J Biol Chem

J Biol Chem. remission but drug costs are high and are not affordable in all countries. In China an extract of the herb Hook F. (TwHF) is frequently used to treat autoimmune and/or inflammatory diseases due to its favourable costCbenefit ratio. Triptolide has turned out to be the active material of TwHF extracts and has been shown to exert potent anti-inflammatory and immunosuppressive effects and Hook F. (TwHF), also known as Lei Gong Teng, are used as one of the most common systemic treatments for inflammatory and (auto)immune disorders in China mainly due to their favourable costCbenefit ratio. TwHF has been used for centuries in traditional Chinese medicine to treat a variety of immunological disorders, including rheumatoid arthritis, immune complex nephritis and systemic lupus erythematosus. Originally, an extract obtained by boiling the root or leaves of TwHF in water (decoction) was used for systemic treatment. Since a number of adverse effects were observed during therapy the extraction method was changed [3]. With the aim to reduce ZED-1227 toxicity an ethyl acetate extract and a chloroformCmethanol extract (T2) were ZED-1227 developed in the 1970s [4]. Both of these preparations are commercially available in China and have been used extensively meanwhile. The extracts of TwHF contain more than 70 ingredients including diterpenoids, triterpenoids, sesquiterpenoids, -sitosterol, dulcitol and glycosides [5]. Triptolide (C20H24O6, chemical structure see Physique 1) turned out to be the most potent bioactive material in the TwHF extracts. It has been shown to possess potent anti-inflammatory and immunosuppressive properties as well as in different animal models in numerous preclinical studies [6C10]. Besides its use for the treatment of psoriasis, it has been shown that triptolide inhibits experimental autoimmune uveoretinitis and prolongs allograft survival [11, 12]. Moreover, it has been demonstrated that a succinyl derivative of triptolide, PG490-88, can prevent graft Hook F 0.05Azithromycin 500 mg day?1, 2 weeksHang 11%,A24 weeks4 weeks46.51%, 0.05Shen 39.6%, and proliferation of murine lymphocytes was inhibited. However, these derivatives were not as potent as triptolide experimentally [116]. In view of this, several triptolide derivatives with improved water solubility have been developed, like PG490-88, LLDT-8 and F60008. PG490-88 is usually a water-soluble 14-succinyl sodium salt of triptolide which was synthesized in early 2000 (Physique 2). This compound is usually a prodrug of triptolide and is metabolized to triptolide after absorption into the blood. Its anti-inflammatory effects were demonstrated to be comparable with triptolide. An early study showed that intraperitoneal injection of PG490-88 at a dose of 0.25 mg kg?1 day?1 for 2 weeks could attenuate inflammation and fibrosis in the bleomycin model of mouse lung fibrosis [117]. 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