RESUMEN
Osteoarthritis (OA) is a degenerative joint disease characterized by destruction of articular cartilage. The inflammatory response is the most important factor affecting the disease process. As interleukin-1ß (IL-1ß) stimulates several key mediators in the inflammatory response, it plays a major role in the pathogenesis of OA. Maslinic acid (MA) is a natural compound distributed in olive fruit. Previous studies have found that maslinic acid has an inhibitory effect on inflammation, but its specific role in the progression of OA disease has not been studied so far. In this study, we aim to assess the protective effect of MA on OA progression by in vitro and in vivo experiments. Our results indicate that, in IL-1ß-induced inflammatory response, MA is effective in attenuating some major inflammatory mediators such as nitric oxide (NO) and prostaglandin E2, and inhibits the expression of IL-6, inducible nitric oxide synthase, cyclooxygenase-2, and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner. Also, MA downregulated the expression levels of thrombospondin motif 5 (ADAMTS5) and matrix metalloproteinase 13 in chondrocytes, resulting in reduced degradation of its extracellular matrix. Mechanistically, MA exhibits an anti-inflammatory effect by inactivating the PI3K/AKT/NF-κB pathway. In vivo, the protective effect of MA on OA development can be detected in a surgically induced mouse OA model. In summary, these findings suggest that MA can be used as a safe and effective potential OA therapeutic strategy.
Asunto(s)
Inflamación/prevención & control , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Triterpenos/uso terapéutico , Anciano , Animales , Supervivencia Celular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Condrocitos/patología , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Humanos , Inflamación/complicaciones , Interleucina-1beta/efectos adversos , Interleucina-6/metabolismo , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Inhibidor NF-kappaB alfa/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transporte de Proteínas/efectos de los fármacos , Proteolisis/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Triterpenos/química , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
AbstractObjective: To establish an acquired aplastic anemia animal model for investigating the function of T lymphocyte and the pathogenesis and treatment of aplastic anemia(AA). METHODS: To establish the acquired aplastic anemia mouse model through the X-ray irradiation in combination with lymphocytes injection. AA Group: the purified Pan T lymphocytes from the spleen of C57BL/6J mice were enriched and injected to the mice through tail vein(5×106), the CB6F1 mice were exposed to 3,4 and 5 Gy X-ray irradiation; TBI Group: the CB6F1 mice were exposed to 3,4 and 5 Gy X-ray irradiation, and were injected with the same volume of PBS buffer; Control group: the CB6F1 mice were only injected with the same volume of PBS buffer. The peripheral blood routine was examined and the number of nucleated cells in bone marrow were calculatedï¼the hematopoiesis changes in bone marrow was examinedï¼flow cytometry was used to examine the distribution of T lymphocytes in bone marrow, and it also used to examine the apoptosis of bone marrow cells and the differentiation of spleen T lymphocytes. RESULTS: Compared with 4, 5 Gy irradiated mice in AA groups, the survival time of 3 Gy irradiated AA groups was significantly prolonged. 3, 4 and 5 Gy X-ray irradiation combined with Pan T lymphocyte injection could successfully induced severe reduction of red blood cells, blood neutrophils, and platelets, severe reduction of bone marrow nucleated cells, severe bone marrow hematopoietic failure, and the significant expansion of T lymphocytes ratio in the bone marrow. CD4+ and CD8+ T cells were both increased, but mainly on CD8+ T cells, and could promote the differentiation of T cells from naïve T cells to effector memory T cells. CONCLUSION: 3, 4 and 5 Gy X-ray irradiation combined with 5×106 pan-T cell injection could successfully induce acquired aplastic anemia through T lymphocyte hyperfunction. Compared with 4, 5 Gy irradiated AA group, the 3 Gy irradiated AA group shows significantly longer survival time, and the peripheral blood routine profile closely resembles the clinical manifestations of AA patients.
Asunto(s)
Anemia Aplásica , Animales , Médula Ósea , Células de la Médula Ósea , Linfocitos T CD8-positivos , Humanos , Ratones , Ratones Endogámicos C57BLRESUMEN
Osteoarthritis (OA), defined as a long-term progressive joint disease, is characterized by cartilage impairment and erosion. In recent decades, magnolol, as a type of lignin extracted from Magnolia officinalis, has been proved to play a potent anti-inflammatory role in various diseases. The current research sought to examine the latent mechanism of magnolol and its protective role in alleviating the progress of OA in vivo as well as in vitro experimentations. In vitro, the over-production of Nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6), induced by interleukin-1 beta (IL-1ß), were all inhibited notably by magnolol in a concentration-dependent manner. Moreover, magnolol could also downregulate the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5). All these changes ultimately led to the deterioration of the extracellular matrix (ECM) induced by IL-1ß. Mechanistically, magnolol suppressed the activation of PI3K/Akt/NF-κB pathway. Furthermore, a powerful binding capacity between magnolol and PI3K was also revealed in our molecular docking research. In addition, magnolol-induced protective effects in OA development were also detected in a mouse model. In summary, this research suggested that magnolol possessed a new therapeutic potential for the development of OA.