Celastrol as an intestinal FXR inhibitor triggers tripolide-induced intestinal bleeding: Underlying mechanism of gastrointestinal injury induced by Tripterygium wilfordii.

BACKGROUND: Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated. METHODS: Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii. RESULTS: Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway. CONCLUSIONS: The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.

[A clinical study of pelvic floor electrical stimulation in treatment of overactive bladder].

OBJECTIVE: To observe the efficacy of electrical stimulation in treatment of overactive bladder (OAB). METHODS: Patients (n = 60) with overactive bladder were randomly divided into 2 groups. Electrical stimulation group (n = 35) used an instrument for electrical stimulation through a special vagina or rectum probe transfer current (8-70 mA), for 20 min, qd, for 20-30 times. Medical group (n = 25) received oral tolterodine 2 mg, bid, for 2-4 weeks. RESULTS: The total effective rate and cure rate were 74%, 37% in electrical stimulation group and 76%, 40% in medical group, respectively, showing no significant difference between two groups (P > 0.05). While patients' satisfactory rate was significantly higher in electrical stimulation group than in medical group (P < 0.05). Side effects were more commonly seen with tolterodine. CONCLUSIONS: Electrical nerve stimulation is effective and safe for overactive bladder. Further studies are needed to show the long term efficacy and cost-effectiveness.