, carbonyl groups, vitamins E and C, erythrocyte-reduced glutathione, and plasma lipids were measured at the onset and at the end of the supplementation period. The paired Student t test was used to compare values before and after supplementation. RESULTS: Mandarin juice exerted a strong antioxidant effect mainly due to its high hydroxyl activity and, to a lesser extent, to its superoxide scavenger activity. At the end of the study, levels of the plasma biomarkers of oxidative stress were significantly decreased (malondialdehyde -7.4%, carbonyl groups -29.1%, P < 0.01), whereas the plasma antioxidants vitamin E and C (13.5%, P < 0.001 and 68.2%, P < 0.00001, respectively) and intraerythrocyte glutathione level (36.7%, P < 0.00001) were significantly increased. Plasma lipids and antibodies to oxidized low-density lipoproteins remained unchanged. CONCLUSIONS: Regular ingestion of mandarin juice significantly reduces plasma biomarkers of lipid and protein oxidation and enhances the antioxidant status of consumers.

Dried apples enriched with mandarin juice by vacuum impregnation improve antioxidant capacity and decrease inflammation in obese children.

BACKGROUND: A favorable effect over development of degenerative diseases is derived of an adecuate intake of fruit and vegetables, mainly due to their antioxidant compounds OBJECTIVES: The goal of this study was to test the effect in vivo over oxidant status and inflammation in obese children of a novel food product made of dried apples enriched with mandarin juice by vacuum impregnation. METHODS: A four-week intervention study was conducted in 41 obese children (> 2 standard deviation score-body mass index). Participants were instructed to follow their usual diet supplemented with 40 g/day of the developed product. Anthropometric parameters were determined including body mass index, waist circumference and estimations of body fat percentage using bioelectrical impedance. Dietary intake was assessed by questionnaire. Metabolic risk factors (blood pressure, lipid profile, glucose and insulin resistance) were recorded. To determine oxidant status, plasma total antioxidant capacity and 8-hydroxydeoxyguanosine, as marker of oxidative damage to DNA, were investigated. High-sensitive C-reactive protein, tumor necrosis factor-α, and interleukins 6 and 1-α were measured as inflammatory markers. Measurements were collected at baseline and at the end of the intervention period. RESULTS: Significant improvement in systolic blood pressure and lipid profile after intervention period was noted. A significant increase in the antioxidant capacity of plasma (ABTS and FRAP assays) and reductions in DNA oxidative damage and inflammatory markers were also found. CONCLUSION: Overall, adding the product to the diet contributes to ameliorate oxidant and inflammatory status in obese children and several risk factors for atherosclerosis.

Antecedentes: Una adecuada ingesta de vegetales previene el desarrollo de enfermedades degenerativas, principalmente debido a sus compuestos antioxidantes. Objetivo: Evaluamos el efecto in vivo en los niños obesos de un nuevo producto alimenticio hecho de manzanas deshidratadas enriquecidas con zumo de mandarina mediante impregnación a vacío. Métodos: Estudio prospectivo longitudinal de cuatro semanas de duración. Se estudiaron 41 niños obesos que suplementaron su dieta habitual con 40 g/día del producto desarrollado. Se determinaron parámetros antropométricos (índice de masa corporal, circunferencia de la cintura) y estimación de la de grasa corporal con impedancia bioeléctrica. La ingesta dietética se evaluó por cuestionario. Se registraron factores de riesgo metabólico (presión sanguínea, perfil lipídico, glucosa y resistencia insulínica). El estado oxidante se investigó mediante la capacidad antioxidante total del plasma y la 8-hydroxideoxiguanosina (marcador de daño oxidativo al ADN) y como marcadores de inflamación valoramos la proteína C-reactiva ultrasensible, el factor de necrosis tumoral-??y las interleukinas 6 y 1-?. Las mediciones se recogieron al inicio y al final del período de intervención. Resultados: Encontramos una mejoría significativa en la presión arterial sistólica y en el perfil lipídico después del período de intervención. Igualmente demostramos un aumento significativo de la capacidad antioxidante del plasma, una reducción del daño oxidativo del ADN y de los marcadores inflamatorios. Conclusión: La adición a la dieta del producto elaborado con manzana deshidratada, y enriquecido con zumo de mandarina mediante impregnación al vacío, contribuye a mejorar el estado oxidante e inflamatorio en los niños obesos, así como diversos factores de riesgo cardiometabólico.

Diet supplementation during early lactation with non-alcoholic beer increases the antioxidant properties of breastmilk and decreases the oxidative damage in breastfeeding mothers.

BACKGROUND: After delivery and birth, mothers and neonates are exposed to oxidative stress. We tested whether supplementing the diet of breastfeeding mothers with non-alcoholic beer, a product rich in antioxidants, could improve their oxidative status and the antioxidant content of their milk. A prospective trial begun on Day 2 postpartum was conducted in mother-infant dyads. SUBJECTS AND METHODS: Sixty breastfeeding mothers and their infants were allocated to either a control group (n=30) on a free diet or a study group (n=30) on a free diet supplemented with 660 mL of non-alcoholic beer/day. The oxidative status of the mothers' breastmilk, plasma, and urine and the infant's urine was analyzed on Days 2 and 30 postpartum. The before-after difference was compared within and between the groups. RESULTS: The increase in antioxidant capacity and coenzyme Q10 content in the breastmilk of the study group at Day 30 was higher than in that of the control group (p<0.001). There was also a change in the oxidative status of the mothers' plasma in the supplemented group regarding the control group; higher values of total antioxidant capacity (p<0.05) and lower levels of 8-hydroxydeoxyguanosine (p<0.05), indicative of DNA oxidative damage, were found. These results indicate a positive effect of non-alcoholic beer supplementation on oxidative stress in mothers. However, no difference in oxidant markers was found in the infant's urine. CONCLUSIONS: The consumption of non-alcoholic beer appears to enhance the antioxidant capacity of breastmilk and decrease oxidative damage in breastfeeding mothers.