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Blood Dec 2021
Topics: Disulfiram; Extracellular Traps; Humans; Pharmaceutical Preparations; Sepsis
PubMed: 34940816
DOI: 10.1182/blood.2021013438 -
BioRxiv : the Preprint Server For... Oct 2023Pyroptosis executor Gasdermin (GsdmD) promotes atherosclerosis in mice and humans. Disulfiram (DSF) was recently shown to potently inhibit GsdmD, but the in-vivo...
Pyroptosis executor Gasdermin (GsdmD) promotes atherosclerosis in mice and humans. Disulfiram (DSF) was recently shown to potently inhibit GsdmD, but the in-vivo efficacy and mechanism of DSF's anti-atherosclerotic activity is yet to be explored. We used human/mouse macrophages and a hyperlipidemic mouse model of atherosclerosis to determine DSF anti-atherosclerotic efficacy and mechanism. DSF-fed hyperlipidemic apoE mice showed significantly reduced IL-1β release upon in-vivo Nlrp3 inflammasome assembly and showed smaller atherosclerotic lesions (∼27% and 29% reduction in males and females, respectively). The necrotic core area was also smaller (∼50% and 46% reduction in DSF-fed males and females, respectively). DSF induced autophagy in macrophages, hepatocytes/liver, and in atherosclerotic plaques. DSF modulated other atheroprotective pathways such as efferocytosis, phagocytosis, and gut microbiota. DSF-treated macrophages showed enhanced phagocytosis/efferocytosis, with a mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic-force microscopy analysis revealed altered biophysical membrane properties of DSF treated macrophages, showing increased ordered-state of the plasma membrane and increased adhesion strength. Furthermore, the 16sRNA sequencing of DSF-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota and a reduction in atherogenic species. Taken together, our data shows that DSF can simultaneously modulate multiple atheroprotective pathways, and thus may serve as novel adjuvant therapeutic to treat atherosclerosis.
PubMed: 37905037
DOI: 10.1101/2023.10.17.562757 -
Molecules (Basel, Switzerland) Oct 2020The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in...
The therapeutic utility of the copper ionophore disulfiram was investigated in a diet-induced obesity mouse model (C57BL/6J background), both through administration in feed (0.05 to 1% ()) and via oral gavage (150 mg/kg) for up to eight weeks. Mice were monitored for body weight, fat deposition (perigonadal fat pads), metabolic changes (e.g., glucose dyshomeostasis) and pathologies (e.g., hepatic steatosis, hyperglycaemia and hypertriglyceridemia) associated with a high-fat diet. Metal-related pharmacological effects across major organs and serums were investigated using inductively coupled plasma mass spectrometry (ICP-MS). Disulfiram treatments (all modes) augmented hepatic copper in mice, markedly moderated body weight and abolished the deleterious systemic changes associated with a high-fat diet. Likewise, another chemically distinct copper ionophore H(gtsm), administered daily (oral gavage), also augmented hepatic copper and moderated mouse body weight. Postmortem histological examinations of the liver and other major organs, together with serum aminotransferases, supported the reported therapeutic safety of disulfiram. Disulfiram specifically altered systemic copper in mice and altered hepatic copper metabolism, perturbing the incorporation of copper into ceruloplasmin (holo-ceruloplasmin biosynthesis) and subsequently reducing serum copper concentrations. Serum ceruloplasmin represents a biomarker for disulfiram activity. Our results establish copper ionophores as a potential class of antiobesity agents.
Topics: Animals; Anti-Obesity Agents; Body Weight; Copper; Disulfiram; Dose-Response Relationship, Drug; Ionophores; Liver; Mice; Mice, Inbred C57BL; Permeability
PubMed: 33120881
DOI: 10.3390/molecules25214957 -
Frontiers in Pharmacology 2021Disulfiram has been used clinically for decades as an anti-alcoholic drug. Recently, several studies have demonstrated the anti-inflammatory effects of disulfiram and... (Review)
Review
Disulfiram has been used clinically for decades as an anti-alcoholic drug. Recently, several studies have demonstrated the anti-inflammatory effects of disulfiram and its metabolism, which can alleviate the progression of inflammation and . In the current study, we summarize the anti-inflammatory mechanisms of disulfiram and its metabolism, including inhibition of pyroptosis by either covalently modifying gasdermin D or inactivating nod-like receptor protein 3 inflammasome, dual effects of intracellular reactive oxygen species production, and inhibition of angiogenesis. Furthermore, we review the potential application of disulfiram and its metabolism in treatment of inflammatory disorders, such as inflammatory bowel disease, inflammatory injury of kidney and liver, type 2 diabetes mellitus, sepsis, uveitis, and osteoarthritis.
