Disulfiram is a potential gut microbiota-dependent drug to ameliorate NASH
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49623 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a significant risk factor for hepatocellular carcinoma (HCC). However, a preclinical model of progressive NAFLD/NASH is largely lacking. Here, we report that mice with hepatocyte-specific deletion of Tid1, encoding a mitochondrial cochaperone, tended to develop NASH-dependent HCC. Mice with hepatic Tid1 deficiency showed impairing mitochondrial function and causing fatty acid metabolic dysregulation; meanwhile, sequentially developed fatty liver, NASH, and cirrhosis/HCC in a diethylnitrosamine (DEN) induced oxidative environment. The pathological signatures of human NASH, including cholesterol accumulation and activation of inflammatory and apoptotic signaling pathways, are also present in these mice. Clinically, low Tid1 expression was associated with unfavorable prognosis in patients with HCC. Empirically, hepatic Tid1 deficiency directly disrupts entire mitochondria that play a key role in the NASH-dependent HCC development. Overall, we established a new mouse model that develops NASH-dependent HCC and provides a promising approach to improve the treatment.
2022-06-02 | E-MTAB-9973 | biostudies-arrayexpress
Project description:Neuroblastoma is the most common pediatric extracranial solid tumor accounting for 10% of cancer death in children. Despite intensive treatments involving surgery, chemotherapy, radiotherapy and stem cell transplantation, children with high-risk neuroblastoma still have a poor outcome. Thus, there is an urgent need to develop new therapeutic approaches that can be rapidly tested in clinical trials and with a safe long-term toxicity profile, particularly for children. A promising approach to meet those needs is drug repurposing. Here, we investigated disulfiram, an approved drug for chronic alcoholism treatment, with known anticancer and epigenetic effects. Disulfiram efficiently produced cell cycle arrest and decreased cell viability in five human neuroblastoma cell lines, with IC50 concentrations more than twenty times below its plasmatic level measured in patients treated for chronic alcoholism. We show that disulfiram induced a transcriptomic shift in neuroblastoma cells causing a decrease in cell replication and an increase in neuronal differentiation pathways. In line with these findings, disulfiram reduced significantly the protein level of the histone acetyltransferase KAT2A (GCN5), resulting in a drastic loss of histone acetylation in lysine residues (H3K9ac, H3K14ac, H3K27ac) targeted by KAT2A. To further investigate the anticancer effects of disulfiram in a high-risk neuroblastoma in vivo model, we developed a disulfiram-loaded emulsion suitable for the delivery of this highly liposoluble drug. Using this formulation, we showed that disulfiram significantly delayed the progression of neuroblastoma in mice. Overall, this study highlights a novel target of disulfiram, which directly impacts KAT2A expression and histone acetylation in neuroblastoma.
2023-04-03 | GSE226162 | GEO
Project description:The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe FDA-approved drug, specifically inhibits the NLRP3 inflammasome, but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not the NLRC4 inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.
2024-07-25 | PXD054126 | Pride
Project description:BACKGROUND & AIMS: Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. METHODS: Microarray was performed to identify differentially expressed genes in NASH. Quantitative real time PCR (qRT-PCR) was used to examine gene expression levels. Western blotting and immunofluorescence staining were employed to examine hemoglobin proteins. Flow cytometry was used to measure intracellular oxidative stress. RESULTS: Analysis of microarray gene expression data has revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopspies from NASH patients. Increased hemoglobin expression in NASH was validated by qRT-PCR. However, the expression of erythrocyte specific marker genes such as SPTA, SPTB, GYPA, GATA1, and ALAS2 did not change, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, induced a dose dependent increase in HBA1 expression in HepG2 cells. Intriguingly, forced hemoglobin expression suppressed oxidative stress. CONCLUSIONS: Oxidative stress upregulates hemoglobin expression in hepatocytes. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage. These findings suggest that hemoglobin is an inducible antioxidant in hepatocytes in response to increased oxidative stress as found in NASH livers. Twelve biopsy diagnosed NASH patients were included in this study. For control groups, total RNA from 5 different subjects were purchased from ADMET. These subjects are free from liver disease.
