Abstract
Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.
Keywords: disulfiram; inflammation; lactoferrin; macrophage-targeting delivery; pyroptosis; sepsis; ulcerative colitis.
【저자키워드】 Inflammation, Sepsis, disulfiram, ulcerative colitis., pyroptosis, lactoferrin, macrophage-targeting delivery, 【초록키워드】 Treatment, Macrophage, Efficacy, macrophages, Infection, alcohol, anti-inflammatory activity, activity, therapeutic, organ dysfunction, Complication, Neutralizing, glycoprotein, inhibitor, patients, therapeutic strategy, Inflammatory cytokine, ulcerative colitis, endotoxin, Inflammatory response, immunosuppressive, Safe, Cellular responses, inflammatory disorders, gasdermin D, ligands, life-threatening, Colitis, therapeutic effect, treat, dysregulated immune response, circulating, offer, murine, effective, caused, addition, applied, contribute, cause, multifunctional, activating, DSF, various inflammatory disease, 【제목키워드】 inflammatory disease,