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Critical Care (London, England) Jul 2022The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the...
BACKGROUND
The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear.
OBJECTIVES
We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19.
METHODS
We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection.
RESULTS
We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage.
CONCLUSION
These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.
Topics: Animals; Disulfiram; Extracellular Traps; Mice; Neutrophils; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35799268
DOI: 10.1186/s13054-022-04062-5 -
Journal of Molecular Medicine (Berlin,... Apr 2024Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors....
Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.
Topics: Humans; Disulfiram; Reactive Oxygen Species; Auranofin; Cell Line, Tumor; Leukemia, Myeloid, Acute
PubMed: 38349407
DOI: 10.1007/s00109-023-02414-4 -
Vojnosanitetski Pregled May 2012Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms produced after ethanol intake. Although it is well tolerated in most...
INTRODUCTION
Disulfiram is used in the treatment of chronic alcoholism, because of the unpleasant symptoms produced after ethanol intake. Although it is well tolerated in most patients, one in 15,000 patients will develop peripheral neuropathy every year, which is frequently misdiagnosed as alcoholic neuropathy.
CASE REPORT
We report clinical, laboratory, electrophysiological and histopathological features in a 19-year-old patient who developed an acute distal sensorymotor neuropathy during the treatment of alcoholism. At the end of 4-month treatment with disulfiram 250 mg/day, the patient complained of weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and the legs below the knees; reduction in foot strength, the absence of ankle jerk tendon reflexes, and tactile stocking pin-pick and vibratory sensory impairment in the lower limbs below the knee. Recovery was successful after treatment cessation.
CONCLUSION
The significance of toxic neuropathy is shown by the fact that the recognition of clinical picture, identifying etiological factors and its elimination may prevent the evolution of polyneuropathy. This allows for more effective treatment of these neuropathies as apposite to idiopathic ones which can be treated only symptomatically. Our case report indicates the possibilities during a period with no serious damage to the axons manifested.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Male; Peripheral Nervous System Diseases; Young Adult
PubMed: 22764551
DOI: 10.2298/vsp1205453v -
Asia-Pacific Journal of Public Health Nov 2023Betel quid (BQ) is commonly used in the Asia-Pacific region. Disulfiram is prescribed for people with alcohol use disorders (PwAUDs) after the completion of... (Observational Study)
Observational Study
Betel quid (BQ) is commonly used in the Asia-Pacific region. Disulfiram is prescribed for people with alcohol use disorders (PwAUDs) after the completion of detoxification as an alternative to rehabilitation. This prospective observational study reported the aversive reactions and common symptoms of disulfiram and BQ in PwAUDs. Participants included PwAUDs admitted to the psychiatric ward at the Jigme Dorji Wangchuck National Referral Hospital for detoxification, who were on Disulfiram and using BQ at the same time. Aversive reactions between disulfiram and BQ were observed for 100 patients over a year. Twenty participants showed aversive reactions between BQ and disulfiram. Common symptoms included sweating, diarrhea, dizziness, tremors, palpitations, shortness of breath, nausea and vomiting, and headache. Since PwAUDs in Bhutan are inducted on disulfiram after detoxification, and most use BQ simultaneously, this study will help inform health care providers to educate people about the aversive reactions of disulfiram and BQ.
Topics: Humans; Alcoholism; Areca; Bhutan; Disulfiram; Inpatients; Substance-Related Disorders; Prospective Studies
PubMed: 37837338
DOI: 10.1177/10105395231204801 -
The Lancet. Child & Adolescent Health Aug 2019The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss... (Review)
Review
The identification of preventive interventions that are safe and effective for cisplatin-induced ototoxicity is important, especially in children because hearing loss can impair speech-language acquisition development. Previous randomised trials assessed systemic drugs such as amifostine, sodium diethyldithiocarbamate or disulfiram, and sodium thiosulfate. Amifostine, sodium diethyldithiocarbamate, and disulfiram did not show hearing preservation. Paediatric trials assessing sodium thiosulfate showed efficacy in terms of hearing protection. The SIOPEL 6 trial consisted solely of patients with localised hepatoblastoma and no effects on survival were shown. In the ACCL0431 trial, which included heterogeneous patients, a post-hoc analysis showed significantly worse overall survival among patients who had disseminated disease receiving sodium thiosulfate than among controls, but not among those with localised disease. Intratympanically administered drugs have mainly been assessed in adults and include N-acetylcysteine and dexamethasone. Inconsistent effects of these drugs were identified but these studies were limited by design, small sample size, and statistical approach. Future studies of systemic drugs will need to consider the measurement of disease outcomes through study design and sample size, and ototoxicity endpoints should be harmonised to enhance comparability between trials.