2010-10-20 | E-GEOD-24807 | biostudies-arrayexpress
Project description:RNA-seq analysis was performed to compare gene expression between glioma cells treated with disulfiram and untreated glioma cells.
2019-10-16 | GSE138863 | GEO
Project description:Cancer stem cells (CSCs) or tumor-initiating cells (TICs) organize a cellular hierarchy in a similar fashion to normal stem cell systems and exhibit high tumorigenic activity in xenograft transplantation assay. Disulfiram (DSF) could preferentially eradicate TICs, but the molecular machinery of its effect against TICs still remains largely unknown. We found that flow cytometric analyses showed that DSF but not 5-FU drastically reduces the number of tumor-initiating HCC cells. We conducted microarray analyses to examine gene expression profiling in DSF-treated tumor-initiating HCC cells. Purified EpCAM-positive HCC cells treated with Disulfiram or 5-FU were subjected to RNA extraction and hybridization on Agilent microarrays. Data were obtained for tripricate samples from three independent experiments.
2012-11-16 | E-GEOD-42318 | biostudies-arrayexpress
Project description:Disulfiram and niclosamide were identified as drugs that induced depletion of an MLL-AF9-luciferase fusion protein in THP-1 AML cells, in a bioluminescence sreen. MLL-fusion protein depletion was confirmed in AML and ALL cell lines expressing different MLL-fusion proteins. Combination of disulfiram with niclosamide was found to enhance depletion of MLL-fusion proteins. To investigate whether this enhanced depletion resulted in increased suppression of downstream target genes. MLL-AF6 expressing SHI-1 cells were exposed to disulfiram/copper, nciclosamide or combined drugs. SHI-1 cells were treated for 16 hours with 0.3uM disulfiram / 1uM copper, 5uM niclosamide or combined drugs and RNAseq performed on isolated RNA.
2024-07-03 | GSE262673 | GEO
Project description:Tumor-associated macrophages correlate with poor prognosis and resistance to immune checkpoint inhibitor therapy in cancer patients. Disulfiram, a drug for alcoholism treatment, has been identified as an inhibitor for FROUNT, which facilitates chemokine-mediated macrophage accumulation to tumor sites. A combination of disulfiram with a PD-1 antibody synergistically inhibits tumor progression in the mouse model. Here, we performed the single-cell transcriptome analysis of gastric cancer specimens before and after treatment with disulfiram plus nivolumab. We explored the immunophenotypical features associated with the response to the treatment.
2022-11-27 | GSE189926 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) is a life-threatening liver disease for which no drug has been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first assess the predictive capacity of different in vitro models and then investigate how the reduction of NASH-specific parameters upon treatment with elafibranor, a PPAR-α/δ agonist, correlates with clinical NASH-resolution obtained through bariatric surgery. Whole genome transcriptomics analyses revealed that in vitro NASH models based on primary human hepatocytes (PHH), HepaRG and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exhibit up to 35% overlap with publicly available datasets of liver biopsies of 4 cohorts of NASH patients. Exposure of the in vitro NASH models to elafibranor partially reverses these human-specific transcriptional NASH signatures, with the hSKP-HPC-derived NASH model showing the most sensitive response. NASH-specific transcriptomic changes observed in patients that underwent bariatric surgery correlated with the changes observed in the in vitro NASH models exposed to the PPAR-α/δ agonist. PPARGC1A, PPARA and SIRT1 are shared upstream regulators in the PHH-, HepaRG- and hSKP-HPC NASH models exposed to elafibranor. Activation of these upstream regulators increases the expression of ANGPTL4, PDK4 and PLIN2, while this does not occur in patients that underwent bariatric surgery, suggesting an adverse effect on lipid metabolism. In conclusion, pathologic and therapeutic (anti-)NASH-specific transcriptional responses can be mimicked in PHH, HepaRG and hSKP-HPC, while the latter most sensitively responds to drug testing. PPAR-α/δ agonism adversely modulates pro-steatogenic genes which deserves attention in further studies.
2022-03-16 | GSE166186 | GEO