CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

Zhang, Feng; Shu, Jin; Liu, Ying; Wu, Yu; Zhang, Xian Zheng; Han, Le; Tang, Xianfeng; Wang, Chen; Wang, Qingtong; Chen, Jing Yu; Cao, Yan; Wu, Hua; Zhang, Ling Ling; Wei, Wei

doi:10.3389/fphar.2017.00933

Cited by 24 publications

(14 citation statements)

References 55 publications

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“…The increase in the number of circulating B cells may be owing to the continuous activation of B cells (Lindenau et al, 2003). Previous studies by our team have found that abnormal activation of B cells does exist in RA patients (Zhang et al, 2017). This study showed that the percentage of CD19 + total B cells, CD19 + CD27 + memory B cells, and CD19 − CD27 + CD138 + plasma B cells, the levels of TNF-a, BAFF, laboratory parameters, and clinical indicators of RA patients all decreased after etanercept treatment.…”

Section: Discussionmentioning

confidence: 86%

“…Further, B cells produce receptor activator of NF-kB ligand (RANKL) near the osteoclast precursors and promote bone destruction in a RANKL dependent way within synovium ectopic lymphoid structures (Sun et al, 2018). A previous study of our research group proved that abnormal activation of B cells participates in the pathological process of RA (Zhang et al, 2017). B cell activating factor (BAFF) belongs to the tumor necrosis factor superfamily, which is a crucial factor for B cell survival and maturation (Shin et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

et al. 2020

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Objective: To explore the role of B cells in rheumatoid arthritis (RA) and the potential effects and mechanisms of etanercept on B cells. Methods: In RA patients, the levels of tumor necrosis factor-a (TNF-a) and B cell activating factor (BAFF) were detected by ELISA. The percentage of B cell subsets was measured by flow cytometry. Laboratory indicators (rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate) and clinical indicators (disease activity score in 28 joints, health assessment questionnaire score, swollen joint counts, tender joint counts) were measured. The correlation between B cell subsets and laboratory indicators or clinical indicators was analyzed. In mice, B cells proliferation was detected by CCK-8 kit. The expression of TNFRII and the percentage of B cell subsets in spleen were detected by flow cytometry. The expressions of TRAF2, p38, P-p38, p65, P-p65 in B cells were detected by WB. Results: The percentage of CD19 − CD27 + CD138 + plasma B cells was positively correlated with ESR or RF. Etanercept could decrease the percentage of CD19 + total B cells, CD19 + CD27 + memory B cells and CD19 − CD27 + CD138 + plasma B cells, reduce the levels of TNF-a, BAFF, relieve clinical and laboratory indicators in RA patients. In addition, etanercept could inhibit the proliferation of B cells, bate the differentiation of transitional B cells to mature B cells, down-regulate the expression of TNFRII, TRAF2, P-p38, P-p65 in B cells. Conclusion: B cells act a key role in the pathogenesis of RA. Etanercept inhibits B cells differentiation by down-regulating TNFRII/TRAF2/NF-kB signaling pathway.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

et al. 2020

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“…Our previous study found that CP-25 inhibited activated human B cells by regulating B-cell activating factor and TNF-α signaling. Compared with the effects of rituximab and etanercept, CP-25 showed modest activity, suggesting that CP-25 may provide a promising approach to the soft regulation of inflammation ( Zhang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

A Modified Compound From Paeoniflorin, CP-25, Suppressed Immune Responses and Synovium Inflammation in Collagen-Induced Arthritis Mice

Chen

Wang

et al. 2018

Front. Pharmacol.

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Paeoniflorin-6’-O-benzene sulfonate (CP-25) is a modified paeoniflorin, which is the main bioactive component of total glucosides of peony. This study evaluated the anti-inflammatory and immunoregulatory effects of CP-25 in mice with collagen-induced arthritis (CIA) and the potential mechanisms underlying these effects. After the onset of CIA, mice were given CP-25 (17.5, 35, or 70 mg/kg) or methotrexate (MTX, 2.0 mg/kg). The arthritis index, swollen joint count, and joint and spleen histopathology were evaluated. T and B cell subsets were assayed using flow cytometry, while the proliferation of these cells and fibroblast-like synoviocytes (FLSs) were evaluated using the Cell Counting Kit-8. β2-adrenoceptor (β2-AR) expression was assayed using flow cytometry, immunohistochemistry, and western blotting. FLS migration and invasion were assayed using Transwells. CP-25 (35 or 70 mg/kg) attenuated the arthritis index and swollen joint count, alleviated joint and spleen histopathology, suppressed excessive T cell activation, and attenuated humoral immunity in CIA mice. CP-25 increased β2-AR expression on T cells, B cells, dendritic cells, and the synovium in CIA mice. CP-25 up-regulated the β2-AR agonist response and attenuated FLS activation; these effects may reflect CP-25-mediated reduction of β2-AR desensitization due to down-regulation of membrane G protein-coupled receptor kinase 2 expression. These results suggest that CP-25 suppressed immune responses and synovium inflammation in mice with CIA, effects that were associated with reduced β2-AR desensitization and the promotion of β2-AR signaling.

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“…CP-25 is a derivative of the natural product paeoniflorin 130 , which is able to inhibit B-cell proliferation in a similar manner to rituximab (CD20 B-cell targeting antibody) and etanercept (TNF receptor chimera) and also downregulate the expression of BAFF-R on B cells. The mechanism of these effects is not reported 131 . It will be interesting to note the progression of this compound and ones with a similar mode of action.…”

Section: B Cell–activating Factor and Tumour Necrosis Factor Alpha Rementioning

confidence: 98%

Emerging small-molecule treatments for multiple sclerosis: focus on B cells

et al. 2019

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Multiple sclerosis (MS) is a major cause of disability in young adults. Following an unknown trigger (or triggers), the immune system attacks the myelin sheath surrounding axons, leading to progressive nerve cell death. Antibodies and small-molecule drugs directed against B cells have demonstrated good efficacy in slowing progression of the disease. This review focusses on small-molecule drugs that can affect B-cell biology and may have utility in disease management. The risk genes for MS are examined from the drug target perspective. Existing small-molecule therapies for MS with B-cell actions together with new drugs in development are described. The potential for experimental molecules with B-cell effects is also considered. Small molecules can have diverse actions on B cells and be cytotoxic, anti-inflammatory and anti-viral. The current B cell–directed therapies often kill B-cell subsets, which can be effective but lead to side effects and toxicity. A deeper understanding of B-cell biology and the effect on MS disease should lead to new drugs with better selectivity, efficacy, and an improved safety profile. Small-molecule drugs, once the patent term has expired, provide a uniquely sustainable form of healthcare.

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CP-25, a Novel Anti-inflammatory and Immunomodulatory Drug, Inhibits the Functions of Activated Human B Cells through Regulating BAFF and TNF-alpha Signaling and Comparative Efficacy with Biological Agents

Cited by 24 publications

References 55 publications

Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

Etanercept Inhibits B Cell Differentiation by Regulating TNFRII/TRAF2/NF-κB Signaling Pathway in Rheumatoid Arthritis

A Modified Compound From Paeoniflorin, CP-25, Suppressed Immune Responses and Synovium Inflammation in Collagen-Induced Arthritis Mice

Emerging small-molecule treatments for multiple sclerosis: focus on B cells

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