Abstract
Sulfur mustard (SM) is a vesicating chemical warfare agent used in numerous military conflicts and remains a potential chemical threat to the present day. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to a series of SM-associated toxic responses. MSTF is the mixture of salvianolic acids (SA) of Salvia miltiorrhiza and total flavonoids (TFA) of Anemarrhena asphodeloides. SA is the main water-soluble phenolic compound in Salvia miltiorrhiza. TFA mainly includes mangiferin, isomangiferin and neomangiferin. SA and TFA possess diverse activities, including antioxidant and anti-inflammation activities. In this study, we mainly investigated the therapeutic effects of MSTF on SM toxicity in Sprague Dawley rats. Treatment with MSTF 1 h after subcutaneous injection with 3.5 mg/kg (equivalent to 0.7 LD50) SM significantly increased the survival levels of rats and attenuated the SM-induced morphological changes in the testis, small intestine and liver tissues. Treatment with MSTF at doses of 60 and 120 mg/kg caused a significant (p < 0.05) reversal in SM-induced GSH depletion. Gene expression profiles revealed that treatment with MSTF had a dramatic effect on gene expression changes caused by SM. Treatment with MSTF prevented SM-induced differential expression of 93.8% (973 genes) of 1037 genes. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 36 pathways, such as the MAPK signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that MSTF attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation. These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries.
Highlights
Sulfur mustard (SM) or bis(2-chloroethyl) sulfide is a powerful bifunctional alkylating and vesicating chemical warfare agent used in numerous military conflicts during the 20th century [1,2]
Signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that mixture of SA and TFA (MSTF) attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation
These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries
Summary
Sulfur mustard (SM) or bis(2-chloroethyl) sulfide is a powerful bifunctional alkylating and vesicating chemical warfare agent used in numerous military conflicts during the 20th century [1,2]. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to accumulation of reactive oxygen species (ROS) and reactive nitrogen species within cells, inactivation of sulfhydryl-containing enzymes, loss of calcium homeostasis, lipid peroxidation, cellular membrane breakdown and, cell death [3,4,5,6,7] These events lead to oxidative stress and macromolecular damage, including DNA, RNA and protein damage, which trigger intricate signaling pathways and modulate gene expression, causing a series of SM-associated toxic responses [5,6,8,9]. Due to the potential for use of SM as a chemical terrorism agent, there is renewed interest in developing effective chemopreventive and therapeutic agents
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