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Cells Mar 2024Disulfiram (DSF), an anti-alcoholism medicine, exerts treatment effects in patients suffering from persistent Borreliosis and also exhibits anti-cancer effects through...
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.
Topics: Humans; Disulfiram; Opsonin Proteins; Phagocytosis; Phagocytes; Macrophages
PubMed: 38534379
DOI: 10.3390/cells13060535 -
Hypertension Research : Official... May 2024This graphic depicts the interplay between copper homeostasis and cuproptosis and their role in cardiovascular diseases. Copper is vital for cardiac mitochondrial... (Review)
Review
This graphic depicts the interplay between copper homeostasis and cuproptosis and their role in cardiovascular diseases. Copper is vital for cardiac mitochondrial function, while its dysregulation induces cuproptosis via Ferredoxin1 (FDX1) and lipoic acid synthase (LIAS). Cuproptosis is linked to myocardial ischemia/reperfusion injury, heart failure, atherosclerosis, and arrhythmias. Copper deficiency impacts atherosclerosis markers. Therapeutic interventions include copper chelators (e.g., ammonium tetrathiomolybdate), and oxidative phosphorylation inhibitors like elesclomol and copper ionophores (CuII(atsm), CuII(gtsm), and disulfiram). These interventions modulate intracellular copper, elevate NO, and reduce inflammatory cytokines, contributing to decreased cardiovascular diseases.
Topics: Animals; Humans; Cardiovascular Diseases; Cell Death; Copper; Homeostasis
PubMed: 38467792
DOI: 10.1038/s41440-024-01636-4 -
Bioactive Materials Jun 2024Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the...
Endometrial cancer (EC) stands as one of the most prevalent gynecological malignancies affecting women, with its incidence and disease-related mortality steadily on the rise. Disulfiram (DSF), an FDA-approved medication primarily used for treating alcohol addiction, has exhibited promising anti-tumor properties. Studies have revealed DSF's capacity for enhanced anti-tumor activity, particularly when combined with copper. The novel Copper-Cysteamine (CuCy) compound, CuCl(SR) (R[bond, double bond]CHCHNH), showcases photodynamic effects and demonstrates significant anti-tumor potential under various conditions, including exposure to ultraviolet light, X-ray, microwave, and ultrasound. This study delves into exploring the synergistic anti-tumor effects and underlying mechanisms by utilizing copper-cysteamine in conjunction with DSF against endometrial cancer. The investigation involved comprehensive analyses encompassing experiments utilizing Ishikawa cells, studies, and transcriptomic analyses. Remarkably, the combined administration of both compounds at a low dose of 0.5 μM exhibited pronounced efficacy in impeding tumor growth, inhibiting blood vessel formation, and stimulating cell apoptosis. Notably, experiments involving transplanted tumors in nude mice vividly demonstrated the significant anti-tumor effects of this combination treatment. Detailed examination through transmission electron microscopy unveiled compelling evidence of mitochondrial damage, cellular swelling, and rupture, indicative of apoptotic changes in morphology due to the combined treatment. Moreover, transcriptomic analysis unveiled substantial downregulation of mitochondrial-related genes at the molecular level, coupled with a significant hindrance in the DNA repair pathway. These findings strongly suggest that the combined application of CuCy and DSF induces mitochondrial impairment in Ishikawa cells, thereby fostering apoptosis and ultimately yielding potent anti-tumor effects.
PubMed: 38440322
DOI: 10.1016/j.bioactmat.2024.02.009 -
WMJ : Official Publication of the State... Feb 2024
Topics: Humans; Metronidazole; Ethanol; Disulfiram; Case-Control Studies
PubMed: 38436628
DOI: No ID Found -
Experimental Neurology May 2024Cerebral small vessel disease (CSVD) is a cerebral vascular disease with insidious onset and poor clinical treatment effect, which is related to neuroinflammation. This...
