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作者

Linshan Yang Leyu Lyu Jie Ming Chengye Che

作者单位

⁴Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China ³Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China ²Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, Shandong Province, China ¹Department 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

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