BackgroundThe up-regulation of CCAAT/enhancer binding protein delta (CEBPD) has frequently been observed in macrophages in age-associated disorders, including rheumatoid arthritis (RA). However, the role of macrophage CEBPD in the pathogenesis of RA is unclear.Methodology and Principal FindingsWe found that the collagen-induced arthritis (CIA) score and the number of affected paws in Cebpd−/− mice were significantly decreased compared with the wild-type (WT) mice. The histological analysis revealed an attenuated CIA in Cebpd−/− mice, as shown by reduced pannus formation and greater integrity of joint architecture in affected paws of Cebpd−/− mice compared with WT mice. In addition, immunohistochemistry analysis revealed decreased pannus proliferation and angiogenesis in Cebpd−/− mice compared with WT mice. CEBPD activated in macrophages played a functional role in promoting the tube formation of endothelial cells and the migration and proliferation of synoviocytes. In vivo DNA binding assays and reporter assays showed that CEBPD up-regulated CCL20, CXCL1, IL23A and TNFAIP6 transcripts through direct binding to their promoter regions. CCL20, IL23A, CXCL1 and TNFAIP6 contributed to the migration and proliferation of synoviocytes, and the latter two proteins were involved in tube formation of endothelial cells. Finally, two anti-inflammatory chemicals, inotilone and rosmanol, reduced the expression of CEBPD and its downstream targets and mitigated the above phenomena.Conclusions and SignificanceCollectively, our findings suggest that CEBPD and its downstream effectors could be biomarkers for the diagnosis of RA and potentially serve as therapeutic targets for RA therapy.

s u m m a r yObjectives: To investigate the association of ultrasound (US) features with pain and the functional scores in patients with equal radiographic grades of osteoarthritis (OA) in both knees. Methods: Fifty-six consecutive patients with knee OA: 85 symptomatic knees (81 knees with medial pain) and 27 asymptomatic knees, and 10 healthy patients without knee OA as a control were enrolled. US was done by two ultrasonographers blinded to patient diagnoses. US features were semiquantitatively scored (0e3) when appropriate. Results: In the OA group, common US findings were marginal osteophyte, suprapatellar synovitis, suprapatellar effusion (SPE), medial meniscus protrusion, medial compartment synovitis (MCS), lateral compartment synovitis, and Baker's cyst. Only SPE and MCS were significantly associated with knee pain. Visual analog pain scale (VAS) scores on motion were positively linearly associated with SPE and MCS (P < 0.01). Only MCS was degree-dependently associated with VAS scores at rest, the Western Ontario and McMaster Universities pain subscale, and the presence of medial knee pain (P < 0.01) after adjustments for age, gender, body mass index (BMI), radiographic grade, and other US features. In the control group, no US features were associated with knee pain. Conclusions: US inflammation features, including SPE and MCS, were positively linearly associated with knee pain in motion. MCS was also degree-dependently associated with pain at rest and the presence of medial knee pain. These findings show that synovitis was one important predictive factor of pain. Further studies to confirm the association of US features and pain are warranted.

Methylene blue (MB) is a widely used dye and photodynamic therapy (PDT) agent that can produce reactive oxygen species (ROS) after light exposure, triggering apoptosis. However, it is hard for the dye to penetrate through the cell membrane, leading to poor cellular uptake; thus, drug carriers, which could enhance the cellular uptake, are a suitable solution. In addition, the defective vessels resulting from fast vessel outgrowth leads to an enhanced permeability and retention (EPR) effect, which gives nanoscale drug carriers a promising potential. In this study, we applied poly(12-(methacryloyloxy)dodecyl phosphorylcholine), a zwitterionic polymer-lipid, to self-assemble into liposomes and encapsulate MB (MB-liposome). Its properties of high stability and fast intracellular uptake were confirmed, and the higher in vitro ROS generation ability of MB-liposomes than that of free MB was also verified. For in vivo tests, we examined the toxicity in mice via tail vein injection. With the features found, MB-liposome has the potential of being an effective PDT nano agent for cancer therapy.

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