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Theranostics 2023Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and...
Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug for chronic alcohol addiction, has anti-inflammatory effects that help prevent various cancers, and Cu can enhance the effects of DSF. Inflammatory bowel diseases (IBD) are characterized by chronic or recurrent relapsing gastrointestinal inflammation. Many drugs targeting the immune responses of IBD have been developed, but their application has many problems, including side effects and high costs. Therefore, there is an urgent need for new drugs. In this study, we investigated the preventive effects of DSF+Cu on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. The anti-inflammatory effects were investigated using the DSS-induced colitis mouse model and lipopolysaccharide (LPS)-induced macrophages. DSS-induced TCRβ mice were used to demonstrate the effect of DSF in conjunction with Cu on CD4 T cell-secreted interleukin 17 (IL-17). In addition, the effect of DSF+Cu on intestinal flora was studied by 16S rRNA microflora sequencing. DSF and Cu could significantly reverse the symptom of DSS-induced UC in mice, such as weight loss, disease activity index score, colon length shortening, and reversal of colon pathological changes. DSF and Cu could inhibit colonic macrophage activation by blocking the nuclear factor kappa B (NF-κB) pathway, reducing nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3)-inflammasome-derived interleukin 1 beta (IL-1β) secretion and caspase-1 (CASP1) activation, and decreasing IL-17 secretion by CD4 T cells. Moreover, the treatment of DSF and Cu could protect the intestinal barrier by reversing the expression of tight junction proteins, zonula occluden-1 (ZO-1), occludin, and mucoprotein-2 (MUC2). Additionally, DSF+Cu could reduce the abundance of harmful bacteria and increase beneficial bacteria in the intestinal tract of mice, effectively improving intestinal microecology. Our study evaluated the effect of DSF+Cu on the immune system and gut microbiota in colonic inflammation and highlighted its potential to treat UC in the clinic.
Topics: Animals; Mice; Colitis, Ulcerative; Disulfiram; Dextran Sulfate; Interleukin-17; RNA, Ribosomal, 16S; Colitis; Colon; NF-kappa B; Inflammation; Inflammatory Bowel Diseases; Anti-Inflammatory Agents; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37284442
DOI: 10.7150/thno.81571 -
Proceedings of the National Academy of... Aug 2023Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and...
Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
Topics: Animals; Mice; Disulfiram; Toll-Like Receptor 4; Lipopolysaccharides; Signal Transduction; Alcoholism; Cytokines
PubMed: 37487070
DOI: 10.1073/pnas.2306399120 -
Translational Research : the Journal of... Apr 2023Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil...
Diabetic foot ulcer (DFU) is among the most frequent complications of diabetes and is associated with significant morbidity and mortality. Excessive neutrophil extracellular traps (NETs) delay wound healing in diabetic patients. Therefore, interventions targeting NET release need to be developed to effectively prevent NET-based wound healing impairment. Gasdermin D (GSDMD), a pore-forming protein acts as a central executioner of inflammatory cell death and can activate inflammasomes in neutrophils to release NETs. A precise understanding of the mechanism underlying NET-mediated delay in diabetic wound healing may be valuable in identifying potential therapeutic targets to improve clinical outcomes. In this study, we reported that neutrophils were more susceptible to NETosis in diabetic wound environments of patients with DFU. By in vitro experiments and using in vivo mouse models of diabetic wound healing (wide-type, Nlrp3, Casp-1, and Gsdmd mice), we demonstrated that NLRP3/caspase-1/GSDMD pathway on activation controls NET release by neutrophils in diabetic wound tissue. Furthermore, inhibition of GSDMD with disulfiram or genic deletion of Gsdmd abrogated NET formation, thereby accelerating diabetic wound healing. Disulfiram could inhibit NETs-mediated diabetic foot ulcer healing impairment by suppressing the NLRP3/Caspase-1/GSDMD pathway. In summary, our findings uncover a novel therapeutic role of disulfiram in inhibiting NET formation, which is of considerable value in accelerating wound healing in patients with DFU.
Topics: Animals; Mice; Caspase 1; Diabetes Mellitus; Diabetic Foot; Disulfiram; NLR Family, Pyrin Domain-Containing 3 Protein; Wound Healing
PubMed: 36336332
DOI: 10.1016/j.trsl.2022.10.008 -
BMJ Case Reports Mar 2021Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when...