Cerebral small vessel disease (CSVD) is a cerebral vascular disease with insidious onset and poor clinical treatment effect, which is related to neuroinflammation. This study investigated whether lipopolysaccharide-induced intestinal inflammation enhanced the level of pyroptosis in the brain of rats with CSVD. The bilateral carotid artery occlusion (BCAO) model was selected as the object of study. Firstly, behavioral tests and Hematoxylin-eosin staining (HE staining) were performed to determine whether the model was successful, and then the AIM2 inflammasome and pyroptosis indexes (AIM2, ASC, Caspase-1, IL-1β, GSDMD, N-GSDMD) in the brain were detected by Western blotting and Immunohistochemistry (IHC). Finally, a single intraperitoneal injection of lipopolysaccharide (LPS) was used to induce intestinal inflammation in rats, the expression of GSDMD and N-GSDMD in the brain was analyzed by Western blotting and to see if pyroptosis caused by intestinal inflammation can be inhibited by Disulfiram, an inhibitor of pyroptosis. The results showed that the inflammatory response and pyroptosis mediated by the AIM2 inflammasome in BCAO rats were present in both brain and intestine. The expression of N-GSDMD, a key marker of pyroptosis, in the brain was significantly increased and inhibited by Disulfiram after LPS-induced enhancement of intestinal inflammation. This study shows that AIM2-mediated inflammasome activation and pyroptosis exist in both brain and intestine in the rat model of CSVD. The enhancement of intestinal inflammation will increase the level of pyroptosis in the brain. In the future, targeted regulation of the AIM2 inflammasome may become a new strategy for the clinical treatment of CSVD.
Topics: Animals; Rats; Brain; Cerebral Small Vessel Diseases; Disulfiram; DNA-Binding Proteins; Inflammasomes; Inflammation; Lipopolysaccharides; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 38428714
DOI: 10.1016/j.expneurol.2024.114746 -
Substance Abuse Treatment, Prevention,... Feb 2024Combinations of alcohol use disorder (AUD) medications have been investigated, but few if any reports describe patients maintained on more than two options at the same...
BACKGROUND
Combinations of alcohol use disorder (AUD) medications have been investigated, but few if any reports describe patients maintained on more than two options at the same time.
CASE PRESENTATION
We report a case of a middle-aged man hospitalized with gastrointestinal bleeding and acute kidney injury who had been maintained on four AUD medications (naltrexone, acamprosate, disulfiram, and gabapentin) and multiple psychiatric medications simultaneously as an outpatient. Direct quotations of his experiences with each AUD medication are included, revealing some deviations from what was prescribed as well as nuanced perceptions of effects. Overall, he tolerated the regimen well, but its AUD effects were insufficient to prevent several episodes of returning to alcohol use. He had very high hospital utilization. This prompted the initiation of an involuntary commitment, which began a period of at least six months of sobriety.
CONCLUSIONS
Quadruple pharmacotherapy for AUD may be well tolerated and supportive of recovery for an extended period of time. However, for our patient the regimen ultimately failed to prevent multiple episodes of returning to alcohol use and serious medical complications. In refractory cases like this, more intensive interventions such as involuntary commitment can be considered.
Topics: Male; Middle Aged; Humans; Alcoholism; Acamprosate; Disulfiram; Naltrexone; Alcohol Drinking
PubMed: 38424567
DOI: 10.1186/s13011-024-00599-6 -
Alcohol (Fayetteville, N.Y.) Feb 2024Harmful use of alcohol effects the health of the population. The treatment coverage of alcohol use disorders (AUD) varies among countries. The study aimed to determine...
Harmful use of alcohol effects the health of the population. The treatment coverage of alcohol use disorders (AUD) varies among countries. The study aimed to determine the inclusion of AUD medicines in various national Essential Medicine Lists (EMLs) and its association with alcohol consumption. It was a secondary data analysis of alcohol consumptions and AUD related medicines in EML. Data were extracted from the WHO Global Essential Medicines database and the WHO Global Status Report on Alcohol and Health 2018. Data were extracted for 194 countries. Only 132 of 194 countries (68.0%) had EML, and among the 132 countries only 27.3% had included AUD medicines in their EML. Only 36 countries had included any of the AUD medicines in their EML. Disulfiram was included by 23 countries, while Acamprosate and Naltrexone was included by only four and 19 countries, respectively. Among the countries, 36.1% were from upper-middle income countries and 16.65 from low-income countries. The inclusion of AUD medicines in national EML was neither associated with alcohol consumption parameters nor the alcohol consumption related policy parameters. Considering the high prevalence of AUD and its complications, there is an urgent need to focus on including AUD medicines in national EML for making AUD treatment available and accessible across the world.
PubMed: 38423262
DOI: 10.1016/j.alcohol.2024.02.007 -
ACS Applied Materials & Interfaces Mar 2024Acute respiratory distress syndrome (ARDS) is a serious respiratory condition characterized by a damaged pulmonary endothelial barrier that causes protein-rich lung...
Acute respiratory distress syndrome (ARDS) is a serious respiratory condition characterized by a damaged pulmonary endothelial barrier that causes protein-rich lung edema, an influx of proinflammatory cells, and treatment-resistant hypoxemia. Damage to pulmonary endothelial cells and inflammation are pivotal in ARDS development with a key role played by endothelial cell pyroptosis. Disulfiram (DSF), a drug that has long been used to treat alcohol addiction, has recently been identified as a potent inhibitor of gasdermin D (GSDMD)-induced pore formation and can thus prevent pyroptosis and inflammatory cytokine release. These findings indicate that DSF is a promising treatment for inflammatory disorders. However, addressing the challenge posed by its intrinsic physicochemical properties, which hinder intravenous administration, and effective delivery to pulmonary vascular endothelial cells are crucial. Herein, we used biocompatible liposomes incorporating a lung endothelial cell-targeted peptide (CGSPGWVRC) to produce DSF-loaded nanoparticles (DTP-LET@DSF NPs) for targeted delivery and reactive oxygen species-responsive release facilitated by the inclusion of thioketal (TK) within the liposomal structure. After intravenous administration, DTP-LET@DSF NPs exhibited excellent cytocompatibility and minor systemic toxicity, effectively inhibited pyroptosis, mitigated lipopolysaccharide (LPS)-induced ARDS, and prevented cytokine storms resulting from excessive immune reactions in ARDS mice. This study presents a straightforward nanoplatform for ARDS treatment that potentially paves the way for the clinical use of this nanomedicine.
Topics: Animals; Mice; Disulfiram; Endothelial Cells; Drug Repositioning; Respiratory Distress Syndrome; Lung; Liposomes; Lipopolysaccharides
PubMed: 38421312
DOI: 10.1021/acsami.3c17659 -
Acta Biomaterialia Apr 2024The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer...
The clinical treatment of inflammatory bowel disease (IBD) is challenging. We developed copper sulfate (CuS)/disulfiram (DSF)/methacrylic acid-ethyl acrylate copolymer (EL)/polyvinylpyrrolidone (PVP) nanoplatform (CuS/DSF/EL/PVP) and evaluated its efficiency for treating IBD. After oral administration, the pH-sensitive EL protected the CuS/DSF/EL/PVP against degradation by acidic gastric juices. Once the colon was reached, EL was dissolved, releasing DSF and Cu. Further, the main in vivo metabolite of DSF can bind to Cu and form copper (II) N, N-diethyldithiocarbamate (CuET), which significantly alleviated acute colitis in mice. Notably, CuS/DSF/EL/PVP outperformed CuS/EL/PVP and DSF/EL/PVP nanoplatforms in reducing colonic pathology and improving the secretion of inflammation-related cytokines (such as IL-4 and IL-10) in the colonic mucosa. RNA-seq analysis revealed that the nanoplatform reduced colonic inflammation and promoted intestinal mucosal repair by upregulating C-type lectin receptor (CLR)-related genes and signaling pathways. Furthermore, CuS/DSF/EL/PVP showed potential for improving colitis Th1/Th17 cells through innate immunity stimulation, down-regulation of inflammatory cytokines, and upregulation of anti-inflammatory cytokines. Additionally, the intervention with CuS/DSF/EL/PVP led to increased intestinal flora diversity, decreased Escherichia-Shigella abundance, and elevated levels of short-chain fatty acid (SCFA)-producing bacteria Prevotella, Lactobacillus, and Bifidobacterium, indicating their potential to modulate the dysregulated intestinal flora and suppress inflammation. STATEMENT OF SIGNIFICANCE: Our study introduces the CuS/DSF/EL/PVP nanoplatform as a therapeutic strategy for treating inflammatory bowel disease (IBD). This approach demonstrates significant efficacy in targeting the colon and alleviating acute colitis in mice. It uniquely modulates gut immunity and microbiota, exhibiting a notable impact on inflammation-related cytokines and promoting intestinal mucosal repair. The nanoplatform's ability to regulate gut flora diversity, combined with its cost-effective and scalable production, positions it as a potentially transformative treatment for IBD, offering new avenues for personalized medical interventions.
Topics: Animals; Mice; Povidone; Disulfiram; Copper; Inflammatory Bowel Diseases; Colitis; Microbiota; Colon; Inflammation; Cytokines; Hydrogen-Ion Concentration; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38417643
DOI: 10.1016/j.actbio.2024.02.034