4Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China3Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China2Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, Shandong Province, China1Department of Cardiovascular Surgery, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China
刊名
Biochimica et Biophysica Acta - Molecular Basis of Disease
年份
2025
卷号
Vol.1871 No.3
页码
167704
ISSN
0925-4439
摘要
Purpose To evaluate the effects of co-treatment with Disulfiram and Resatorvid on sepsis. Methods Monocytes were isolated from the peripheral blood of sepsis patients with Staphylococcus aureus -induced infective endocarditis and healthy controls. The expression of Gasdermin D was analyzed using quantitative polymerase chain reaction , Western blotting, and immunofluorescence. An in vitro cellular model of sepsis was established by stimulating monocytes with heat-killed Staphylococcus aureus . ...更多
Purpose To evaluate the effects of co-treatment with Disulfiram and Resatorvid on sepsis. Methods Monocytes were isolated from the peripheral blood of sepsis patients with Staphylococcus aureus -induced infective endocarditis and healthy controls. The expression of Gasdermin D was analyzed using quantitative polymerase chain reaction , Western blotting, and immunofluorescence. An in vitro cellular model of sepsis was established by stimulating monocytes with heat-killed Staphylococcus aureus . Cells were pre-treated with Disulfiram and/or Resatorvid. Caspase-1, GSDMD, and interleukin-1 beta expression were measured by qRT-PCR and Western blotting. A cecal ligation and puncture mouse model was used to study in vivo sepsis. Outcomes assessed included survival rate, sickness behavior score, lung wet-to-dry weight ratio, and neutrophil count in the lung. Results Compared to healthy controls, GSDMD expression was elevated in monocytes from sepsis patients. Cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β increased in monocytes were stimulated with HK S. aureus over time. Disulfiram pre-treatment reduced the secretion of IL-1β in HK S. aureus-stimulated monocytes. Resatorvid pre-treatment decreased levels of cleaved Caspase-1, N-terminal GSDMD fragments, and secreted IL-1β. Co-treatment with Disulfiram and Resatorvid resulted in greater reductions in cleaved Caspase-1, N-terminal GSDMD fragments, and IL-1β, and improved outcomes in the CLP mouse model, including higher survival rates, lower sickness behavior scores, reduced lung wet-to-dry weight ratios, and fewer neutrophils in the lung. Conclusion These findings indicated that pyroptosis of monocytes was activated in sepsis. Disulfiram and Resatorvid pre-treatment effectively suppressed the pyroptosis of monocytes through the Caspase-1/GSDMD/IL-1β signaling pathway. The combination of Disulfiram and Resatorvid showed potential as a therapeutic strategy to mitigate sepsis severity.收起