Disulfiram has been widely used for over six decades in the treatment of alcohol dependence, as an aversive therapeutic agent. Despite having very few side effects when taken without concurrent alcohol consumption, some of these may underlie serious clinical complications. Epileptic seizure induction is a rare adverse effect of disulfiram and its aetiological mechanism is unknown. We present a hospitalised 47-year-old male patient with two episodes of generalised tonic-clonic seizures during treatment with disulfiram while abstinent from alcohol.
Topics: Anticonvulsants; Carbamazepine; Disulfiram; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Male; Middle Aged; Seizures
PubMed: 33731397
DOI: 10.1136/bcr-2020-236296 -
Blood Dec 2021
Topics: Disulfiram; Extracellular Traps; Humans; Pharmaceutical Preparations; Sepsis
PubMed: 34940816
DOI: 10.1182/blood.2021013438 -
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 -
International Journal of Antimicrobial... May 2022The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of... (Review)
Review
The objective of this systematic review was to retrieve and examine published studies related to in vitro and in vivo evaluation of disulfiram for the treatment of bacterial infections. Five scientific databases (PubMed, Embase, Scopus, Web of Science, and Latin American and Caribbean Health Sciences Literature) were searched to retrieve the maximum literature regarding the study's aim. The search strategy retrieved a total of 870 studies, of which 31 were included and 19 approached disulfiram as the primary aim and 12 included it as a secondary finding from other investigational objectives. The evidence pointed out five main aspects of pre-clinical testing regarding disulfiram antibacterial activity, namely spectrum of antimicrobial action, drug combinations, intracellular studies, animal studies and bacterial targets. Findings to emerge from this study are the observed potential of disulfiram as a non-antibiotic drug being proposed as a potential drug to contribute to the treatment of bacterial diseases usually with few treatment alternatives in the context of drug resistance. We evaluated the potency and selectivity of disulfiram, which indeed until now shows potential to be explored for use as an adjunctive chemical to antimicrobial ones. Even with the level of evidence being reserved, the potential of combining disulfiram with other drugs, already used or new to be used for the treatment of mycobacterial diseases, as well as its likely immunomodulatory effect, deserve to be further investigated. Furthermore, the copper-dependent mode of action in Gram-positive bacteria is an alternative to be explored in drug design or repurposing of chemicals.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Disulfiram; Gram-Positive Bacteria
PubMed: 35367599
DOI: 10.1016/j.ijantimicag.2022.106578 -
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 -
The American Journal on Addictions Sep 2023Alcohol use disorder (AUD) is a significant public health concern, with underutilized effective treatments, particularly in special populations. This article summarizes... (Review)
Review
BACKGROUND AND OBJECTIVES
Alcohol use disorder (AUD) is a significant public health concern, with underutilized effective treatments, particularly in special populations. This article summarizes the current evidence and guidelines for treating AUD in special populations.
METHODS
This article is a literature review that synthesizes the latest research on AUD treatment for special populations. We screened 242 articles and included 57 in our final review.
RESULTS
There are four food and Drug Administration-approved medications for AUD (MAUD): disulfiram, oral naltrexone, extended-release injectable naltrexone (XR-NTX), and acamprosate. Naltrexone and disulfiram have the potential to cause liver toxicity, and acamprosate should be avoided in patients with severe kidney disease. Psychosocial treatments should be considered first-line for pregnant and nursing patients. Naltrexone is contraindicated in patients on opioids, as it may precipitate acute withdrawal. For patients experiencing homelessness, nonabstinent treatment goals may be more practical, and XR-NTX should be considered to improve adherence. Limited evidence suggests medication can improve AUD treatment outcomes in adolescents and young adults. For patients with poor treatment response despite adequate medication adherence, switching to a different medication and augmentation with psychosocial treatments should be considered.
DISCUSSION AND CONCLUSIONS
Understanding the unique considerations for special populations with AUD is crucial, and addressing their special needs may improve their treatment outcomes.
SCIENTIFIC SIGNIFICANCE
Our study significantly contributes to the existing literature by summarizing crucial information for the treatment of AUD in special populations, highlighting distinct challenges, and emphasizing tailored approaches to improve overall health and well-being.
Topics: Humans; Adolescent; Alcoholism; Naltrexone; Acamprosate; Disulfiram; Analgesics, Opioid; Narcotic Antagonists
PubMed: 37551638
DOI: 10.1111/ajad.13455 -
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