PubMed: 35185542
DOI: 10.3389/fphar.2021.795078 -
American Family Physician Mar 2016The U.S. Preventive Services Task Force recommends that clinicians screen adults for alcohol misuse and provide persons engaged in risky or hazardous drinking behaviors... (Review)
Review
The U.S. Preventive Services Task Force recommends that clinicians screen adults for alcohol misuse and provide persons engaged in risky or hazardous drinking behaviors with brief behavioral counseling to reduce alcohol misuse. However, only a minority of American adults with high-risk alcohol use receive treatment. Three medications are approved by the U.S. Food and Drug Administration to treat alcohol use disorder: acamprosate, disulfiram, and naltrexone. Acamprosate and naltrexone reduce alcohol consumption and increase abstinence rates, although the effects appear to be modest. Disulfiram has been used for years, but evidence supporting its effectiveness is inconsistent. Other medications may be beneficial to reduce heavy alcohol use. The anticonvulsants topiramate and gabapentin may reduce alcohol ingestion, although long-term studies are lacking. Antidepressants do not decrease alcohol use in patients without mood disorders, but sertraline and fluoxetine may help depressed patients decrease alcohol ingestion. Ondansetron may reduce alcohol use, particularly in selected subpopulations. Further study is needed for genetically targeted or as-needed medications to reduce alcohol use.
Topics: Alcohol Deterrents; Alcohol-Related Disorders; Antidepressive Agents; Counseling; Humans; Practice Guidelines as Topic
PubMed: 26977830
DOI: No ID Found -
JCI Insight Mar 2022Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps... (Review)
Review
Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram - an FDA-approved drug for alcohol use disorder - dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.
Topics: Acetaldehyde Dehydrogenase Inhibitors; Acute Lung Injury; Animals; COVID-19; Disease Models, Animal; Disulfiram; Extracellular Traps; Lung; Rodentia; SARS-CoV-2
PubMed: 35133984
DOI: 10.1172/jci.insight.157342 -
Redox Biology Feb 2024Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by...
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors and the fourth leading cause of cancer-related death globally, which is characterized by complicated pathophysiology, high recurrence rate, and poor prognosis. Our previous study has demonstrated that disulfiram (DSF)/Cu could be repurposed for the treatment of HCC by inducing ferroptosis. However, the effectiveness of DSF/Cu may be compromised by compensatory mechanisms that weaken its sensitivity. The mechanisms underlying these compensatory responses are currently unknown. Herein, we found DSF/Cu induces endoplasmic reticulum stress with disrupted ER structures, increased Ca level and activated expression of ATF4. Further studies verified that DSF/Cu induces both ferroptosis and cuproptosis, accompanied by the depletion of GSH, elevation of lipid peroxides, and compensatory increase of xCT. Comparing ferroptosis and cuproptosis, it is interesting to note that GSH acts at the crossing point of the regulation network and therefore, we hypothesized that compensatory elevation of xCT may be a key aspect of the therapeutic target. Mechanically, knockdown of ATF4 facilitated the DSF/Cu-induced cell death and exacerbated the generation of lipid peroxides under the challenge of DSF/Cu. However, ATF4 knockdown was unable to block the compensatory elevation of xCT and the GSH reduction. Notably, we found that DSF/Cu induced the accumulation of ubiquitinated proteins, promoted the half-life of xCT protein, and dramatically dampened the ubiquitination-proteasome mediated degradation of xCT. Moreover, both pharmacologically and genetically suppressing xCT exacerbated DSF/Cu-induced cell death. In conclusion, the current work provides an in-depth study of the mechanism of DSF/Cu-induced cell death and describes a framework for the further understanding of the crosstalk between ferroptosis and cuproptosis. Inhibiting the compensatory increase of xCT renders HCC cells more susceptible to DSF/Cu, which may provide a promising synergistic strategy to sensitize tumor therapy and overcome drug resistance, as it activates different programmed cell death.
