Skeletal muscle atrophy is a common phenomenon during the prolonged muscle disuse caused by cast immobilization, extended aging states, bed rest, space flight, or other factors. However, the cellular mechanisms of the atrophic process are poorly understood. In this study, we investigated the involvement of mitogen-activated protein kinase (MAPK) in the expression of muscle-specific RING finger 1 (MuRF1) during atrophy of the rat gastrocnemius muscle. Histological analysis revealed that cast immobilization induced the atrophy of the gastrocnemius muscle, with diminution of muscle weight and cross-sectional area after 14 days. Cast immobilization significantly elevated the expression of MuRF1 and the phosphorylation of p38 MAPK. The starvation of L6 rat skeletal myoblasts under serum-free conditions induced the phosphorylation of p38 MAPK and the characteristics typical of cast-immobilized gastrocnemius muscle. The expression of MuRF1 was also elevated in serum-starved L6 myoblasts, but was significantly attenuated by SB203580, an inhibitor of p38 MAPK. Changes in the sizes of L6 myoblasts in response to starvation were also reversed by their transfection with MuRF1 small interfering RNA or treatment with SB203580. From these results, we suggest that the expression of MuRF1 in cast-immobilized atrophy is regulated by p38 MAPK in rat gastrocnemius muscles.

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR ( < 0.001) and SKOV3-TR ( < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone ( < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma. These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. .

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Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-α, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-α-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT-PCR and luciferase promoter assay. When MH7A cells were treated with TNF-α, we observed that TNF-α increased the expression of hBAFF and hVEGF. TNF-α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-α. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-α-induced BAFF expression through c-Fos. Data suggest that TNF-α-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments.