Disulfiram: Mechanisms, Applications, and Challenges

Lanz, Jenna; Biniaz-Harris, Nicholas; Kuvaldina, Mara; Jain, Shubham; Lewis, Kim; Fallon, Brian A.

doi:10.3390/antibiotics12030524

Cited by 24 publications

(12 citation statements)

References 188 publications

(394 reference statements)

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“…Ethanol is primarily metabolized in the liver, but is also metabolized by the stomach and the brain (Zakhari, 2006), which was reflected in the high enrichment of network genes in the liver, gastrointestinal tissues, and the brain. Disulfiram, by inhibiting ALDH1A1 - which was a gene in the alcohol consumption network - is an effective treatment for alcohol use disorder (Lanz et al ., 2023), suggesting that other genes identified by our network could also be viable pharmacological targets.…”

Section: Discussionmentioning

confidence: 99%

Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network

Leger,

Meredith,

Ideker

et al. 2024

Preprint

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Genome-wide association studies (GWAS) have identified hundreds of common variants associated with alcohol consumption. In contrast, rare variants have only begun to be studied for their role in alcohol consumption. No studies have examined whether common and rare variants implicate the same genes and molecular networks. To address this knowledge gap, we used publicly available alcohol consumption GWAS summary statistics (GSCAN, N=666,978) and whole exome sequencing data (Genebass, N=393,099) to identify a set of common and rare variants for alcohol consumption. Gene-based analysis of each dataset have implicated 294 (common variants) and 35 (rare variants) genes, including ethanol metabolizing genes ADH1B and ADH1C, which were identified by both analyses, and ANKRD12, GIGYF1, KIF21B, and STK31, which were identified only by rare variant analysis, but have been associated with related psychiatric traits. We then used a network colocalization procedure to propagate the common and rare gene sets onto a shared molecular network, revealing significant overlap. The shared network identified gene families that function in alcohol metabolism, including ADH, ALDH, CYP, and UGT. 74 of the genes in the network were previously implicated in comorbid psychiatric or substance use disorders, but had not previously been identified for alcohol-related behaviors, including EXOC2, EPM2A, CACNB3, and CACNG4. Differential gene expression analysis showed enrichment in the liver and several brain regions supporting the role of network genes in alcohol consumption. Thus, genes implicated by common and rare variants identify shared functions relevant to alcohol consumption, which also underlie psychiatric traits and substance use disorders that are comorbid with alcohol use.

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Section: Discussionmentioning

confidence: 99%

Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network

Leger,

Meredith,

Ideker

et al. 2024

Preprint

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“…Disulfiram was also identified to inhibit B. burgdorferi growth by its high affinity for metal ions zinc and manganese, which are necessary for the spirochaetes’ metabolism [ 55 ]. Likewise, disulfiram combined with zinc enhanced the toxicity of zinc on macrophage phagocytosis [ 13 ], because diethyldithiocarbamate (DDTC), a unique metabolite of disulfiram, played a crucial role in chelating metal ions, e.g., copper and zinc, as well as metal-containing enzymes that are indispensable in cell activities [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Disulfiram Inhibits Opsonin-Independent Phagocytosis and Migration of Human Long-Lived In Vitro Cultured Phagocytes from Multiple Inflammatory Diseases

Li,

Schneider,

Schneider

2024

Cells

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Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through its copper chelating derivatives and induction of oxidative stress in mitochondria. Since chronic/persistent borreliosis is characterized by increased amounts of pro-inflammatory macrophages, this study investigated opsonin-independent phagocytosis, migration, and surface marker expression of in vivo activated and in vitro cultured human monocyte-derived phagocytes (macrophages and dendritic cells) with and without DSF treatment. Phagocytosis of non-opsonized Dynabeads® M-450 and migration of macrophages and dendritic cells were monitored using live cell analyzer Juli™ Br for 24 h, imaging every 3.5 min. To simultaneously monitor phagocyte function, results were analyzed by a newly developed software based on the differential phase contrast images of cells before and after ingestion of Dynabeads. DSF decreased the phagocytic capacities exhibited by in vitro enriched and long-lived phagocytes. Although no chemotactic gradient was applied to the test system, vigorous spontaneous migration was observed. We therefore set up an algorithm to monitor and quantify both phagocytosis and migration simultaneously. DSF not only reduced phagocytosis in a majority of these long-lived phagocytes but also impaired their migration. Despite these selective effects by DSF, we found that DSF reduced the expression densities of surface antigens CD45 and CD14 in all of our long-lived phagocytes. In cells with a high metabolic activity and high mitochondrial contents, DSF led to cell death corresponding to mitochondrial oxidative stress, whereas metabolically inactive phagocytes survived our DSF treatment protocol. In conclusion, DSF affects the viability of metabolically active phagocytes by inducing mitochondrial stress and secondly attenuates phagocytosis and migration in some long-lived phagocytes.

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“…Based on the available reports, MCC950, an inhibitor of the NACHT domain of NLRP3, may exhibit adverse renal effects with the augmentation of renal inflammation and the emergence of glomerulosclerosis in diabetic individuals [ 161 ]. Disulfiram, a therapeutic agent targeting GSDMD, has rare side effects, including papular acne, pruritus, exfoliative dermatitis, myopathy, and cardiomyopathy [ 162 , 163 , 164 ]. Celastrol, an inhibitor of the ROS-NF-κB-NLRP3 inflammasome axis, may induce hepatotoxicity, ototoxicity, or cardiotoxicity [ 165 ].…”

Section: Therapeutic Potential By Targeting the Nlrp3 Inflammasomementioning

confidence: 99%

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review

Chen,

Tang,

Chen

2024

IJMS

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Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by chronic synovitis and the progressive destruction of cartilage and bone. RA is commonly accompanied by extra-articular comorbidities. The pathogenesis of RA and its comorbidities is complex and not completely elucidated. The assembly of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activates caspase-1, which induces the maturation of interleukin (IL)-1β and IL-18 and leads to the cleavage of gasdermin D with promoting pyroptosis. Accumulative evidence indicates the pathogenic role of NLRP3 inflammasome signaling in RA and its comorbidities, including atherosclerotic cardiovascular disease, osteoporosis, and interstitial lung diseases. Although the available therapeutic agents are effective for RA treatment, their high cost and increased infection rate are causes for concern. Recent evidence revealed the components of the NLRP3 inflammasome as potential therapeutic targets in RA and its comorbidities. In this review, we searched the MEDLINE database using the PubMed interface and reviewed English-language literature on the NLRP3 inflammasome in RA and its comorbidities from 2000 to 2023. The current evidence reveals that the NLRP3 inflammasome contributes to the pathogenesis of RA and its comorbidities. Consequently, the components of the NLRP3 inflammasome signaling pathway represent promising therapeutic targets, and ongoing research might lead to the development of new, effective treatments for RA and its comorbidities.

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Disulfiram: Mechanisms, Applications, and Challenges

Cited by 24 publications

References 188 publications

Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network

Rare and Common Variants Associated with Alcohol Consumption Identify a Conserved Molecular Network

Disulfiram Inhibits Opsonin-Independent Phagocytosis and Migration of Human Long-Lived In Vitro Cultured Phagocytes from Multiple Inflammatory Diseases

The NLRP3 Inflammasome as a Pathogenic Player Showing Therapeutic Potential in Rheumatoid Arthritis and Its Comorbidities: A Narrative Review

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