Background and Purpose: Extracellular matrix (ECM) is mainly derived from activated hepatic stellate cells (HSC), and its excessive deposition is one of the characteristics of liver fibrosis. Monomer derivative of paeoniflorin (MDP) inhibits inflammatory responses. However, the role and fundamental mechanism of MDP in liver fibrosis was still unclear. Experimental Approach: The effect of MDP was evaluated on CCl4-induced C57BL/6J mice and TGF-β1-induced LX-2 cells. The level of SA-β-Gal was detected by SA-β-Gal kits. The cell cycle was evaluated by flow cytometry. The expression of p16, p21, α-SMA and Col. I proteins were analyzed by qRT-PCR, Western blots and immunofluorescence staining and IHC staining. The pathological changes of liver tissue were evaluated by histological analysis. Key Results: We demonstrated that MDP inhibited the progression of liver fibrosis in vivo and in vitro, concomitant with the elevated expression of Ago2, miR-708 and p53 as well as the downregulated expression of ZEB1. MDP could combined with Ago2. Upregulation of miR-708 and p53 and downregulation of ZEB1 increased the number of SA-β-Gal-positive HSCs and the expression levels of p16 and p21 as well as decreased the expression of α-SMA and Col. I in activated HSCs. Meanwhile, miR-708 directly targeted ZEB1, thus inhibiting the mRNA of ZEB1. ZEB1 could bind to the E‐box of p53 promoter and restrain its promoter activity as well as thus block the expression of p53. Conclusion and Implications: MDP could induce senescence of activated HSCs via regulating Ago2/miR-708/ZEB1/p53 aixs and may be applied to treat liver fibr

Background and purpose: To investigate the effect of hIgDFc-Ig (DG), a new biological agent that competitively binds to IgD receptors, on collagen-induced arthritis and its potential mechanism in regulating B cell antigen-receptor signaling pathway. Experimental approach: DBA1 mice were used to establish collagen-induced arthritis model, three doses of DG were administered by intraperitoneal injection. Clinical assessment of CIA, histopathological examination, flow cytometry, western blotting, immunofluorescence staining, protein chips and other methods were used to evaluate the therapeutic effects. The effects of DG on Daudi cells and IgαIgβ KO Ramos cells stimulated by IgD were also evaluated. Key results: We found that DG has a significant therapeutic effect on CIA mice. DG relieved the clinical assessment of CIA mice and improved the pathology of joints and spleen. In addition, DG can also regulate B cell subsets in the PBMC and spleen of CIA mice, and decrease the level of immunoglobulins. DG can inhibit the BCR signaling activation stimulated by IgD and effect the expression of transcription factors in vitro. In Ramos cells, Igβ or IgαIgβ knockout may reverse the activation of BCR signal pathway under the stimulation of IgD. Conclusion and Implications: DG may play a therapeutic role in CIA mice by regulating BCR-Lyn-Syk-NF-κB signaling pathway, and may be a new promising biological agent for rheumatoid arthritis.

Abstract Background and purpose: To investigate the effect of hIgDFc-Ig (DG), a new biological agent targets competition for binding to IgD receptors, on collagen-induced arthritis and its potential mechanism in regulating B cell antigen-receptor signaling pathway. Experimental approach: DBA1 mice were used to establish collagen-induced arthritis model, three doses DG were administered by intraperitoneal injection. Clinical assessment of CIA, histopathological examination, flow cytometry, western blotting, immunofluorescence staining, protein chips and so on were used to evaluated therapeutic effects. The competitive effects on BCR-NF-κB signaling pathway were also evaluated in Daudi cell lines in vitro. Key results: We found that DG has a obvious therapeutic effect on CIA mice. DG relieved the clinical assessment of CIA mice and improved the pathology of joints and spleen. In addition, regulated B cell subsets in the PBMC and spleen of CIA mice, and decreased level of immunoglobulins. DG can inhibit the over-activation of BCR signal by increasing p-Lyn level, Co-treatment with DG (0.1-10 μg·ml-1) dose-dependently down-regulated the BCR signaling and decreased the iteraction between Syk and Btk stimulated by IgD in Daudi cell. Conclusion and Implications: DG may play a therapeutic role in CIA mice by regulating BCR-Lyn-Syk-NF-KB signaling pathway, and may be a new promising biological agent for rheumatoid arthritis. Key words: hIgDFc-Ig; B cell antigen receptor; Collagen-induced arthritis; NF-κB signaling pathway