Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

W, Guo; Chen, Shihong; Chengqing, Li; Xu, Jianwei; Wang, Lei

doi:10.3389/fphar.2021.795078

Cited by 19 publications

(12 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5 d), as was previously published 35 . Disulfiram is used to treat alcoholism 59 and there has been recent enthusiasm for its repurposing for numerous diseases including cancer 60 , neurological 61 and inflammatory conditions 62 . Two potential anti-inflammatory mechanisms have been proposed: suppression of gasdermin D’s pore-forming ability via modification of C 192 of GSDMD 57 or suppression of the upstream pyroptotic mediator NLRP3 63 .…”

Section: Resultsmentioning

confidence: 99%

Reconstitution of human pyroptotic cell death in Saccharomyces cerevisiae

Hawkins

2023

Sci Rep

View full text Add to dashboard Cite

Pyroptosis is a lytic form of programmed cell death induced by the activation of gasdermins. The precise mechanism of gasdermin activation by upstream proteases remains incompletely understood. Here, we reconstituted human pyroptotic cell death in yeast by inducible expression of caspases and gasdermins. Functional interactions were reflected by the detection of cleaved gasdermin-D (GSDMD) and gasdermin-E (GSDME), plasma membrane permeabilization, and reduced growth and proliferative potential. Following overexpression of human caspases-1, -4, -5, and -8, GSDMD was cleaved. Similarly, active caspase-3 induced proteolytic cleavage of co-expressed GSDME. Caspase-mediated cleavage of GSDMD or GSDME liberated the ~ 30 kDa cytotoxic N-terminal fragments of these proteins, permeabilized the plasma membrane and compromised yeast growth and proliferation potential. Interestingly, the observation of yeast lethality mediated by co-expression of caspases-1 or -2 with GSDME signified functional cooperation between these proteins in yeast. The small molecule pan-caspase inhibitor Q-VD-OPh reduced caspase-mediated yeast toxicity, allowing us to expand the utility of this yeast model to investigate the activation of gasdermins by caspases that would otherwise be highly lethal to yeast. These yeast biological models provide handy platforms to study pyroptotic cell death and to screen for and characterize potential necroptotic inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

Reconstitution of human pyroptotic cell death in Saccharomyces cerevisiae

Hawkins

2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…39 Moreover, patients with inflammatory diseases may benefit from DSL owing to its antiinflammatory mechanism. 40 Based on the current study, we assume that DSL may also work as an alternative drug therapy for SAP. However, excessive alcohol consumption is one of the etiologies of AP.…”

Section: Discussionmentioning

confidence: 99%

Disulfiram relieves severe acute pancreatitis by inhibiting GSDMD‐dependent NETs formation

Xin

Nie

Ding

et al. 2023

J of Digest Diseases

View full text Add to dashboard Cite

ObjectivesSevere acute pancreatitis (SAP) is characterized by pancreatic and systemic inflammation. Neutrophil extracellular traps (NETs) are considered to play an important role in the development of SAP. Disulfiram (DSL) is a newly recognized anti‐inflammatory drug. We aimed to explore the effect of DSL on NETs and SAP.MethodsMouse model of SAP was induced by caerulein and lipopolysaccharide. The severity of SAP was evaluated according to the morphological and biochemical change. In addition, we examined the expression of gasdermin D (GSDMD) in vivo and vitro to verify the effect of DSL. We further investigated the expressions of NETs in vivo and vitro, in the condition of SAP with or without DSL intervention, to explore the possible mechanism of DSL affecting SAP.ResultsPancreatic inflammatory injury increased in the SAP group. DSL could alleviate the pancreatic inflammation. GSDMD, the NETs formation related protein, increased in SAP condition. Expressions of NETs were also promoted by SAP in vivo or by phorbol myristate acetate (PMA) in vitro. Moreover, DSL could inhibit the expressions of GSDMD and NETs in vivo, hence, it relieved SAP. The experiment in vitro further confirmed the result.ConclusionsNETs are highly associated to the inflammatory injury of SAP. DSL inhibits NETs formation by down‐regulating GSDMD, which in turn relieves the inflammation of SAP. Our study provides a possible therapeutic target for SAP.

show abstract

“…Disulfiram inhibits membrane pore formation in GSDMD, but not in other GSDMs families, hence covalently modifying GSDMD in Cys191/Cys192 of human/mice to inhibit pore formation. Disulfiram and its metabolism exhibit anti-inflammatory activities, which can alleviate inflammation in vitro and in vivo ( 201 ). Disulfiram relieves severe acute pancreatitis induced by caerulein and related lung injury, and inhibits IL-1β and IL-18 production by targeting GSDMD cleavage ( 202 ).…”

Section: Inhibitors Of the Nlrp3 Inflammasome Pathwaymentioning

confidence: 99%

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

et al. 2023

View full text Add to dashboard Cite

The inflammasome regulates innate immunity by serving as a signaling platform. The Nod-like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1, is by far the most extensively studied and well-characterized inflammasome. A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro-caspase-1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and pyroptosis. However, the aberrant activation of the NLRP3 inflammasome has been linked to various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Therefore, the NLRP3 inflammasome has emerged as a promising therapeutic target for inflammatory diseases. In the present review, systematic searches were performed using 'NLRP3 inhibitor(s)' and 'inflammatory disease(s)' as key words. By browsing the literature from 2012 to 2022, 100 articles were retrieved, of which 35 were excluded as they were reviews, editorials, retracted or unavailable online, and 65 articles were included. According to the retrieved literature, the current understanding of NLRP3 inflammasome pathway activation in inflammatory diseases was summarize, and inhibitors of the NLRP3 inflammasome pathway targeting the NLRP3 protein and other inflammasome components or products were highlighted. Additionally, the present review briefly discusses the current novel efforts in clinical research.

show abstract

Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

Cited by 19 publications

References 93 publications

Reconstitution of human pyroptotic cell death in Saccharomyces cerevisiae

Reconstitution of human pyroptotic cell death in Saccharomyces cerevisiae

Disulfiram relieves severe acute pancreatitis by inhibiting GSDMD‐dependent NETs formation

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

Contact Info

Product

Resources

About