Topics: Humans; Disulfiram; Copper; Carcinoma, Hepatocellular; Cell Line, Tumor; Ferroptosis; Lipid Peroxides; Liver Neoplasms
PubMed: 38150993
DOI: 10.1016/j.redox.2023.103007 -
The Primary Care Companion For CNS... Nov 2023
Topics: Humans; Disulfiram; Acetic Acid; Ethanol; Alcohol Deterrents; Alcoholism
PubMed: 38055873
DOI: 10.4088/PCC.23cr03537 -
Pharmaceutics May 2023Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer... (Review)
Review
Disulfiram (DSF) is a thiocarbamate based drug that has been approved for treating alcoholism for over 60 years. Preclinical studies have shown that DSF has anticancer efficacy, and its supplementation with copper (CuII) significantly potentiates the efficacy of DSF. However, the results of clinical trials have not yielded promising results. The elucidation of the anticancer mechanisms of DSF/Cu (II) will be beneficial in repurposing DSF as a new treatment for certain types of cancer. DSF's anticancer mechanism is primarily due to its generating reactive oxygen species, inhibiting aldehyde dehydrogenase (ALDH) activity inhibition, and decreasing the levels of transcriptional proteins. DSF also shows inhibitory effects in cancer cell proliferation, the self-renewal of cancer stem cells (CSCs), angiogenesis, drug resistance, and suppresses cancer cell metastasis. This review also discusses current drug delivery strategies for DSF alone diethyldithocarbamate (DDC), Cu (II) and DSF/Cu (II), and the efficacious component Diethyldithiocarbamate-copper complex (CuET).
PubMed: 37376016
DOI: 10.3390/pharmaceutics15061567 -
Kidney International Dec 2022Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an...
Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an alcohol-aversion drug, inhibits monocyte/macrophage migration by inhibiting FROUNT, a cytosolic protein that enhances chemokine receptor signaling. Our study found that disulfiram at a human equivalent dose successfully blocked albuminuria and crescent formation with podocyte loss, and later stage kidney fibrotic lesions, in a rat model of anti-GBM glomerulonephritis. A disulfiram derivative, DSF-41, with more potent FROUNT inhibition activity, inhibited glomerulonephritis at a lower dose than disulfiram. Disulfiram markedly reduced the number of monocytes or macrophages at the early stage of glomerulonephritis and that of CD3 and CD8 lymphocytes at the established stage. Impaired pseudopodia formation was observed in the glomerular monocytes/macrophages of the disulfiram group; consistent with the in vitro observation that disulfiram blocked chemokine-dependent pseudopodia formation and chemotaxis of bone marrow-derived monocytes/macrophages. Furthermore, disulfiram suppressed macrophage activation as revealed by reduced expression of inflammatory cytokines and chemokines (TNF-α, CCL2, and CXCL9) and reduced CD86 and MHC class II expressions in monocytes/macrophages during glomerulonephritis. The dramatic reduction in monocyte/macrophage number might have resulted from disulfiram suppression of both the chemotactic response of monocytes/macrophages and their subsequent activation to produce cytokines and chemokines, which further recruit monocytes. Additionally, FROUNT was expressed in CD68 monocytes/macrophages infiltrating the crescentic glomeruli in human anti-GBM glomerulonephritis. Thus, disulfiram can be a highly effective and safe drug for the treatment of glomerulonephritis by blocking the chemotactic responses of monocytes/macrophages and their activation status in the glomerulus.
Topics: Rats; Humans; Animals; Disulfiram; Rats, Inbred WKY; Chemokines; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Cytokines
PubMed: 36049642
DOI: 10.1016/j.kint.2022.07.031