1. The aim of this study was to investigate the effects of glycyrrhizin on the pharmacokinetics of celastrol in rats. 2. Twelve male Sprague-Dawley rats were randomly assigned to two groups: control group and test group. Test group was pretreated with glycyrrhizin at a dose of 100 mg/kg/day for 10 days, and then the two groups were orally administered with celastrol at a dose of 1 mg/kg. The concentration of celastrol was determined using a sensitive and reliable LC-MS method. 3. The results showed that glycyrrhizin could significantly decrease the plasma concentration (from 64.36 ng/mL to 38.42 ng/mL) and AUC (from 705.39 to 403.43 μg·h/L) of celastrol in rats. To investigate its potential mechanism, the effects of glycyrrhizin on the transport and metabolic stability of celastrol were investigated using Caco-2 cell monolayer transwell model and rat liver microsome incubation systems. The Caco-2 cell monolayer transwell experiments indicated that glycyrrhizin could increase the efflux ratio of celastrol (4.02 versus 6.51). However, the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase the intrinsic clearance rate of celastrol from 20.3 ± 3.37 to 38.8 ± 4.18 μL/min/mg protein. 4. In conclusion, these results indicated that the herb-drug interaction between glycyrrhizin and celastrol might occur when they were coadministered.
Osteoarthritis (OA) is a frequently observed condition in aged people. OA cartilage is characterized by chondrocyte apoptosis, chondrocyte inflammation, and hyperactive catabolism of extracellular matrix. However, the specific molecular mechanisms remain unclear. Recent data has shown that Angptl4, a multifunctional cytokine, is involved in the regulation of inflammatory and apoptosis responses in different tissues. This study is aimed at defining the role of Angptl4 in the development of OA. We employed X-ray analysis, safranin O-fast green (S-O) staining, and hematoxylin staining to evaluate histomorphological characteristics in the knee joint of mice. Real-time quantitative polymerase chain reaction, Western blot assays, immunofluorescence staining, and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the changes in gene and protein expression. Mechanically, our data demonstrated that Angptl4 knockdown improved the degradation of extracellular matrix and reduced TNF-α-mediated chondrocyte inflammation and apoptosis by suppressing sirtuin 1/NF-κB signaling pathway. In addition, animal studies showed that the suppression of Angptl4 expression might alleviate OA development. In conclusion, our findings revealed the underlying mechanisms of Angptl4 regulation in chondrocytes and its potential value in the treatment of OA.
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