Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
Cysteine persulfide (CysSSH) and polysulfides (CysS[S]nH, n > 2) are cysteine derivatives having sulfane sulfur atoms bound to cysteine thiol. Accumulating evidence has suggested that cysteine per/polysulfides are abundantly present in prokaryotes and eukaryotes, and play important roles in diverse biological processes such as antioxidative host defense. Reagents that can increase intracellular per/polysulfide levels become powerful chemical tools for understanding of the physiological and pathological roles of persulfide species in biological systems. We here describe the synthesis of N-acetyl-L-cystine polysulfides (NAC polysulfides) and application of them as potent per/polysulfide donors in cell culture and in animal models. Mass spectrometry-based sulfur metabolomics revealed that NAC polysulfides very efficiently donate their sulfane sulfur atoms to acceptor thiols such as reduced glutathione, leading to generation of hydroper/polysulfides in test tubes as well as in cultured cells. Importantly, NAC polysulfides exhibited strong anti-inflammatory activities against macrophages stimulated with lipopolysaccharide as evidenced by marked suppression of pro-inflammatory cytokine production including tumor necrosis factor-α and interferon-γ. Inhibitions of IKK/NF-κB axis as well as TRAM-TRIF pathway were suggested to be involved in anti-inflammatory activities of NAC polysulfides. Furthermore, we demonstrated that NAC polysulfide treatment protected mice from lethal endotoxin shock diseases. Taken together, NAC polysulfides can become powerful chemical tools to study biological processes that are sensitive to endogenous per/polysulfide levels and to develop new strategies to treat pathological conditions associated with dysregulated inflammatory responses.
