Psoriasis is chronic inflammatory skin disease mediated by interactions between Th17 cells and keratinocytes that lead to excessive proliferation of keratinocytes, suggesting that anti-inflammatory and anti-proliferation molecules may be effective for the treatment. Paeoniflorin-6'-O-benesulfonic acid (CP-25), an esterified modifier of paeoniflorin, has exhibited potent anti-inflammatory and immunomodulatory properties in arthritis animal models and experimental Sjögren's syndrome. However, the involvement of CP-25 and its target G protein-coupled receptor kinase 2 (GRK2) in the development of psoriasis has not been explored. In this study, we found that GRK2 expression was abnormally elevated in the skin tissues of both psoriasis patients and imiquimod-induced psoriasis model mice. Furthermore, its inhibitor CP-25 reduced skin damage and systemic inflammation in model mice. Mechanically, CP-25 inhibited GRK2 translocation to the cytomembrane, thus decreasing colocalization of GRK2 and the βγ subunit of G protein (Gβγ), increasing colocalization of GRK2 with Janus kinase 1 (JAK1), and downregulating the JAK1-signal transduction and activator of transcription (STAT3) signaling pathway to reduce the hyperproliferation of keratinocytes, besides, CP-25-mediated inhibition of GRK2 translocation to the cytomembrane involved the GRK2 amino acid alanine 321 in keratinocytes. Our findings indicate that targeting GRK2 with CP-25 is a promising treatment for psoriasis.

2025-01-27·International Journal of Biological Sciences

Inhibition of GRK2-PDE4D Axis Suppresses Fibroblast-Like Synoviocytes Hyperplasia and Alleviates Experimental Arthritis

Article

作者: Ma, Yang ; Sun, Hanfei ; Li, Rui ; Ge, Hui ; Zhang, Renhao ; He, Shufang ; Han, Yongsheng ; Chu, Rui ; Wang, Qingtong ; Han, Dafei ; Tu, Jiajie ; Wei, Wei ; Fang, Ruhong ; Guo, Paipai

PDE4D has been reported to exhibit significantly elevated levels in the synovium of RA patients compared with OA, yet its role in RA remains underexplored. This study aimed to elucidate the role of the GRK2-PDE4D axis in FLSs and explore its potential as a therapeutic target for RA. Abundant expression of both PDE4D and GRK2 was observed in synovial tissues from both experimental arthritis animals and RA patients, with synchronized expression noted in RA patients. Global deletion of Pde4d reduced disease incidence and alleviated arthritis in CIA mice. TNF-α upregulated PDE4D expression, causing abnormal FLSs activation and hyperproliferation. Inhibiting PDE4D restored cAMP levels, thereby reducing FLSs hyperproliferation, migration, and anti-apoptosis. Mechanistically, TNF-α-induced PDE4D upregulation was dependent on GRK2. Inhibition of GRK2 with CP-25, an esterification modification of paeoniflorin, reduced PDE4D expression and FLSs proliferation, while restoring cAMP levels. Both genetic deficiency and pharmacological inhibition of GRK2 decreased PDE4D expression, ameliorating arthritis severity in animal models. This is the first study to investigate the role of PDE4D in RA and to clarify that it can be regulated by GRK2. These findings suggest that targeting the GRK2-PDE4D axis represents a promising therapeutic strategy for RA.

2024-09-01·INTERNATIONAL IMMUNOPHARMACOLOGY

Inhibition of GRK2 ameliorates the pristane-induced mouse SLE model by suppressing plasma cells differentiation

Article

作者: Jiang, Chunru ; Chu, Rui ; Zhang, Renhao ; Ge, Hui ; Yan, Shangxue ; Wang, Qingtong ; Wang, Mingzhu ; Han, Dafei ; Xu, Huihui ; Fang, Ruhong ; Wei, Wei ; Lu, Meiyue ; Tai, Yu

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by diverse clinical manifestations and organ damage. Despite its elusive etiology, dysregulated subsets and functions of B cells are pivotal in SLE pathogenesis. Peoniflorin-6'-O-benzene sulfonate (CP-25), an esterification modification of Paeoniflorin, exhibits potent anti-inflammatory and immunomodulatory properties in autoimmune diseases (AID). However, the involvement of CP-25 and its target, GRK2, in SLE development has not been explored. In this study, we demonstrate that both genetic deficiency and pharmacological inhibition of GRK2 attenuate autoantibodies production, reduce systemic inflammation, and mitigate histopathological alterations in the spleen and kidney in the pristane-induced mouse SLE model. Importantly, our findings highlight that both genetic deficiency and pharmacological inhibition of GRK2 suppress plasma cells generation and restore dysregulated B-cell subsets by modulating two crucial transcription factors, Blimp1 and IRF4. Collectively, targeting GRK2 with CP-25 emerges as a promising therapeutic approach for SLE.

100 项与 CP-25 相关的药物交易

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