Co-treatment with disulfiram and glycyrrhizic acid suppresses the inflammatory response of chondrocytes

Abstract

Background Osteoarthritis (OA) is a kind of systemic musculoskeletal disorder and a most important factor for causing disability and physical painfulness. Nevertheless, due to the fact that OA can be triggered by multiple etiological factors, this disease is hard to be cured. Therefore, it is of great necessity for us to find novel targets or drugs for OA treatment. Materials and methods The chondrocytes were treated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP) to induce pyroptosis in OA. The cell proliferation was detected by Cell Counting Kit-8 assay (CCK-8 assay). Enzyme-linked immunosorbent assay (ELISA) was used for the detection of pyroptosis-related inflammatory factors. Then, the antagonists for gasdermin D (GSDMD) (disulfiram) and high mobility group box 1 (HMGB1) (glycyrrhizic acid) were used to treat the cell model to observe the effects of disulfiram and glycyrrhizic acid on the proliferation of chondrocytes in OA. The protein levels of pyroptosis-related inflammatory factors were measured by western blot, and the levels of aldehyde dehydrogenase (ALDH) and reactive oxygen species (ROS) were measured by corresponding commercial kits. Results After chondrocytes were induced by LPS and ATP, the cell proliferation was decreased and the expressions of pyroptosis-related inflammatory factors were increased. Disulfiram and glycyrrhizic acid treatment led to enhanced cell proliferation and increased expressions of pyroptosis-related inflammatory factors, while disulfiram showed better alleviative effects on the inflammation in chondrocytes in OA. However, co-treatment with disulfiram at a high concentration and glycyrrhizic acid did not result in higher proliferation of chondrocytes and alleviated inflammation, but led to oxidative stress. Conclusion In conclusion, co-treatment with disulfiram and glycyrrhizic acid at a standard concentration suppresses the inflammatory response of chondrocytes, which may provide guidance for the use of the drugs in the treatment of OA.

Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

“…Co-treatment with disulfiram and glycyrrhizic acid promote the proliferation and alleviate pyroptosis in LPS and ATP stimulated C28/I2 chondrocytes, and can reduce the production of ROS. DSF, when used at high concentrations, shows little effect on cell proliferation and pyroptosis (Li et al, 2021). This may provide new ideas for the treatment of osteoarthritis.…”

“…Degenerative changes in articular cartilage can result in osteoarthritis (Goldring and Berenbaum, 2015). In C28/I2 cells (human chondrocytes), LPS and ATP can induce inflammation and pyroptosis (Li et al, 2021). Co-treatment with disulfiram and glycyrrhizic acid promote the proliferation and alleviate pyroptosis in LPS and ATP stimulated C28/I2 chondrocytes, and can reduce the production of ROS.…”

Targeting inflammasome-dependent mechanisms as an emerging pharmacological approach for osteoarthritis therapy

“…Targeting pyroptosis in OA has been proposed in in vitro experimental studies, where chondrocytes were activated by LPS and ATP, and treatment with disulfiram and glycyrrhizin acid resulted in suppression of the inflammatory response and reduction of pyroptosis. 102 Another interesting finding was that treatment with Icariin also suppressed GSDMD expression, and chondrocyte pyroptosis, and protected against cartilage degeneration in the MIA rat OA model. 54 Other molecules; for instance, morroniside and loganin were assessed in a mouse model of OA, and the authors found that those two iridoid glycosides extracted from Cornus officinalis were protective against cartilage degradation by reducing chondrocyte pyroptosis via inhibition of NF-κB signaling.…”

Pyroptosis and degenerative diseases of the elderly

“…Preclinical studies have demonstrated that icariin [ 128 ], loganin [ 129 ], licochalcone Am [ 130 ], irisin [ 131 ], quercetin [ 126 ], morroniside [ 132 ], and rapamycin [ 133 ] inhibit the classical pyroptotic pathway and reduce chondrocyte death, suggesting future roles in the treatment of OA. In addition, combined treatment with antagonists of GSDMD (disulfiram) and HMGB1 (glycyrrhizic acid) can attenuate chondrocyte pyroptosis, inhibit inflammation, and promote chondrocyte proliferation in vitro, thereby suggesting a therapeutic approach for OA [ 134 ]. In summary, pyroptosis is a well-defined pathogenic mechanism of OA.…”