peoniflorin and Sjogren-s-Syndrome

Total glycoside of paeony (TGP) has been widely used to treat inflammation and immune diseases in China. Paeoniflorin (Pae) is the major active component of TGP. Although TGP has few adverse drug reactions, the slow onset and low bioavailability of Pae limit its clinical use. Enhanced efficacy without increased toxicity is pursued in developing new agents for inflammation and immune diseases. As a result, paeoniflorin-6'-O-benzene sulfonate (CP-25) derived from Pae, is developed in our group, and exhibits superior bioavailability and efficacy than Pae. Here we describe the development process and research advance on CP-25. The pharmacokinetic parameters of CP-25 and Pae were compared in vivo and in vitro. CP-25 was also compared with the first-line drugs methotrexate, leflunomide, and hydroxychloroquine in their efficacy and adverse effects in arthritis animal models and experimental Sjögren's syndrome. We summarize the regulatory effects of CP-25 on inflammation and immune-related cells, elucidate the possible mechanisms, and analyze the therapeutic prospects of CP-25 in inflammation and immune diseases, as well as the diseases related to its potential target G-protein-coupled receptor kinases 2 (GRK2). This review suggests that CP-25 is a promising agent in the treatment of inflammation and immune diseases, which requires extensive investigation in the future. Meanwhile, this review provides new ideas about the development of anti-inflammatory immune drugs.

Topics: Animals; Anti-Inflammatory Agents; Cell Line, Tumor; Glucosides; Humans; Immunologic Factors; Inflammation; Lymphocytes; Mononuclear Phagocyte System; Monoterpenes; Sjogren's Syndrome

Paeoniflorin (PF), an active compound extracted from Paeony root, has been used in therapy of autoimmune diseases with effective clinical efficiency and higher safety. Sjogren's syndrome (SS) is a chronic, systemic, immune-mediated inflammatory disease. In this study, we demonstrated that novel pro-inflammatory factor Cyr61/CCN1 was up-regulated in epithelial cells of salivary glands of primary SS patients and submandibular gland autoantigen-induced experimental SS mice. Blocking Cyr61 expression with special monoclonal antibody improved saliva secretion by ameliorating inflammatory infiltration and cytokines production in vivo. Furthermore, we showed that PF could alleviate inflammation by down-regulating Cyr61 expression in experimental SS mice. In conclusion, our new findings revealed for the first time that Cyr61 involves the pathogenesis of primary SS and PF alleviates SS-like symptoms associated with inhibiting Cyr61 expression, providing new insights into the potential molecular mechanism of PF in primary SS treatment.

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents; Cysteine-Rich Protein 61; Female; Glucosides; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Models, Animal; Monoterpenes; Paeonia; Plant Roots; Salivary Glands; Sjogren's Syndrome; Up-Regulation

This study determined the effects of paeoniflorin (PF) on the expression of purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) expressed on peripheral blood mononuclear cells (PBMCs) and production of ATP-induced pro-inflammatory cytokines released by PBMCs in patients with primary Sjögren's syndrome (pSS). The pharmacological functions and cytotoxic effects of PF were dose dependent in PBMCs from 20 newly diagnosed pSS patients and 20 normal individuals. The optimum dose of PF was 100μM. PF significantly down-regulated the production of interleukin (IL)-1β and IL-6 from pSS PBMCs, and significantly inhibited ATP-induced expression of P2X7R, that might contribute to reduced IL-1β and IL-6. mRNA and protein levels of P2X7R on pSS PBMCs were significantly higher than in normal individuals (p=0.03, p<0.001). When PBMCs from subjects were stimulated in vitro with ATP in the presence of PF, P2X7R mRNA and protein levels were decreased significantly (p<0.001, p<0.001, respectively versus ATP group) in the pSS. Supernatant IL-1β and IL-6 levels were significantly lower in the PF group compared with ATP group (p<0.001, p<0.001). We show for the first time that PF-mediated reduction of IL-1β and IL-6 was due in part to the reduced expression and activation of the ATP sensor P2X7R on pSS PBMCs, indicating that PF might be useful for the management of pSS via down-regulating P2X7R expression. Thus, PF may provide a new therapeutic approach to regulate P2X7R-mediated pathologic responses of pSS.

Topics: Adenosine Triphosphate; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Cell Survival; Cytokines; Dose-Response Relationship, Drug; Down-Regulation; Female; Glucosides; Humans; Interleukin-1beta; Interleukin-6; Male; Middle Aged; Monocytes; Monoterpenes; Receptors, Purinergic P2X7; RNA, Messenger; Sjogren's Syndrome