Background: To explore the mechanisms of raw rhubarb and wine-processed rhubarb treatment in a rat model of intracerebral hemorrhage (ICH).Methods: After adapting to their environment, 30 male Wistar rats were divided into 5 treatment groups: blank control group (CK) (normal saline), sham operation group (SICH) (normal saline), ICH model group (ICH) (normal saline), ICH + raw rhubarb enema group (RO) (raw rhubarb 3.60 g/kg), and ICH + wineprocessed rhubarb enema group (WRO) (wine-processed rhubarb 3.60 g/kg). The rhubarb enema (once a day) was given since 3 days before ICH treatment, and was consistently given until 12 hours, 24 hours, 3 days, and 7 days post operation. Serum oxidative stress and inflammatory markers were detected by ELISA, and differences between raw rhubarb and wine-processed rhubarb treatment in ICH rats were screened by proteomics and metabolomics.Results: Both rhubarb treatments effectively improved oxidative stress and inflammatory responses. After ICH, the proteins and metabolites in the brain tissue were significantly altered. Compared with raw rhubarb, wine-processed rhubarb had a better protective effect by dysregulating amino acid metabolism in the ICH model. Conclusions:Our study provides a basis for further research into the mechanisms of rhubarb treatment from different processing technologies, and promotes the application of rhubarb as a therapeutic approach to ICH.

Oxidative stress, endoplasmic reticulum (ER) stress, and neuronal cell apoptosis have been considered as the main pathogenesis factors of brain injury after intracerebral hemorrhage (ICH). Chrysophanol (CHR) has been proved to have neuroprotective effects, but the role and underlying mechanisms of CHR in ICH remain unclear. HT22 cells were dealt with hemin to mimic an in vitro ICH model and then subjected to treatment with or without CHR. The cell viability, apoptosis, ER stress, and oxidative stress were evaluated by conducting the cell counting kit-8 (CCK-8), TdT-mediated dUTP nick end labeling (TUNEL) staining assays, western blot, and corresponding kit, respectively. Further, microRNA-sequencing, bioinformatic analysis, dual-luciferase reporter method, and rescue experiments were conducted to explore the molecular mechanisms of CHR alleviating hemin-induced ER in HT22 cell. Our data revealed that CHR increased cells viability, antiapoptosis, anti-ER stress, and antioxidative stress under conditions of hemin-induced HT22 cell injury. Mechanically, it was observed that Wnt3a was competitively sponged by miR-320-5p, and CHR activated β-catenin pathway by regulating miR-320-5p/Wnt3a molecular axis. Finally, results from the rescue experiment suggested that CHR inhibited hemin-induced cells apoptosis, ER stress, and oxidative stress through regulating the miR-320-5p/Wnt3a axis in HT22 cells. In conclusion, CHR prevented hemin-induced apoptosis, ER stress, and oxidative stress via inhibiting the miR-320-5p/Wnt3a/β-catenin pathway in HT22 cells. Our results certified that CHR could be served as a promising treatment for brain damage following ICH.

Introduction: Gout arthritis is an inflammatory disease characterized by severe acute pain. The goal of pharmacological gout arthritis treatments is to reduce pain, and thereby increase the patient's quality of life. The Kv7/M channel activators retigabine and flupirtine show analgesic efficacy in animal models of osteoarthritic pain. We hypothesized that these drugs may also alleviate gout arthritis pain. Objective: To determine the effects of retigabine and flupirtine on pain behavior associated with monosodium urate (MSU)-induced gout arthritis. Methods: The gout arthritis model was established with an intra-articular injection of MSU into the right ankle joint, animals were treated with retigabine or flupirtine, and pain-related behaviors were assessed. Results: Retigabine and flupirtine significantly increased the mechanical threshold and prolonged the paw withdrawal latency in a rat model of gout arthritis pain in a dose-dependent manner. The antinociceptive effects of retigabine and flupirtine were fully antagonized by the Kv7/M channel blocker XE991. Conclusion: Retigabine and flupirtine showed antinociceptive effects for MSU-induced gout pain at different times during pain development.

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Lumiracoxib is a selective cyclooxygenase‐2 inhibitor, which has been reported to cause rare but severe liver injury. Considering that lumiracoxib has a carboxylic group in the molecule, glucuronidation to form acylglucuronide would be one of the possible mechanisms of lumiracoxib‐induced liver injury. The aim of this study was to identify the metabolites of lumiracoxib that were formed via acyl‐glucuronidation in human liver microsomes using glutathione (GSH) and N‐acetyl‐lysine (NAL) as trapping agents by liquid chromatography combined with high resolution mass spectrometry. The structures of the detected metabolites were identified by their accurate masses, fragment ions, and retention times. Under the current conditions, eight lumiracoxib associated metabolites were identified. With the presence of UDPGA, lumiracoxib was biotransformed into lumiracoxib‐1‐O‐acylglucuronide (M1) and 4′‐hydroxyl‐lumiracoxib‐1‐O‐acylglucuronide (M2), both of which were reactive and prone to react with GSH to form drug‐S‐acyl‐GSH adducts (M3 and M4) through transacylation. In addition to reaction with GSH, the formed 1‐O‐acylglucuronides were chemically unstable (T1/2 = 1.5 h in phosphate buffer) and rearranged to 2‐, 3‐, and/or 4‐isomers, which further underwent ring‐opening to form aldehyde derivatives and then reacted with NAL to yield Schiff base derivatives (M5–M8). The present study provides a clear bioactivation profile of lumiracoxib through acyl glucuronidation, which would be one of the mechanisms attributed to liver injury caused by lumiracoxib.