Topics: Acetylcysteine; Adolescent; Amifostine; Anti-Inflammatory Agents; Antineoplastic Agents; Chelating Agents; Child; Cisplatin; Cytoprotection; Dexamethasone; Disulfiram; Ditiocarb; Humans; Neoplasms; Ototoxicity; Thiosulfates
PubMed: 31160205
DOI: 10.1016/S2352-4642(19)30115-4 -
Respiratory Research Dec 2022Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune...
BACKGROUND
Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis.
METHODS
To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1β, both of which are the primary methods for assessing pyroptosis.
RESULTS
IL-18 and IL-1β concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1β and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs.
CONCLUSIONS
Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.
Topics: Mice; Rats; Animals; Pyroptosis; Phosphate-Binding Proteins; Inflammasomes; Disulfiram; Interleukin-18; Hypertension, Pulmonary; Vascular Remodeling; Intracellular Signaling Peptides and Proteins; Hypoxia
PubMed: 36527086
DOI: 10.1186/s12931-022-02279-0 -
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 -
Molecular Interventions Aug 2009The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps... (Review)
Review
The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine beta-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.
Topics: Animals; Clinical Trials as Topic; Cocaine-Related Disorders; Disulfiram; Dopamine beta-Hydroxylase; Enzyme Inhibitors; Humans; Secondary Prevention
PubMed: 19720750
DOI: 10.1124/mi.9.4.6 -
Pharmacogenomics Oct 2020Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus... (Review)
Review
Alcohol use disorder (AUD) is highly prevalent and among the leading causes of morbidity and mortality in the United States. Pharmacotherapies for AUD are limited, thus making identification of patient subgroups that are most likely to respond favorably crucial. In this article, pharmacogenetic research on US FDA-approved and commonly prescribed off-label medications for the treatment of AUD is comprehensively reviewed. While the field has advanced in understanding pharmacotherapies for AUD and potential genetic moderators of treatment responses, the pharmacogenetic data to guide the prescribing clinician are limited and should be interpreted with caution. Precision medicine for AUD with more beneficial treatment responses and minimal side effects remains a high priority for further research.
Topics: Alcohol Deterrents; Alcoholism; Disulfiram; Humans; Naltrexone; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine
PubMed: 32807012
DOI: 10.2217/pgs-2020-0079 -
Revista de Neurologia Dec 2022Disulfiram-induced-encephalopathy is a rare complication that has been well described in adults. Although it usually occurs in acute intoxication with high doses of...
INTRODUCTION
Disulfiram-induced-encephalopathy is a rare complication that has been well described in adults. Although it usually occurs in acute intoxication with high doses of disulfiram, late onset encephalopathy has also been reported. Some authors propose the inhibition of dopamine beta-hydroxylase mediated by toxic metabolites of disulfiram as the main responsible, but the exact mechanism remains unclear. The aim of this report was to describe the clinical and neuroimaging findings in an unusual case of acute encephalitis due to disulfiram toxicity associated to chronic intranasal consume.
CASE REPORT
A chronic alcoholic who referred snorted use of a very high dose of disulfiram without simultaneous alcohol intake developed an acute encephalopathy with a rapidly progressive respiratory failure. A characteristic neuroimage finding consisting in extensive bilateral symmetric involvement of both pallidal nuclei was described. Recovery and neurologic improvement were slow. Two months after the intoxication, the patient still had slight intentional tremor and a scheduled magnetic resonance imaging. showed evolution of symmetrical areas of cytotoxic edema to necrosis.
CONCLUSION
Disulfiram-induced neurotoxicity must be suspect during chronic therapy with disulfiram or after acute ingestion of high doses. Symptoms such as symmetric sensory and motor neuropathy, confusion, catatonia, parkinsonism, ataxia, choreoathetosis, seizures and encephalopathy should make us rule out this disorder. A brain imaging test should be performed in these patients since a characteristic involvement of both nuclei pallidus has been described, but it is not present in all patients.
Topics: Adult; Humans; Disulfiram; Brain Diseases; Magnetic Resonance Imaging; Neuroimaging; Brain
PubMed: 36440748
DOI: 10.33588/rn.7511.2021415